Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].[B:12](OC)([O:15]C)[O:13]C.Cl>>[F:2][C:3]1[CH:4]=[C:5]([B:12]([OH:15])[OH:13])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Cl
Agent: [Mg]
Product: OB(O)c1cc(F)c(F)c(F)c1
Temperature: 32 °C
Reaction time: 2.5 h

Procedure:
A nitrogen- or argon-inertized reactor was initially charged with 83.2 g (3.42 mol) of magnesium turnings and then 1646.2 g of dry, unstabilized tetrahydrofuran were added. 30 g (0.14 mol) of 3,4,5-trifluorobromobenzene were added dropwise at 25° C. with stirring and the startup of the Grignard reaction was awaited. The startup of the Grignard reaction was perceptible by a spontaneous temperature increase to approx. 32° C. Subsequently, 571.9 g (2.71 mol) of further 3,4,5-trifluorobromobenzene were metered in at 25-35° C. within 5 h. To complete the reaction, the mixture was stirred at 25-30° C. for a further 2 h. A 2nd reactor was initially charged with a solution of 328.0 g (3.16 mol) of trimethyl borate and 452 g of dry, unstabilized tetrahydrofuran, which were precooled to −5° C. Thereafter, the Grignard solution was metered in from the 1st reactor within 2.5 h. The excess magnesium remained in the 1st reactor. After the metered addition had ended, the mixture was stirred at 20-25° C. for another 2 h. For hydrolysis, 1326.1 g (2.76 mol) of 7.6% hydrochloric acid were then metered in at 25° C., after which the mixture was stirred at 25° C. for another 1 h. The mixture was heated to 50° C. and the phases were separated. Thereafter, the organic phase was re-extracted with 603.9 g of water at 50° C. and the washing water phase was removed again. Subsequently, the organic phase was concentrated by distilling off a tetrahydrofuran/water mixture. This afforded 1032.6 (82%) of a 40% solution of 3,4,5-trifluorophenylboronic acid in tetrahydrofuran, which was used directly for the subsequent reactions.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=3[CH:24]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[C@H:1]([N:5]([CH3:32])[C:6]1[C:7]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=3[CH:24]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1cc2cc(F)ccc2o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of (R)-methyl 3-(sec-butylamino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylate (100 mg, 0.33 mmol) in THF (20 mL) was added NaH (90 mg, 2.24 mmol) and CH3I (159 mg, 1.12 mmol). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 5 with hydrochloric acid (1N). The resulting solution was extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting (10% dichloromethane in methanol) to afford (R)-3-(sec-butyl(methyl)amino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylic acid as a yellow solid (25 mg, 23%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)=[C:13]([CH3:24])[CH:12]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[N:19]=[C:20]([NH:23][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)[S:21][CH:22]=3)=[C:13]([CH3:24])[CH:12]=2)=[CH:25][CH:26]=1
Reactant: COCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (12-6, 322.3 mg, 0.90 mmol) in CH2Cl2 (10.0 ml) was added triethylamine (0.40 mL, 2.6 mmol) followed by isonicotinoyl chloride hydrochloride (387.2 mg, 2.1 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-(4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (12, 230 mg) as white solids in 56% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (brs, 1 H), 8.78 (d, J=5.8 Hz, 2 H), 7.98 (d, J=5.8 Hz, 2 H), 7.12 (s, 1 H), 6.96-7.00 (m, 4 H), 6.67 (s, 2 H), 4.01-4.07 (m, 2 H), 3.63-3.64 (m, 2 H), 3.26 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 476.4 (M+H)+.
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].[C:9](OC)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(#N)C.C(=O)=O>C1COCC1>[O:16]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]#[N:8]
Reactant: CC#N
Reactant: COC(=O)c1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To 50 mL of THF at −78° C. was added n-BuLi (58.8 mL, 147.0 mmol, 2.5 M in hexanes). After the reaction temperature equilibrated (˜15 min), a solution of acetonitrile (7.7 mL, 147.0 mmol in 100 mL of THF) was added dropwise via an addition funnel over a 20 min period. The resulting milky-white slurry was allowed to stir for 1 hr before a solution of methyl benzoate (10.0 g, 73.5 mmol in 20 mL of THF) was added down the inside of the flask over a 15 min period. After 1 hr, the reaction was warmed to −45° C. (acetonitrile/CO2) and allowed to stir for 2 hr. The reaction was quenched cold by the dropwise addition of 2 N HCl, pH=7 and then diluted with EtOAc. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (quantitative yield) as a colorless solid that was used without further purification. LRMS m/z (APCl) 144 (M−1); 500 MHz 1H NMR (CDCl3) δ 7.92 (dd, J=8.4, 1.2 Hz, 2H), 7.66-7.64 (m, 1H), 7.55-7.50 (m, 2H), 4.09 (s, 2H).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][C:57]=1[CH2:66][NH2:67]>CN(C)C=O>[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([F:63])([F:64])[F:65])=[CH:58][C:57]=1[CH2:66][NH:67][C:8](=[O:10])[C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:11][CH3:12]
Reactant: NCc1cc(C(F)(F)F)ccc1F
Reactant: CC[C@H](C(=O)O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C(=O)NCc1cc(C(F)(F)F)ccc1F)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of (S)-2-phenylbutanoic acid (1-d, 50 mg, 0.30 mmol, Sigma-Aldrich, Milwaukee, Wis.) and diisopropylethylamine (98 uL, 0.60 mmol) in N,N-dimethylformamide (1 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 158 mg, 0.30 mmol). After 15 min, (2-fluoro-5-(trifluoromethyl)phenyl)methanamine (1-g, 60 mg, 0.30 mmol, Synthesis, Inc., Wyndham, N.H.) was added. The reaction mixture was stirred for 3 h, partitioned between dichioromethane and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was concentrated in vacuo to give the desired product (1-1); HRMS (M+1)=340.129; 1H NMR (500 MHz, CDCl3) δ7.49 (bs, 1H), 7.41 (d, 1H, J=6.5 Hz), 7.34-7.26 (m, 5H), 7.10 (t, 1H, J=9.0 Hz), 5.77 (bs, 1H), 4.47 (d, 1H, J=3.0 Hz), 3.30 (t, 2H, J=7.5 Hz), 2.22 (m, 1H), 1.82 (m, 1H), 0.89 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:15][C:16]([OH:18])=[O:17])[C:8]2=[O:19].S(=O)(=O)(O)O.[CH3:30]O>O>[CH3:30][O:17][C:16](=[O:18])[CH2:15][N:9]1[C:8](=[O:19])[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][C:3]3[C:2]([CH3:1])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:24])[CH:6]=2)[C:10]1=[O:14]
Reactant: CO
Reactant: Cc1cccc(C)c1Oc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CN1C(=O)c2ccc(Oc3c(C)cccc3C)cc2C1=O
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of [5-(2,6-Dimethyl-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid in MeOH (1 mL/mmol) was added concentrated sulfuric acid (35 μl/mmol) and the mixture was refluxed with stirring for 16 h before it was diluted with water (6.5 mL/mmol) and extracted twice with EtOAc. The combined organic phases were washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated in vacuo to give the title compound as a tan solid (yield: 96%); MS-(+)-ion: M+1=340.5.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=1.CCN(C(C)C)C(C)C>C(O)CCC>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[N:24]=[C:25]([NH2:30])[N:26]=[C:27]([CH3:29])[N:28]=3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccc(F)cc3n2-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (100 mg, 0.31 mmol), 4-chloro-6-methyl-[1,3,5]triazin-2-ylamine (48.4 mg, 0.34 mmol) and DIPEA (0.26 mL, 1.52 mmol) in n-butanol (2 mL) was stirred at 90° C. in a sealed vial for 16 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (C18, gradient 20-45% MeOH in 0.5% TFA/H2O) then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording 258 as a white solid (94.2 mg, 85%). LCMS (Method K): RT 3.04 min [M+H]+ 364.1. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.65 (1H, dd, J=8.7, 4.8 Hz), 7.61-7.57 (2H, m), 7.55-7.51 (3H, m), 7.04 (1H, ddd, J=9.8, 8.7, 2.5 Hz), 6.91 (1H, bs), 6.77 (1H, dd, J=9.0, 2.5 Hz), 6.13 (2H, bs), 5.26 (1H, quintet, J=7.3 Hz), 2.02 (3H, s), 1.44 (3H, d, J=6.9 Hz)
Reaction SMILES: [F:1][C:2]1[C:3]([CH:20]=[CH2:21])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[O:7][C:8]1[C:9]([N+:14]([O-])=O)=[N:10][CH:11]=[CH:12][CH:13]=1.C1COCC1>CO>[CH2:20]([C:3]1[C:2]([F:1])=[CH:17][C:6]([O:7][C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:21]
Reactant: C=Cc1cc(OC)c(Oc2cccnc2[N+](=O)[O-])cc1F
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(OC)c(Oc2cccnc2N)cc1F

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene by 3-(5-fluoro-2-methoxy-4-vinylphenoxy)-2-nitropyridine (3.7 mmol, 1.1 g) and THF by methanol, the title compound was prepared as a white solid (800 mg; 80.5%) and used without further purification.
Reaction SMILES: [C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=2[N+:26]([O-:28])=[O:27])[O:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=2[N+:26]([O-:28])=[O:27])[O:18][CH2:19][CH2:20][CH2:21][O:22][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(OCCCO)cc1CS(=O)(=O)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propan-1-ol (12.9 g, 32.1 mmol), p-toluenesulfonyl chloride (24.6 g, 129 mmol) and triethylamine (37 mL, 270 mmol) in methylene chloride (300 mL) was stirred at ambient temperature under nitrogen. After 2 hours, a second portion of p-toluenesulfonyl chloride (12.1 g, 63.5 mmol) was added. The reaction was stirred for 2 more hours and then concentrated. The residue was partitioned in methylene chloride and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 20-50% ethyl acetate in hexane, 100% ethyl acetate and then 100% methylene chloride (due to limited solubility). A yellow solid (13.0 g, 73.0%) was obtained as toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-propyl ester: MP: 162-4° C.; Mass Spectrum (−EI, [M−H]−) m/z 554. 1HNMR (500 MHz, DMSO-d6): δ8.52-8.54 (m, 1H), 8.31 (d, 1H, J=8.18 Hz), 8.09-8.11 (m, 1H), 7.97-8.00 (m, 2H), 7.62-7.73 (m, 5H), 7.35 (d, 2H, J=7.93 Hz), 6.92 (dd, 1H, J=9.15 Hz and 2.81 Hz), 6.73 (d, 1H, J=2.80 Hz), 5.22 (s, 2H), 4.09 (t, 2H, J=5.98 Hz), 3.79-3.82 (m, 2H), 2.29 (s, 3H), 1.91-1.97 ppm (m, 2H). Elemental Analysis for C27H25NO8S2: Calcd: C, 58.37; H, 4.54; N, 2.52; Found: C, 58.13; H, 4.43; N, 2.41.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:21][C:22]1[N:23]=[C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[S:25][CH:26]=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30][N:1]2[CH:2]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[S:25][CH:26]=1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1cccc(-c2nc(Cl)cs2)c1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(-c2nc(Cl)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 3-(4-chlorothiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 444.95 g/mol.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2([CH2:18][CH2:19][OH:20])[CH:17]=[CH:16][CH2:15][CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O>[C:6]1([C:12]2([CH2:18][CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[CH:16][CH2:15][CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(c2ccccc2)C=CCC=C1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC1(c2ccccc2)C=CCC=C1

Procedure:
18.6 g. of methanesulfonyl chloride are added dropwise while stirring and cooling with ice to a solution of 27 g. of 1-phenyl-2,5-cyclohexadien-1-ethanol in 270 ml. of absolute pyridine. After stirring at room temperature for 3 hours, about 250 ml. of water are added. The separated product is filtered off under suction, washed with water and dried. The crude product is recrystallized from benzene/hexane, there being obtained methansulfonic acid 2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester as colorless crystals of melting point 64°-65° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13]C)=[O:12].CO.[OH-].[Na+]>O>[OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1sc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 5B (2.38 g) and methanol (20 ml) was added to a stirred solution of sodium hydroxide (1.68 g) in water (20 ml). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was cooled to 5° C. and acidified with concentrated HCI (3.5 ml). The resulting suspension was stirred at 5° C. for 30 minutes. The solid was collected by filtration, washed with water, then dried in vacuo at 35-40° C. to give the free acid (1.45 g, 65 %).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:2]1.[C:16]1([CH2:22][C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[C:16]1([CH2:22][C:23]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)[N:11]=2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nc(-c2c[nH]c3ncccc23)cs1
Reactant: O=C(O)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Temperature: 160 °C

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (216 mg, 1.0 mmol), phenylacetic acid (150 mg, 1.10 mmol) and N-(1-methanesulfonyl)benzotriazole (220 mg, 1.10 mmol) were placed in a microwave reaction vessel (Personal Chemistry, Uppsala, Sweden). THF (2 mL) was added followed by triethylamine (0.5 mL, 3.59 mmol) and the mixture heated in the sealed tube at 160° C. for 10 minutes. Upon cooling to room temperature the reaction was concentrated to 1 mL, and then acetonitrile was added (4 mL) and the product 2-Phenyl-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide precipitated, was filtered, washed with acetonitrile and dried. (150 mg, 45%). 1H NMR (500 MHz, DMSO-d6) 12.39 (1H, s), 11.83 (s,1H), 8.50 (1H, d, J=7.91 Hz), 8.27 (m,1H), 7.84 (1H, d, J=2.48 Hz), 7.36-7.15 (7H, m), 3.81 (2H, s). LC-MS Rt=2.8 min, [M+H]+=335.0, [M−H]−=333.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[CH2:23](Br)[CH:24]=[CH2:25]>[OH-].[Na+]>[CH2:25]([S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1

Procedure:
0.5 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 2.6 ml of 2 N sodium hydroxide solution while stirring. 0.367 g of allyl bromide is added, the mixture is stirred at room temperature for 10 minutes, extracted by shaking twice with 10 ml of toluene each time, the combined aqueous phases are washed twice with 5 ml of 2 N sodium hydroxide solution each time, dried over magnesium sulphate, concentrated by evaporation under reduced pressure and crystallised from hexane. 2-Allylthio-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 57°-58° is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[OH:12].CO.C[O-].[Na+].[CH2:18]([OH:21])[CH:19]=[CH2:20].C1(C)C=CC=CC=1>>[C:8]([C:4]1[CH:5]=[C:6]([CH2:20][CH2:19][CH2:18][OH:21])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:12])([CH3:9])([CH3:11])[CH3:10]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: C=CCO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(CCCO)cc(C(C)(C)C)c1O
Temperature: 210 °C
Reaction time: 7 h
Yield: 52 %

Procedure:
A pressure container was charged with 62.7 g (0.38 mol) of 2-methyl-6-t-butylphenol and 7.3 g (0.038 mol) of a methanol solution containing 28% of sodium methoxide. Then the mixture was heated under reduced pressure to distill 6.5 g (0.2 mol) of methanol. Thereafter, 22.2 g (0.92 mol) of allyl alcohol and 18.7 g (0.19 mol) of toluene were added to the reaction system, the atmosphere in the reaction system was replaced by nitrogen and then, the reaction system was tightly closed. Then, the reaction system was raised up to 210° C. and kept at that temperature for 7 hours. Then, the reaction mixture was cooled to room temperature. A sample of the reaction solution was analyzed by gas-chromatography. The desired product, 3-(3-t-butyl-4-hydroxy-5-methylphenyl)propanol was obtained in a yield of 52%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[C:26]([CH2:37]Cl)=[CH:25]2>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH2:37][C:26]3[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[N:28][C:29]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(=O)ccn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.05 g, 0.308 mmol), Cs2CO3 (0.1515 g, 0.46 mmol, 1.5 eq), and KI (0.0051 g, 0.0309 mmol, 0.1 eq) in DMF (1 mL) was added 8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (0.1 g, 0.309 mmol, 1.0 eq) and the mixture was stirred at 140° C. for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 14 min as eluent to provide 4-amino-8-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=33 nM] as white solid. 1H NMR (DMSO-d6) δ ppm 9.52 (1 H, d, J=4.7 Hz), 8.25 (1 H, s), 8.11 (1 H, d, J=4.7 Hz), 8.09 (1 H, s), 8.04 (1 H, dd, J=8.4, 1.4 Hz), 7.97 (1 H, dd, J=7.6, 1.4 Hz), 7.81 (1 H, d, J=7.8 Hz), 7.63 (1 H, d, J=7.8 Hz), 7.57-7.61 (1 H, m), 7.42-7.53 (3 H, m), 6.14 (1 H, d, J=7.8 Hz), 5.40 (2 H, s). Mass Spectrum (ESI) m/e=448.0 and 450.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[NH:5][N:4]=1.C1C(=O)N([Cl:21])C(=O)C1>CC#N>[Cl:21][C:7]1[C:6]([C:8]([F:9])([F:10])[F:11])=[N:5][NH:4][C:3]=1[C:2]([F:1])([F:12])[F:13]
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: FC(F)(F)c1n[nH]c(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 3,5-bistrifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][OH:10]>CCO>[OH:10][N:9]=[C:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Solvent: CCO
Product: NC(=NO)c1ccccc1
Yield: 99.9 %

Procedure:
Benzonitrile (0.99 cm3, 1 g, 9.7 mmol) and hydroxylamine (50% in water, 0.89 cm3, 0.96 g, 14.55 mmol, 1.5 eq) were stirred under reflux in EtOH (10 cm3) for 48 hours. The solvent was evaporated under reduced pressure and water (10 cm3) was added to the residue. The mixture was extracted with dichloromethane (100 cm3) and the organic extract was evaporated under reduced pressure. The residue was purified by column chromatography to give the product N′-hydroxybenzimidamide (1.32 g, 100%) as a white crystalline solid, mp 79-81° C. (lit 79-80° C. This procedure is suitable for all starting materials bearing a benzene ring.