Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH2:37]([S:39](Cl)(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])[N:15]=[C:14]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN
Product: CCS(=O)(=O)NCCOc1nc(-c2ccncc2)nc(NS(=O)(=O)c2ccc(C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 107 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with ethanesulfonylchloride to give 100 mg 5-methyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=3.89 min, [M+1]+=601.50, [M−1]−=599.53.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[B:15]([O:24]C(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCCCCC.C1COCC1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([O:16][B:15]([OH:24])[OH:20])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
To a mixture of 1-bromo-4-ethylbenzene (743 mmol) and 500 ml of THF, was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was added dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 4-ethylphenyl boric acid (515 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.Cl.[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH3:43])[N:4]=1
Reactant: CC(C)(C)CN
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(NCC(C)(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of Example C2 (0.100 g, 0.238 mmol) in DCM (5 mL) was treated with mCPBA (0.059 g, 0.238 mmol), stirred at RT for 2 h, treated with 2,2-dimethylpropan-1-amine hydrochloride (0.410 g, 3.32 mmol) and TEA (0.464 mL, 3.33 mmol) and stirred at RT for 5 days. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-N-neopentylpyrimidin-2-amine (81 mg, 74%). MS (ESI) m/z: 460.3 (M+H+).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)C(O)=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:28]1[CH:27]=[CH:23][CH:22]=[C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:29]=1)[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCc1cccc(C(=O)O)c1
Product: CCCCCCCCc1cccc(C(=O)N[C@@H](C)C#N)c1
Yield: 34.8 %

Procedure:
General procedure D was used to deprotect 1.15 mmol of 4 and was then immediately coupled to 1.15 mmol of 35. After flash chromatography 0.115 g (0.4 mmol) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.68-7.55 (m, 2H), 7.34 (dd, J=2.9, 9.5, 2H), 6.73 (d, J=7.7, 1H), 5.16 (p, J=7.2, 1H), 2.63 (t, J=7.7, 2H), 1.66 (d, J=7.2, 2H), 1.61 (s, 2H), 1.30 (dd, J=21.4, 28.1, 10H), 0.87 (t, J=7.0, 3H). 13C NMR (126 MHz, CDCl3) δ 166.89, 143.81, 143.59, 132.58, 132.52, 128.60, 127.34, 124.32, 119.40, 52.60, 48.47, 36.28, 35.81, 31.86, 31.43, 31.38, 29.42, 29.27, 29.23, 22.66, 19.54, 18.65, 14.11.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=O)[S:15][CH:16]=1>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[S:15][CH:16]=1
Reactant: Cc1csc(C=O)c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1csc(C=C2C(=O)Nc3ccccc32)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A reaction mixture of 133.0 mg of oxindole, 151.2 mg of the 4-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 3 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 147.3 mg (61%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.C(Cl)(Cl)Cl>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.51 %

Procedure:
A solution of N-(4-hydroxyphenyl)-acetamide (paracetamol) (1) (1.50 g, 0.01 mol) and 1,2-dibromoethane (8) (10.0 ml) in ethyl methyl ketone (25.0 ml) containing potassium carbonate (5.0 g) was stirred for 8 hr at room temperature. The reaction mixture was filtered, residue washed with ethyl methyl ketone and solvent evaporated under reduced pressure to get the residue. The residue was dissolved in chloroform (200.0 ml), washed with 5% NaOH solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(2-bromo-ethoxy)-phenyl]-acetamide (10) (2.01 g, 78.51%), mp 126-127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:18][C:19]([C:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[CH:22]=2)=[O:20])[CH:11]2[CH2:15][CH:14]([CH3:16])[C:13](=[O:17])[O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39]>>[CH2:36]([NH:40][C:13]([CH:14]([CH3:16])[CH2:15][CH:11]([OH:12])[CH:10]([NH:18][C:19]([C:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[CH:22]=1)=[O:20])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:17])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCN
Reactant: CC1CC(C(Cc2cc(F)cc(F)c2)NC(=O)C2=Cc3ccccc3Oc3ccccc32)OC1=O
Product: CCCCNC(=O)C(C)CC(O)C(Cc1cc(F)cc(F)c1)NC(=O)C1=Cc2ccccc2Oc2ccccc21
Reaction time: 16 h

Procedure:
Dibenzo[b,f]oxepine-10-carboxylic acid [2-(3,5-difluoro-phenyl)-1-(4-methyl-5-oxo-tetrahydrofuran-2-yl)-ethyl]-amide (50 mg, 0.105 mmol) is dissolved in 2 ml butylamine and stirred for 16 h. The solution is concentrated in vacuo and the residual solid recrystallized from EtOAc/hexane. Yield 27 mg (48%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Li]CCCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:31]=[O:32])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (65) (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of nBuLi in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield the title compound (1.50 g, 77%)
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[Cl:18][CH2:19][C:20](Cl)=[O:21].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]([O:7][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][Cl:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(CCl)C(=O)N(Cc1ccccc1Cl)OC(=O)CCl

Procedure:
This compound was prepared in the manner of Example 13, using 4.0 g (0.014 mole) of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide (prepared in Example 1), 1.6 g (0.014 mole) of chloroacetyl chloride, and 1.2 g (0.015 mole) of pyridine, in 50 ml toluene. The product was a liquid, of which nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21]C(=O)OCC)[NH:6]2.[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[NH2:21][C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([NH:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])[N:10]=[C:9]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20])[N:8]=2
Reactant: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(N)nc12

Procedure:
The titled compound was prepared from the product of example 5, step (e) (50 mg) and 2-amino-2-methyl-1-propanol (66 μl) using the method of example 5, step (f) and purified by preparative HPLC to yield a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[C:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[OH:15][CH2:14][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:17](=[O:19])[CH3:18])[CH:25]=3)=[CH:3][CH:4]=2)[O:9][C:10]=1[CH3:16]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)c1cccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)c1
Yield: 55.2 %

Procedure:
Add 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (0.200 g, 709 mmol) [which is obtained by the method of D. Brooks, J. Med. Chem., 2001, 44, 2061-2064 or see WO 0116120], Pd(Ph3)4 (0.036 g, 0.031 mmol), 3-acetylphenylboronic acid (0.174 g, 1.06 mmol), 2N Na2CO3 (1.8 mL), and 1,4-dioxane (1.5 mL) to a microwave vessel. Subject the reaction mixture to microwave irradiation at 30 W, 90° C. for 30-45 minutes. Concentrate and purify on silica gel eluting with 10% 2N NH3 in methanol/dichloromethane to give 1-{4′-[4-(2-hydroxy-ethyl)-5-methyl-oxazol-2-yl]-biphenyl-3-yl}-ethanone (0.188 g, 83%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2]C.[CH3:15]C1C=C2C(=CC=1)NC(=O)C2=O.C(Br)C>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:15])=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH3:2]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CCBr
Product: CCN1C(=O)C(=O)c2cc(C)ccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using commercially available 5-methyl isatin (purchased from Fisher Scientific) and ethyl bromide (purchased from Fisher Scientific). 1H-NMR δ 7.42-7.38 (m, 2H), 6.80 (d, 1H), 3.77 (q, 2H), 2.34 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[P:18](Cl)([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>N1C=CC=CC=1>[CH3:9][C:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][P:18]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:19])=[CH:15][CH:16]=1)([C:5]1[CH:4]=[CH:3][C:2]([O:1][P:18]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:7][CH:6]=1)[CH3:10]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(C)(c1ccc(OP(=O)(Oc2ccccc2)Oc2ccccc2)cc1)c1ccc(OP(=O)(Oc2ccccc2)Oc2ccccc2)cc1

Procedure:
Bisphenol A bis(diphenyl phosphate) was prepared by the reaction of 11.4 g of bisphenol A with 29.6 g of diphenyl chlorophosphate in 100 ml of pyridine, which was performed by the protocol of Example 2. Recrystallization from isopropanol gave 12 g of the title compound of mp=56°-58° C. Mass spectrum: m/e 692. Elemental analysis found weight percent C=68.2 and weight percent H=5.04.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Br)c(S)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(SC)c1
Reaction time: 2 h

Procedure:
The product of step (c) above (140 mg) was dissolved in dry dimethyl formamide (2 ml). Potassium carbonate (114 mg) was added followed by methyl iodide (47 ml). The mixture was stirred for 2 hours, poured onto water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine then dried and evaporated to leave the subtitle compound as a pale brown oil MS MW 232/4 bp 232.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:10])[CH3:9].[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=[O:16]>CN(C)C=O>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH:8]([CH3:10])[CH3:9])[CH:15]=[O:16]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (10.28 g, 7.4 mmol) and 2-bromopropane (8.7 ml) were added to 3-bromo-4-hydroxybenzaldehyde (7.46 g, 3.7 mmol) in N,N-dimethylformamide (20 ml). The mixture was stirred at room temperature for 3 hours, then partitioned between ethyl acetate and water. The organic phase was washed with brine and dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10 increasing to 80:20) to give the title compound (5.34 g). 1H NMR (250 MHz, CDCl3) δ 9.82 (1H, s), 8.03 (1H, d, J=2.0 Hz), 7.82-7.78 (1H, dd, J=6.0, 2.0 Hz), 7.00 (1H, d, J=6.0 Hz), 4.72 (1H, septet, J=6.0 Hz), and 1.40 (6H, d, J=6.0 Hz).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH3:35])[CH:14]2[Si:20]([CH:23]1[C:31]2[C:26](=[C:27](Br)[C:28]([CH3:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:34])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([C:10]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[C:13]([CH3:35])[CH:14]3[Si:20]([CH:23]2[C:31]3[C:26](=[C:27]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:28]([CH3:32])=[CH:29][CH:30]=3)[CH:25]=[C:24]2[CH3:34])([CH3:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=Cc2c(ccc(C)c2Br)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2Br
Reactant: Br[Mg]c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(ccc(C)c2-c2ccccc2)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2-c1ccccc1
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF, 13.0 ml of 1.0 M phenylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.51 g (5.0 mmol) of 2 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.36 g (95%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=[O:8].OC1C(=O)[NH:15][S:16](=[O:25])(=[O:24])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:11][C:6]1[C:7](=[O:8])[NH:15][S:16](=[O:24])(=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1NS(=O)(=O)C(c2ccccc2)=C1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NS(=O)(=O)C(c2ccccc2)=C1Cl
Temperature: 25 °C
Yield: 49.6 %

Procedure:
Dry DMF (1.2 ml) was added dropwise to a mixture of oxalyl chloride (4.96 g, 39.1 mmol) and 4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (2.2 g, 9.77 mmol) in DCM. The resulting solution was heated under reflux until it turned orange. The mixture was then cooled to room temperature and filtered affording the title compound (1.18 g, 50%) as white solid. 1H NMR (400 MHz, d6-DMSO): δ 7.41-7.54 (m, 3H), 7.77-7.80 (m, 2H), 12.70 (br.s, 1H); 13C-NMR (100 MHz, d6-DMSO): δ 126.1, 127.1, 128.3, 129.9, 130.6, 144.9, 162.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8](Br)[CH:7]=1)=[O:5])[CH3:2].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1ccnc(Br)c1
Product: CCOC(=O)c1ccnc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
Electrospray MS (positive ion): (M+H) 272.8; from 2-bromo4-pyridinecarboxylic acid ethyl ester (900 mg), tetrakis(triphenylphosphine)paliadium (136 mg), and 3-nitrophenylboronic acid (783 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:18][CH:17]3[O:19][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH:14]12[O:19][CH:17]([CH2:16][CH2:15]1)[CH2:18][N:12]([C:4]1[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=13)[CH2:13]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.40 g, 1.4 mmol), 4-aminophenylboronic acid pinacol ester (0.47 g, 2.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.16 g, 10 mol %) in toluene/ethanol (1:1, 7 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was triturated with dichloromethane and the light brown solid was collected by Buchner filtration to furnish 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. MS (ES+): 337.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:4]=1.C([Mg]Cl)(C)C.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1.CCCCC>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([B:24]([OH:29])[OH:25])[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COc2cc(I)ccc2Cl)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(COc2cc(B(O)O)ccc2Cl)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 145 g (387 mmol) of 2-[(4-methoxybenzyl)oxy]-1-chloro-4-iodobenzene in 1.2 L of anhydrous THF, placed under argon and stirred at −50° C., are added dropwise 220 mL (440 mmol) of a 2N solution of iPrMgCl in THF, while maintaining the temperature between −40 and −50° C. The reaction mixture is allowed to warm to −10° C. and stirring is continued for 1 hour. 94 mL (406 mmol) of triisopropyl borate are then added and the reaction mixture is then allowed to warm slowly to 0° C. After stirring for 2 hours, the mixture is treated with 500 mL of aqueous 5N HCl solution and then extracted with ether (2×600 mL). The organic phase is washed with 2×1 L of water, dried over Na2SO4 and then concentrated under reduced pressure. The residue obtained is solidified in 300 mL of pentane, filtered off on a sinter funnel and washed with 200 mL of pentane. 96 g of [3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]boronic acid are thus obtained in the form of a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[C:17](=[O:31])[N:18]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]([CH3:22])=[CH:20][CH:21]=1.[C:32]1([CH2:38][CH:39]=O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)(=O)C.ClCCCl>[CH3:22][C:19]1[N:18]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17](=[O:31])[C:16]([NH:15][CH2:39][CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:21][CH:20]=1
Reactant: O=CCc1ccccc1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(NCCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Yield: 47.6 %

Procedure:
Sodium triacetoxyborohydride (0.67 g, 3.15 mmol) was added to a stirred solution of tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (EXAMPLE 1, STEP 1-3), (0.5 g, 2.10 mmol) and phenyl acetaldehyde (0.18 mL, 2.33 mmol) in 0.24 M acetic acid (0.14 mL) in 1,2-dichloroethane (11 mL). After 16 h the mixture was quenched with water and extracted into ethylacetate. The ethyl acetate layer was washed with sodium carbonate solution and brine, dried (Na2SO4) and evaporated under reduced pressure to a glass. The crude product was purified by flash column chromatography (silicagel, eluant CH2Cl2/MeOH=40/1) to give 0.34 g (1.00 mmol) of a light blue solid compound.