Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[C:18]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)NCCCCNc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCCCNc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
1,4-Diaminobutane (4.19 g) was dissolved in tetrahydrofuran (THF: 300 ml) to which, at -10° C., was subsequently added dropwise 2,4-difluoronitrobenzene (3.00 g) dissolved in THF (100 ml). The reaction solution was warmed up to room temperature, stirred for 3 hours and then mixed with di-tert-butyl dicarbonate (8.22 g). The reaction solution was further stirred overnight, the thus formed insoluble matter was separated by filtration, the resulting filtrate was concentrated, and a mixed solution (150 ml) of n-hexane:ethyl acetate=1:2 was added to the residue. The thus formed insoluble matter was again separated by filtration and then the filtrate was concentrated under a reduced pressure. The resulting yellow solid was purified by a silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give N-(4-tert-butoxycarbonylaminobutyl)-5-fluoro-2-nitroaniline (4.67 g). The resulting aniline compound (3.20 g) and imidazole (4.00 g) were dissolved in DMSO (50 ml). The solution was stirred at 150° C. for 4 hours, spontaneously cooled down to room temperature and, after addition of water (500 ml), extracted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting solid substance was washed with water and dried under a reduced pressure to give N-(4-tert-butoxycarbonylaminobutyl)-5-(1H-imidazol-1-yl)-2-nitroaniline (3.13 g). In an atmosphere of hydrogen, the thus formed product (3.00 g) was subjected to 4 hours of reduction in ethanol under ordinary pressure, using palladium-carbon as the catalyst. The reaction solution was filtered and concentrated under a reduced pressure. Then, oxalic acid (2.16 g) and 4 N hydrochloric acid (40 ml) were added to the residue, followed by heating under reflux for 8 hours. The reaction solution was filtered, and the resulting filtrate was concentrated to about half of the volume. The thus precipitated crystals were collected by filtration and dried under a reduced pressure to give 1-(4-aminobutyl)-7-(1H-imidazol-1-yl)-2,3(1H,4H)-quinoxalinedione dihydrochloride (2.87 g).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH:36]([CH3:38])[CH3:37]>C(#N)C>[F:1][C:2]1[C:3]([O:27][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)CBr
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.29 g, 0.76 mmol, see Example 23) and K2CO3 (0.21 g, 1.5 mmol) in 5 mL ACN stirred at room temperature, was treated with 1-bromo-2-methylpropane (0.52 g, 3.8 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then warmed to 80° C. and stirred for 24 hours. The mixture was concentrated in vacuo and purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.25 g of the title compound as a white solid. MS (m/z)=458 (M+Na)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:10]1)#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C#N)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 176.3 %

Procedure:
Ethyl 2-cyanoacetate (0.85 g, 7.5 mmol, 1 equiv), 1,2-dibromoethane (1.3 mL, 15 mmol, 2 equiv) and K2CO3 (3.18 g, 22.5 mmol, 3 equiv) was dissolved in acetone (6 mL), and the mixture was stirred for 16 h at 80° C. The reaction mixture was filtered, concentrated to give the crude product as a yellow oil (1.84 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ: 4.18 (t, 2H), 1.75 (t, 2H), 1.60 (m, 2H), 1.20 (t, 3H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38].C(O)(=O)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C=O)o1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(CNCCS(C)(=O)=O)o1
Reaction time: 96 h
Yield: 48.1 %

Procedure:
Prepared in a similar manner to Procedure D from 5-(4-(4-benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride(78 mg, 0.16 mmol), 2-methanesulphonylethylamine(33 mg, 0.27 mmol), acetic acid(15 mg, 0.25 mmol) and triethylamine(18 mg, 0.18 mmol) in 3 ml of 1,2-dichloroethane added to sodium triacetoxyborohydride(102 mg, 0.48 mmol) portionwise over a two day period. The reaction mixture was stirred four days and then partitioned between 10 ml of 0.5M NaHCO3 solution and 50 ml of ethyl acetate. The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel with methanol/methylene chloride(1:49 to 2:48). The resulting solid was crystallized from a small volume of ethyl acetate, suspended in ether and filtered to give 43 mg of product as a pale yellow solid. δ1H NMR (400 MHz, DMSO-d6) 9.78(s, 1H), 8.73(s, 1H), 8.42(s, 1H), 6.64(d, 2H), 7.47(m, 2H), 7.40(m, 2H), 7.33(m, 1H), 7.25(s, 1H), 7.04(d, 2H), 6.98(d, 1H), 6.46(d, 1H), 5.12(s, 2H), 4.04(s, 3H), 3.86(s, 2H), 3.28(t, 2H), 3.01 (s, 3H), 2.99(t, 2H). ESI-MS m/z 559(M+1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([Cl:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Clc1nc2c(Br)cccn2n1
Product: Clc1nc2c(-c3ccc(Br)cc3)cccn2n1

Procedure:
198 a) 8-(4-Bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 4.5 mmol) and 4-bromobenzeneboronic acid (1.0 g, 5.0 mmol) in a manner analogous to Example 2c. Product isolated as an off-white solid (1.0 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 7.88 (d, J=7.1 Hz, 2H), 7.70 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.1 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H). MS=310, 312 (MH)+. 198 b) To an oven dried tube was added 8-(4-bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.90 g, 2.9 mmol), methylphosphinoylmethane (0.24 g, 3.1 mmol)(prepared as described in WO2005/009348), palladium acetate (13.5 mg, 0.0601 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36.0 mg, 0.0622 mmol), cesium carbonate (1422.0 mg, 4.3644 mmol) and 1,4-dioxane (9 mL). The tube was evacuated, carefully, and backflushed with nitrogen. The tube was sealed and heated at 90° C. for 24 hours then cooled to room temperature, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→7% dichloromethane:methanol). 2-Chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine was isolated as a white solid (0.303 g, 34%). MP=220-223° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, J=6.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.94-7.86 (m, 2H), 7.77 (t, J=7.4 Hz, 1H), 7.21 (t, J=6.9 Hz, 1H), 1.80 (s, 3H), 1.77 (s, 3H). MS=306, 308 (MH)+. 198 c) {8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3271 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (28.0 mg, 0.0512 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.097 g, 64%). MP=243-246° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.92-7.84 (m, 2H), 7.63-7.50 (m, 1H), 7.34 (s, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.02-6.96 (m, 2H), 6.84 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.30-3.25 (m, 4H), 2.63-2.58 (m, 4H), 2.37 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H). MS=461 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CCO>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: OB(O)c1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OB(O)c1cnc(N2CCOCC2)nc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
A mixture of 2-chloropyrimidin-5-ylboronic acid (3 g, 19.0 mmol), morpholine (1.66 mL, 19 mmol) and triethylamine (1.67 mL, 19.19 mmol) in EtOH (20 mL) was stirred at 80° C. for 5 h. LCMS indicated completion of the reaction. The reaction mixture was concentrated in vacuo and the residue was taken up in ethanol (approximately 5 mL). Diethyl ether was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68%) as an off-white solid. δH (DMSO-d6) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES+) 210 (M+H)+, RT 0.15 minutes.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[N:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]=2)[O:7][C:6]([CH3:30])([CH3:29])[CH2:5]1)=[N+]=[N-].O.CP(C)C>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[C:13]3[C@H:4]([NH2:1])[CH2:5][C:6]([CH3:30])([CH3:29])[O:7][C:8]3=[N:9][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[CH:19][CH:18]=1
Reactant: CC1(C)C[C@@H](N=[N+]=[N-])c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C[C@@H](N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Step A (9.5 g, 20.7 mmol) in 50 mL of THF was added 2.5 mL of H2O and 31.0 mL of trimethylphosphine in THF (1.0 M, 31.0 mmol). After stirring at rt for 3 h, the solvent was evaporated. Chromatography on a Biotage 40+M cartridge using 1:19 v/v CH3OH/CH2Cl2 as the eluant afforded the product: 1H NMR δ 1.42 (s, 3H), 1.54 (s, 3H), 1.78 (t, J=12.5, 1H), 2.18 (dd, J=5.9, 13.4, 1H), 4.16 (dd, J=6.0, 11.7, 1H), 7.04 (d, J=8.5, 2H), 7.17-7.26 (m, 5H), 7.93 (s, 1H).
Reaction SMILES: [CH:1]1([CH:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[NH:9][C:8](=[O:19])[CH:7]2[C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(#N)C.O.ClCCl>[CH:1]1([C:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]=3[NH:9][C:8](=[O:19])[C:7]=2[C:20]#[N:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC(=O)C(C#N)C2C1CCCC1
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=O)c2c([nH]c(=O)c(C#N)c2C2CCCC2)C1
Temperature: 60 °C

Procedure:
11.0 g 4-Cyclopentyl-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydro-quinoline-3-carbonitrile are suspended in 160 ml acetonitrile, heated to 60° C. and mixed dropwise with a solution of 85 g ammonium cer-(IV)-nitrate in 80 ml water. After heating for 1 h the mixture is diluted with 1200 ml dichloromethane and vigorously stirred. The aqueous bottom phase is discarded and the organic phase is washed successively with saturated sodium bicarbonate and brine. After drying with magnesium sulphate the solvents are evaporated in vacuo and the residue is triturated with diethylether. The solid is isolated by filtration, washed with diethylether and dried in vacuo.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].S(C1C=CC(C)=CC=1)(O[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])(=O)=O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 72 °C
Yield: 77.3 %

Procedure:
N-(tert-Butoxycarbonyl)-N-(3,6,9-trioxadecyl)-O-benzylhydroxylamine (14 ) was synthesized by adding sodium hydride (80% oil dispersion, 0.488 g, 16.3 mmol) to N-(tert-butoxycarbonyl)-O-benzylhydroxylamine [Ramasamy, supra] (2.66 g, 11.9 mmol) in dry DMF (20 mL), and stirring was continued for several minutes. 3,6,9-Trioxadecyl tosylate [Schultz et al, supra] (4.93 g, 15.5 mmol) in DMF (3 mL) was added by syringe, and the suspension was heated at 72° C. for 18 hours under nitrogen. After cooling, the reaction was quenched with water (100 mL) and then extracted with ether (4×50 mL). The combined organic layers were washed with brine (100 mL) and the solvent was removed in vacuo. Column chromatography with 4% EtOH/CHCl3 produced 3.40 g (77%) of (14) as a liquid: NMR δ 1.50 (s, 9 H), 3.31 (s, 3 H), 3.5-3.7 (m, 12 H), 4.82 (s, 2 H), 7.25-7.41 (m, 5 H), Analysis: (C19H31NO6) C, H, N.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])[CH:13]=2)[CH2:6]1)C.C(=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37].O.O.O.C([O-])(=O)C.[Na+]>CCO>[NH2:37][C:36]1[N:38]=[CH:4][C:5]2[CH2:6][N:7]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=4)=[O:19])[CH:13]=3)[CH2:8][CH2:9][C:10]=2[N:35]=1
Reactant: CN(C)C=C1CN(c2ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)CCC1=O
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ncc2c(n1)CCN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 80 °C
Reaction time: 23 h
Yield: 14.3 %

Procedure:
A solution of 4-[3-(dimethylamino)methylidene-4-oxopiperidin-1-yl]-N-[3-(trifluoromethyl)phenyl]pyridine-2-carboxamide (417 mg, 0.997 mmol) in EtOH (10 ml) was treated with guanidine carbonate (719 mg, 3.99 mmol), followed by adding sodium acetate trihydrate (1.09 g, 7.98 mmol). The reaction mixture was stirred at 80° C. for 23 hours and concentrated. The residue was partitioned between EtOAc and water resulting in the formation of a yellow, amorphous solid. The solid was collected, washed with water, EtOAc, MeOH, and dried to give the title compound (59 mg, 14%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11](C(O)=O)[N:12]=[C:13]([O:14][CH:15]([CH3:17])[CH3:16])[C:8]2=[CH:7][N:6]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([O:14][CH:15]([CH3:17])[CH3:16])[C:8]2=[CH:7][N:6]=1
Reactant: CC(C)Oc1nn(C(=O)O)c2nc(Oc3ccc(F)cc3F)ncc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Yield: 36.1 %

Procedure:
6-(2,4-Difluoro-phenoxy)-3-isopropoxy-pyrazolo[3,4-d]pyrimidine-1-carboxylic acid (190 mg) was treated with a solution of CF3CO2H (0.3 mL) in CH2Cl2 (5 mL) at room temperature for four hours. The reaction mixture was then concentrated under reduced pressure and the residue was purified by flash column chromatography flushing with 30% ethyl acetate in hexanes to give 60 mg of 6-(2,4-difluoro-phenoxy)-3-isopropoxy-1H-pyrazolo[3,4-d]pyrimidine, m.p. 143.7-145.0° C., MS (M+1)+: 307.
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:6]2[CH2:7][CH2:8][C:3]([CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[N:28][CH:29]=1
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of ethyl 4-methylpiperidine-4-carboxylate hydrochloride (0.9 g, 4.35 mmol) in EtOH (10 mL) was added DIPEA (2.30 mL, 13 mmol) at rt. The resulted mixture was stirred at rt for 10 minutes followed by addition of 5-bromo-2-chloropyrimidine (0.7 g, 3.6 mmol). The mixture was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue was purified over 100-200 M silica-gel by using 1.5% EtOAc:hexane to obtain the desired product as an off white solid compound (0.90 g, 75%). 1H NMR (DMSO-d6): δ 1.17 (s, 3H), 1.21 (t, J=7.20 Hz, 3H) 1.40 (m, 2H), 2.00 (m, 2H), 3.24 (m, 2H), 4.11 (m, 2H), 4.15 (q, J=7.20 Hz, 2H), 8.43 (s, 2H). MS: 328.08 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2I)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(OC[N:51]1[C:55](B2OC(C)(C)C(C)(C)O2)=[CH:54][CH:53]=[N:52]1)C.FC(F)(F)C(O)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:11]1[CH:12]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[C:53]2[NH:52][N:51]=[CH:55][CH:54]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[S:34][N:33]=[CH:32][N:31]=1)(=[O:9])=[O:8]
Reactant: CCOCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(C(F)(F)F)cc3I)cc2F)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(C(F)(F)F)cc2-c2ccn[nH]2)cc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
A suspension of N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 363, 100 mg, 0.14 mmol), potassium carbonate (48 mg, 1.12 mmol) and 1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 337, 70 mg, 0.28 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was degassed and palladium tetrakis (16 mg, 0.014 mmol) added before heating at 80° C. for 16 hours. Dicholoromethane (20 mL) and water (10 mL) were added and the organics separated and evaporated in vacuo to afford the crude product. Dicholoromethane (10 mL) and trifluoroacetic acid (5 mL) were added and the reaction mixture was stirred at room temperature for 16 hours before concentrating in vacuo. Hydrochloric acid (4 M in 1,4-dioxane, 10 mL) was added and the reaction mixture was stirred for 16 hours before concentrating in vacuo. The residue was purified by reverse phase chromatography to afford the desired product, 6 mg, 9% yield.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C.O>[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:27][CH:26]=1)=[O:24]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccccc3Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 83.2 %

Procedure:
To a solution of theophylline (0.90 g) in DMF (20 ml) were added potassium carbonate (0.83 g) and 4-(2-chlorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 13 hours. This reaction mixture was diluted with water and extracted with ethyl acetate and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as needles (1.70 g, 83%). 1H-NMR (CDCl3) δ: 3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.30-7.48(6H,m), 7.63(1H,s), 7.76-7.85(2H,m).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([CH2:21][CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24])[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[CH2:1]([S:8][CH2:9][CH:10]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(CSCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC(CSCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a cooled solution (5° C.) of dibenzyl 2-[(benzylsulfanyl)methyl]pentanedioate (15.2 g, 33.9 mmol) in tetrahydrofuran (750 mL) was added 0.1 N NaOH (745 mL, 74.5 mmol NaOH) with stirring. The cloudy reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture had become homogenous. The solution was concentrated under reduced pressure to remove the tetrahydrofuran. The remaining aqueous solution was washed with ethyl acetate, then made acidic (pH 1) with concentrated HCl. The mixture was extracted twice with ethyl acetate. The ethyl acetate was removed under reduced pressure and the resulting waxy solid was purified by column chromatography to yield 6.9 g (76%) of white solid.