Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][C:24]([O:26]CC)=[O:25])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:29][CH3:30])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].O>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][C:24]([OH:26])=[O:25])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:29][CH3:30])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)COc1ccccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3OCC(=O)O)nc(=O)c1-2
Yield: 74.9 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-[2-(ethoxycarbonylmethoxy)pheny]pyrazolo[3,4-d]pyrimidin-4-one (3.0 g, 7.3 mmol), K2CO3 (3.04 g), water (20 ml) and ethanol (50 ml) was refluxed for 1.5 hours. The reaction mixture was cooled, the solvent was removed in vacuo and the residue was slurried with water and acidified. A precipitate formed which was collected by filtration, recrystallized from isopropanol and dried at 90° C. The solid was dissolved in 10% K2CO3 (100 ml), treated with DARCO®, filtered and the filtrate was acidified with acetic acid. A precipitate formed which was collected by filtration and dried at 110° C. The solid product was combined with the solid product obtained from a similar experimental run, stirred with 6N HCL (100 ml), filtered and dried with P2O5 at 100° C. under vacuum to afford 2.09 g of 1-cyclopentyl-3-ethyl-6-[2-(carboxymethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one 1/2 hydrate, m.p. 208°-209° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[I:14]I.[OH-].[K+]>CC(N(C)C)=O>[I:14][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc2c(I)n[nH]c2c1
Reaction time: 1 h

Procedure:
To a solution of methyl 1H-indazole-6-carboxylate D-2 (5.0 g, 28 mmol) in DMAC (50 mL) at 0° C. was added iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 114 mmol) portionwise. After addition, the mixture was kept stirring for 1 h, then quenched with aq. Na2S2O3 and extracted with EtOAc. The combined organics were concentrated and trituated with hexane. The precipitate was collected by filtration to afford the title compound as a brown solid. LCMS (ESI) calc'd for C9H8IN2O2 [M+H]+: 302.9. found: 302.9.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][C:30]#[N:31])=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClC1C=CC=CC=1Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][C:30]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([Cl:12])=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:11])[N:31]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(Cl)cccc2Cl)cc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1Cc1ccc(Cl)cc1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
To a solution of 1.0 g of N-methyl-N-(p-toluenesulfonyl)-2,6-dichlorobenzohydrazonoyl chloride in 10 ml of o-dichlorobenzene at room temperature, were added 0.46 g of p-chlorobenzyl cyanide and 0.41 g of anhydrous aluminum chloride. The reaction mixture was heated at 120° C. for 30 minutes. Aster cooling, the section mixture was poured into iced-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.7 g of 5-(4-chlorobenzyl)-3 (2,6-dichlorophenyl)-1-methyl-1H-1,2,4-triazole. m.p.112°-115° C.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:2]2[CH:12]=[C:6]3[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:13])[N:3]=2)=[CH:17][CH:16]=1
Reactant: OCc1ccc(F)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(F)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-fluorophenyl)methanol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:17])[N:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[N:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][NH:22][CH3:23]>CC(O)C>[NH2:17][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:22]([CH3:23])[CH2:21][CH2:20][N:19]([CH3:24])[CH3:18])[N:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: CNCCN(C)C
Reactant: CC(C)(C)c1cc(N)n(-c2ccnc(Cl)n2)n1
Solvent: CC(C)O
Product: CN(C)CCN(C)c1nccc(-n2nc(C(C)(C)C)cc2N)n1
Yield: 98.6 %

Procedure:
A solution of Intermediate 140a (250 mg, 0.99 mmol) and N,N,N′-trimethylethylenediamine (0.32 mL, 2.48 mmol) in IPA (2.5 mL) was heated to 120° C. for 10 mins under microwave irradiation. The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (0.31 g, quant.) as a golden oil that was used in the next step without purification. LCMS (Method 3): Rt 2.51 min, m/z 318.3 [MH+].
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18](O)=[O:19])=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:26]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27]1>>[CH:26]1([N:30]2[CH2:35][CH2:34][N:33]([C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[CH:17]4)=[O:19])[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F)N1CCN(C2CCC2)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 46, intermediate e), from 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid and 1-cyclobutylpiperazine (commercially available), to give the desired product as a white solid (50%).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[ClH:1].[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)CCC21CCNCC1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A solution of spiro[indene-1,4'-piperidine]hydrochloride (1.9 g, 8.6 mmol) in ethanol (50 ml) was hydrogenated at 50 p.s.i. for 1 hour, in the presence of 10% palladium on carbon (0.3 g, 16% (w/w)). The catalyst was filtered off, and the ethanol removed in vacuo. The remaining solid was recrystallised from 4:1 ethyl acetate:ethanol to give spiro[indane-1,4'-piperidine]hydrochloride (814 mg, 43%) as a white crystalline solid. N.M.R. (D2O) δ 1.79 (2H, d, J=14 Hz), 2.06 (2H, t of d, J=14 and 4 Hz), 2.14 (2H, t, J=7 Hz), 2.98 (2H, t, J=7 Hz), 3.25 (2H, t of d, J=14 and 2 Hz), 3.48 (2H, m), 7.33 (4H, m)
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1(=O)O[C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]2[CH2:16]1.C(N(CC)CC)C>C(#N)C>[O:20]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[CH2:2][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[NH:14]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: COC(=O)c1cccc(C#N)c1CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1Cc1c-2[nH]c(=O)c2ccccc12
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of methyl 2-bromomethyl-3-cyanobenzoate (14.1 g, 55.5 mmol) and homophthalic anhydride (22.5 g, 138.8 mmol) in acetonitrile (150 ml) was stirred at room temperature, and a solution of triethylamine (23.2 ml) in acetonitrile (100 ml) was added dropwise to the mixture over the period of 1 h. After the completion of addition, the resultant suspension was refluxed for 4 hours. The reaction mixture was then cooled down to room temperature and filtered. The filtered solid was washed thoroughly with acetonitrile (100 ml) and ethanol (2×100 ml) and dried under vacuum at 50° C. Compound 17a was obtained in 81% yield (13.1 g). 1H NMR (DMSO-d6): δ 12.21 (s, 1H); 8.20 (m, 2H); 7.83 (d, J=7.5 Hz, 1H); 7.71 (m, 2H); 7.47 (m, 2H); 4.07 (s, 2H); 3.89 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
To a solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (78.9 mg, 0.200 mmol), prepared in Step A of Example 13a, triethylamine (44.6 mg, 0.221 mmol) and dichloroethane (10 mL) was added thiophene-2-sulfonyl chloride (40.3 mg, 0.221 mmol). The reaction was stirred for 24 h and additional triethylamine (0.221 mmol) and thiophene-2-sulfonyl chloride (40.3 ing, 0.221 mmol) were added. After stirring for 24 h at room temperature the reaction was heated at reflux for 24 h and was cooled to room temperature. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (58 mg). MS 539 (M+1).
Reaction SMILES: [Br:1][C:2]([F:6])=[C:3]([F:5])[F:4].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[OH-].[K+]>CC(C)=O>[Br:1][CH:2]([F:6])[C:3]([F:5])([F:4])[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc(O)c1
Reactant: FC(F)=C(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OC(F)(F)C(F)Br)c1
Yield: 68 %

Procedure:
72.3 parts by weight of bromotrifluoroethene are passed, over 10 hours, into a mixture of 45.6 parts by weight of methyl 3-hydroxybenzoate and 9.5 parts by weight of potassium hydroxide powder in 50 parts by weight of acetone under reflux at 45°-52° C. After having been concentrated on a rotary evaporator under reduced pressure, the reaction mixture is taken up in methylene chloride and this solution is extracted with sodium bicarbonate solution, dried and concentrated. Methyl 3-(2'-bromo-1',1',2'-trifluoroethoxy)-benzoate of nD 25 =1.4850 is obtained in a yield of 68% of theory, and can be hydrolyzed, in a yield of 98% of theory, to 3-(2'-bromo-1',1',2'-trifluoroethoxy)-benzoic acid, of melting point 88°-90° C..
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[C:25]([CH2:26][NH2:27])=[CH:24][C:23]2[C:18](=[C:19]([Cl:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[C:25]([CH2:26][NH:27][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][NH:34]3)=[CH:24][C:23]2[C:18](=[C:19]([Cl:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1OCc1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OCc2ccccc2)c(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (2-(2-(benzyloxy)-5-fluorophenyl)-8-chloroquinolin-3-yl)methanamine (0.021 g, 0.053 mmol), 6-chloropurine (0.012 g, 0.06 mmol, 1.5 eq) and DIEA (0.1 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-(benzyloxy)-5-fluorophenyl)-8-chloroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=31 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.38 (s, 1 H), 8.12 (s, 1 H), 8.07 (s, 1 H), 7.90 (s, 1 H), 7.88 (s, 1 H), 7.52-7.59 (t, 1 H), 7.21-7.25 (m, 2 H), 7.19 (m, 4 H), 7.06-7.12 (m, 2 H), 5.05-5.10 (m, 2H), 4.90-4.96 (s, 2H), Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[C:6]([CH3:13])[CH:5]=1.[C:14]([C:16]1[CH:17]=[C:18]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:19]=[CH:20][C:21]=1[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])#[N:15]>C1COCC1>[C:14]([C:16]1[CH:17]=[C:18]([NH:27][C:28](=[O:29])[O:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][C:6]=2[CH3:13])[CH:19]=[CH:20][C:21]=1[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])#[N:15]
Reactant: Cc1cc(Br)ccc1CCO
Reactant: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2C)cc1C#N
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
NaH (230 mg, 4.4 mmol, 60% disperson in oil) was added portionwise to a solution of 30B (490 mg, 2.3 mmol) in THF (12 mL) and the mixture was stirred for 30 min. The solution was cooled to −40° C. and 25A (760 mg, 2.3 mmol) was added in one portion. The cooling bath was removed and the reaction was stirred for 2 h. The reaction mixture was cooled to −40° C. and quenched by the addition of NH4Cl (5 mL, sat. aq.). The resulting mixture was partitioned between water (50 mL) and EtOAc (100 mL). The organic phase washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromoatography (0 to 100% EtOAc in hexanes) to yield 31A (745 mg, 72%) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.94 (t, J=7.42 Hz, 3 H) 3.11 (s, 3 H) 4.19 (q, J=7.15 Hz, 2 H) 5.14 (t, J=6.87 Hz, 2 H) 7.99 (d, J=8.24 Hz, 1 H) 8.14 (dd, J=7.70, 2.20 Hz, 1 H) 8.21 (d, J=1.65 Hz, 1 H) 8.72-8.77 (m, 1 H) 8.79-8.84 (m, 1 H) 8.90 (d, J=2.20 Hz, 1 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(CO)n2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(COS(C)(=O)=O)n2)CC1
Temperature: 0 °C

Procedure:
tert-Butyl 4-{[6-(hydroxymethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.34 g, 1.10 mmol) and methanesulfonyl chloride (0.13 mL, 1.64 mmol) were dissolved in DCM (15 mL) and stirred at 0° C. (ice bath). DIPEA (0.57 mL, 3.29 mmol) was added to the reaction mixture and stirred for 2 hours. The resulting mixture washed with water (2×15 mL), dried over a phase separator, concentrated in vacuo and was used directly in the next step.
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:35])[N:19]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C@@H:20]4[C@H:24]([C:25]=3[OH:26])[CH2:23][CH2:22][CH2:21]4)=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1>CN(C)C=O.CO.[Pd]>[O:38]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:35])[N:19]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C@@H:20]4[C@H:24]([C:25]=3[OH:26])[CH2:23][CH2:22][CH2:21]4)=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(4aR,7aS)-3-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (prepared as described in Example 44, 45 mg, 0.081 mmol) was dissolved in a 1:5 mixture of N,N-dimethylformamide and methanol (12 mL). 5% Palladium on charcoal (100 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite, washed with 10% methanol/dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 40-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product as an inseparable mixture of two diastereomers, (4aR,7aS)-3-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (20 mg, 0.036 mmol, 44%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.44-1.60 (3H, m), 1.95-2.40 (10H, m), 3.22-3.36 (3H, m), 3.86 (1H, bs), 4.47 (1H, d, J=14.4 Hz), 4.56 (1H, dd, J=12.4, 8.0 Hz), 4.91 (1H, d, J=15.2 Hz), 7.15 (2H, t, J=8.4 Hz), 7.39 (2H, m), 7.61 (1H, d, J=8.8 Hz), 7.71 (1H, dd, J=8.4, 2.4 Hz), 7.82 (1H, s). LC-MS (ESI) calcd for C26H26FN3O6S2 559.12, found 560.3 [M+H+].
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH2:12]([NH2:15])[CH:13]=[CH2:14].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:12]([NH:15][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:20][CH:21]=1)[CH:13]=[CH2:14]
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: C=CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 2.5 h
Yield: 96 %

Procedure:
To a solution of 1-hydroxybenzotriazole hydrate (5.4 g, 40 mmol), allyl amine (60 mmol), and 4-(trifluoromethoxy)benzoic acid (8.3 g, 40 mmol) in DMF (110 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (11.5 g, 60 mmol) at R.T. After the reaction mixture was stirred for 2.5 hrs, the solution was partitioned between 10% citric acid and ether. The organic layer was washed with sat. aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated. The residue was purified by silica gel chromatography (20% ether/hexanes) to yield the title compound (colorless solid 96%). 1H NMR (400 MHz, CDCl3) δ7.85 (d, J=7.1 Hz, 2 H, Ar), 7.28 (d, J=5.9 Hz, 2 H, Ar), 6.31 (s, 1 H, NH), 5.94 (m, 1 H, CH2CHCH2), 5.25 (dd,J=8.6, 7.1 Hz, 2 H, NHCH2CH), 4.10 (m, 2 H, CHCH2);
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1.[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC>[O:19]1[C:15]2([CH2:20][CH2:21][CH:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:32]4[CH:33]=[CH:34][C:29]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:30][CH:31]=4)=[N:3]3)[CH2:13][CH2:14]2)[O:16][CH2:17][CH2:18]1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.8 %

Procedure:
3-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate X) (4.0 g, 11.3 mmol), 4-phenoxyphenylboronic acid (Intermediate V) (2.66 g, 12 mmol), sodium carbonate (2.87 g, 27 mmol), palladium tetrakis(triphenyphosphine) (0.78 g, 0.6 mmol) in dimethoxyethane (120 mL)/water (60 mL) mixture was heated at 85° C. under nitrogen for 4 hrs. Cool to room temperature and stand for 72 hrs. The solid which precipitated was filtered and washed with water and diethylether (100 mL of each). Dry in vacuo for 3 hrs to furnish 4.2 g of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a beige solid (87%). 1H NMR (400 MHz, d6-DMSO) 8.24 (1H, s), 7.67 (2H, m), 7.45 (2H, m), 7.19 (5H, m), 4.78 (1H, m), 3.90 (4H, m), 2.25 (2H, m), 1.71-1.84 (6H, m) Mass Spec.: MH+=444.2
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[Cl:18][C:12](=[O:14])[CH2:11][N:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnn(CC(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the compound (2.0 g) obtained in Example 115b in dichloromethane (20 mL) was cooled in an ice bath, and oxalyl chloride (2.5 g) and N,N-dimethylformamide (2 drops) were added. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]>C(O)(C)C>[OH:31][C:26]1([C:27]([F:30])([F:29])[F:28])[CH2:25][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:13]1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2cccs2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2cccs2)cc1
Temperature: 82.5 °C
Yield: 39.7 %

Procedure:
To a mixture of the amidine of step 1 (2.0 g, 7.1 mmol) and sodium bicarbonate (1.2 g, 14.3 mmol) in isopropanol (200 ml), 3-bromo-1,1, 1-trifluoroacetone 1.1 ml, 10.7 mmol) was added. After heating at 80-85° C. for 16 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (25.7 g) was purified by chromatography (silica gel, ethyl acetate/hexane 55/45) to give the 4,5-dihydro-imidazole (1.1 g, 38%) as a white solid: mp (DSC) 214° C. Anal. Calc'd. for C15H13N2S2O3F3: C, 46.15, H, 3.36, N, 7.18, S, 16.43. Found: C, 46.09, H, 3.26, N, 7.07, S, 16.71.