Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[I:30][C:31]1[CH:32]=[C:33]([OH:42])[CH:34]=[C:35]([C:37]2[CH:41]=[CH:40][S:39][CH:38]=2)[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:42][C:33]2[CH:34]=[C:35]([C:37]3[CH:41]=[CH:40][S:39][CH:38]=3)[CH:36]=[C:31]([I:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: Oc1cc(I)cc(-c2ccsc2)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a mixture of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.99 g, 6.35 mmol), 3-iodo-5-thiophen-3-yl-phenol (1.92 g, 6.35 mmol), and potassium carbonate (1.75 g, 12.7 mmol) were added N,N-dimethylformamide (50 mL) and acetone (100 mL) at room temperature. The resulting suspension was heated to reflux for 2 days. Then, the reaction mixture was cooled to room temperature and diluted with water (200 mL). The organic compound was extracted into ethyl acetate (3×100 mL) and the combined organic extracts were washed with water (300 mL) and brine solution (200 mL). The organic layers were dried over anhydrous magnesium sulfate and filtration of the drying agent and concentration of the solvent gave the crude product which was purified by using an ISCO 80 g column, eluting with 0-20% ethyl acetate in hexanes to afford 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (4.39 g, 99%) as a colorless oil: ES(+)-HRMS m/e calculated for C33H41IO6S (M+Na)+ 715.1561, found 715.1561.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ncnc2c1c(I)cn2C1CCNCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (1.0 g, 2.16 mmol) in dichloromethane (10 mL) at 0° C. was treated with a cold solution of trifluoroacetic acid (20%) in dichloromethane (total volume 56 mL). Reaction stirred at 0° C. under a nitrogen atmosphere for 3 hours. The solvent was evaporated under reduced pressure at ambient temperature. Ethyl acetate (50 mL) and 5 N hydrochloric acid (50 mL) were added to the solid. The layers were partitioned, and the organic layer was extracted with 5 N hydrochloric acid (150 mL). The aqueous layers were combined, cooled to 0° C., and basified using 50% sodium hydroxide aqueous solution at 0° C. The aqueous layer was extracted with dichloromethane (300 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting product, 4-chloro-5-iodo-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidine (0.520 g, 99%) was dried 5 under high vacuum. 1H NMR (DMSO-d6, 400 MHz); 8.63(s, 1H), 8.12(s, 1H), 4.75-4.68 (m, 1H), 3.09-3.06(d, 2H, J=12 Hz), 2.70-2.60(m, 2H), 1.99-1.83(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 m, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 4.022 min.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2O1.ClC1N=C(NC2CCCCC2)C(F)=CN=1.[CH2:42]1[CH2:52]OC2C=CC(N)=CC=2[O:43]1>>[CH:5]1([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]4[O:43][CH2:42][CH2:52][O:26][C:22]=4[CH:21]=3)[N:13]=2)[CH2:6][CH2:7][CH2:8][CH2:3][CH2:4]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: Fc1cnc(Cl)nc1NC1CCCCC1
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1NC1CCCCC1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-cyclohexyl-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-cyclohexyl-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.62 (d, 1H, J=4.2 Hz), 7.31 (d, 1H, J=2.1 Hz), 6.86 (dd, 1H, J=2.4 and 8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 4.23-4.16 (m, 4H), 3.99-3.89 (m, 1H), 2.03 (dd, 2H, J=2.1 and 12.3 Hz), 1.80 (dt, 2H, J=3.0 and 13.5 Hz), 1.72-1.65 (m, 1H), 1.49-1.20 (m, 5H); 19F NMR (CD3OD): −48332; LCMS: ret. time: 24.54 min.; purity: 95%; MS (m/e): 345 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[CH2:50]([N:52]([CH2:63][CH3:64])[C@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:54](O)=[O:55])[CH3:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH2:63]([N:52]([CH2:50][CH3:51])[C@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:54]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:4](=[O:42])[C@@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:41])=[CH:17][CH:16]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:22][CH:23]=1)=[O:29])=[O:55])[CH3:64]
Reactant: CCN(CC)[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc2)c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58.3 %

Procedure:
The product from Example 10A (15 mg, 0.022 mmol) was combined with (R)-2-(diethylamino)-2-phenylacetic acid (6.04 mg, 0.029 mmol), HATU (9.38 mg, 0.025 mmol) and Hunig's base (0.024 mL, 0.135 mmol) in DMSO (1.0 mL) and the mixture was stirred at room temperature for 45 min. Diluted with water and collected the solid by filtration. The product was purified by chromatography on silica gel, eluting with 0-5% MeOH in CH2Cl2 to give the title compound (11 mg, 57.2% yield). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.87 (t, J=7.10 Hz, 6 H) 0.94 (s, 9 H) 1.59-1.68 (m, 1 H) 1.78-1.86 (m, 2 H) 1.92-2.00 (m, 1 H) 2.04-2.12 (m, 2 H) 2.43-2.52 (m, 2 H) 2.55-2.67 (m, 4 H) 3.23-3.30 (m, 1 H) 3.56-3.61 (m, 2 H) 3.62 (s, 3 H) 3.71-3.78 (m, 1 H) 4.30 (d, J=9.61 Hz, 1 H) 4.48 (s, 4 H) 4.55 (s, 1 H) 4.72-4.77 (m, 2 H) 5.31 (d, J=9.77 Hz, 1 H) 6.63 (t, J=7.25 Hz, 1 H) 6.67 (d, J=7.93 Hz, 2 H) 7.06-7.12 (m, 6 H) 7.24-7.32 (m, 3 H) 7.33 (d, J=8.54 Hz, 2 H) 7.35-7.42 (m, 4 H) 9.22 (s, 1 H) 9.64 (s, 1 H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:26]1(=[O:31])[CH2:30][CH2:29][CH:28]=[CH:27]1>O1CCOCC1.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>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:28]3[CH2:29][CH2:30][C:26](=[O:31])[CH:27]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C1C=CCC1
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
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
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 105 °C
Reaction time: 6 h

Procedure:
A suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (500 mg, 1.268 mmol), 2-cyclopenten-1-one (0.410 mL, 5.07 mmol), 105° C. and bis(tri-tert-butylphosphine)palladium (0) (64.8 mg, 0.127 mmol) in Dioxane (4 mL) was capped, degassed and backfilled with argon. The reaction was heated at 105° C. After 6 h, the reaction was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluant: 40-100% EtOAc/hexane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 396.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]([OH:16])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[F:29])[N:25]=[C:24]([CH:30]=[CH2:31])[CH:23]=[CH:22]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[F:29])[N:25]=[C:24](/[CH:30]=[CH:31]/[C:2]1[CH:3]=[CH:4][C:5]3[O:15][CH2:14][C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:8]4[CH:7]([OH:16])[C:6]=3[CH:17]=1)[CH:23]=[CH:22]2
Reactant: OC1c2cc(Br)ccc2OCc2ncccc21
Reactant: C=Cc1ccc2cc(F)c(F)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: OC1c2cc(/C=C/c3ccc4cc(F)c(F)cc4n3)ccc2OCc2ncccc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
0.37 g (1.26 mmol) of the bromo derivative of step 3 are mixed with 0.27 g (1.41 mmol) of the vinyl derivative of step 4, 8.5 mg (0.0378 mmol) of palladium acetate and 36.2 mg (0.118 mmol) of tri(o-tolyl)phosphine in 2.5 ml of DMF. The solution is degassed and cooled with an ice bath. In a nitrogen atmosphere it is dropped inside a solution of 0.27 ml (0.196 g; 1.937 mmol) of N,N,N-triethylamine in 1.2 ml DMF. The whole is stirred at 100° C. for 1 hr. Once at room temperature, 4 ml of water are dropped inside and the solid is filtered, washed with water and dried. The yield is 0.5 g (98%).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.Cl[P:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O1CCCC1>[CH3:9][C:7]1[CH:8]=[C:3]([P:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=[C:5]([CH3:10])[CH:6]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(P(c2ccccc2)c2ccccc2)c1

Procedure:
In a 3-neck 1 liter flask equipped with blade stirrer, nitrogen inlet, Claissen adaptor, condenser, drying tube and constant pressure dropping funnel, was placed 6.67 g (0.274 g atoms) of magnesium turnings. Under a nitrogen flow, the glassware was dried with heating via a heat gun. To the magnesium was added a portion of a solution of 55.5 g (0.30 mol) of 5-bromo-m-xylene in 150 ml dry THF (tetrahydrofuran). Reaction was initiated with external heating and the balance of the solution was added dropwise over approximately 30 min, maintaining gentle reflux. The mixture was then stirred for another 1 hr after which a solution of 41.3 g (0.188 mol) of chlorodiphenylphosphine in 150 ml of dry THF was added over approximately 10 min. The mixture was then heated at reflux for 2 hr, cooled and poured into ice. The mixture was neutralized with concentrated HCl and nitrogen was bubbled through the mixture overnight. The organic layer was taken up in methylene chloride and separated from the aqueous layer. Concentrating the organic layer afforded an oil which crystallized on standing. After triturating with an equal volume of methanol, the solid was collected and recrystallized from methanol. The yield of 3,5-dimethylphenyldiphenylphosphine was 37.5 g (68.7% of theory); mp=67°-9° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(C(C)(C)C)cc1
Yield: 16.9 %

Procedure:
A solution of (±) N-tert-butoxycarbonyl-1,2-iminoindane (5 g, 22 mmol), 4-tert-butylphenol (3.34 g, 22 mmol) and pyridinium p-toluenesulfonate (109 mg) in chloroform (150 ml) was heated at reflux for 2 h. On cooling, the solution was washed sequentially with 10% aq. NaOH, water and then brine. After drying over MgSO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (1.42 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC1(C)C(C)(C)[O:12][B:11]([C:16]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:17]=2[O:18][C@@H:19]([CH3:27])[C:20]([O:22]C(C)(C)C)=[O:21])[O:10]1>C(Cl)Cl>[B:11]([C:16]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:17]=1[O:18][C@@H:19]([CH3:27])[C:20]([OH:22])=[O:21])([OH:12])[OH:10]
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
TFA (10 ml) was added to a solution of the product from step (iii) (4.0 g) in DCM (100 ml) and stirred for 30 min. The TPA was evaporated and the residue dissolved in a mixture of 1M hydrochloric acid (30 ml) and acetonitrile (30 ml) After 1 h the mixture was evaporated to dryness, dissolved in 1M sodium hydroxide, washed with ether and adjusted to pH 2 with concentrated hydrochloric acid. The aqueous was then extracted with ether, washed with brine, dried (MgSO4) and evaporated. Yield 2.0 g. The crude material was carried forward to step (v).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[NH:5][C:6]=1[CH3:7].Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:37]=[C:38]([Cl:40])[N:39]=2)[C:33]([O:35][CH3:36])=[O:34])[CH2:26][CH2:25]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:31]=[C:32]([CH:37]=[C:38]([Cl:40])[N:39]=3)[C:33]([O:35][CH3:36])=[O:34])[CH2:28][CH2:29]2)=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (intermediate 17, 1.81 g, 4.90 mmol) and TEA (682 μl, 4.9 mmol) were added to methyl 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinate hydrochloride salt (Intermediate 93; 1.5 g, 4.90 mmol) in anhydrous DMA (10 ml). The mixture was stirred at room temperature 18 h then partitioned between EtOAc and water. The organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum. The solid material was purified by flash chromatography eluting with EtOAc/n-hexanes mixture (7:3) to give the title compound as a brown solid (1.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Br)c(N)nc2n1
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Br

Procedure:
The title compound was prepared using 0.30 g of 6-(2-bromo-6-chloro-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 104 and 0.105 mL of tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with 1:1CHCl3 :EtOAc; mp 314° C. (dec); MS(CI).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([F:21])[CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Reactant: COc1ccc(B(O)O)cc1F
Product: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2ccc(OC)c(F)c2)C1=O
Yield: 25.1 %

Procedure:
100 mg of 5-{4-(aminosulfonyl)phenyl}-2-ethyl-4-iodo-2-methyl-3(2H)-furanone was reacted with 80 mg of 3-fluoro-4-methoxybenzeneboronic acid by following a procedure similar to the procedure for the Step 2 of Example 35 to give 25 mg of 5-{4-(aminosulfonyl)phenyl}-2-ethyl-4-(3-fluoro-4-methoxyphenyl)-2-methyl-3(2H)-furanone as a solid. mp: 113-114° C. NMR: δ0.94 (t, J=7.5 Hz, 3H), 1.53 (s, 3H), 1.95 (q, J=7.5 Hz, 2H), 3.91 (s, 3H), 4.96 (br s, 2H), 6.99 (m, 3H), 7.80 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H). IR (cm−1): 3259, 1689, 1608, 1517, 1270, 1159. MS (FAB): 406 (m+1).
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1.CN(C)C=O.S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:20][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1
Reactant: OCc1cc(-c2ccsc2)cs1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: ClCc1cc(-c2ccsc2)cs1

Procedure:
100 mg of 2-hydroxymethyl-4-(3-thienyl)thiophene was suspended in 5 ml of chloroform, and with stirring under ice cooling, 2 microliters of dimethylformamide and 80 microliters of thionyl chloride were added. The mixture was stirred for 30 minutes, and neutralized with a saturated aqueous solution of sodium hydrogen carbonate under ice cooling. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the chloroform was evaporated to give 2-chloromethyl-4-(3-thienyl)thiophene as a yellow powder.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:27])[C:25]=1[OH:26])[CH:21]=O>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH:15]=[CH:21][C:20]2[CH:23]=[C:24]([CH3:27])[C:25]([OH:26])=[C:18]([CH3:17])[CH:19]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(C(C)=O)cc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: CCCCCCCc1ccc(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1

Procedure:
This compound was synthesized from 4′-heptylacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:17]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1)[CH3:18]
Reactant: CCc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of 6-bromo-3-ethyl-1-phenyl-1H-indazole (0.10 g, 0.33 mmol, 1.00 equiv) in toluene (20 mL), piperazine (0.14 g, 1.628 mmol, 2.00 equiv), Cs2CO3 (0.16 g, 5.00 mmol, 1.50 equiv), Pd(OAc)2 (20 mg, 0.09 mmol, 0.03 equiv), BINAP (20 mg, 0.03 mmol, 0.03 equiv). The resulting solution was stirred for 20 h at 100° C. in an oil bath. The solids were filtered out. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue (50 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed)): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and MeOH (10% MeOH up to 55% in 2.5 min, hold 55% in 2.5 min, up to 100% in 0.1 min, hold 100% in 0.3 min, down to 10% in 0.1 min); Detector, UV254 nm to yield 3-ethyl-1-phenyl-6-(piperazin-1-yl)-1H-indazole as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C(Cl)=CC=CN=1.[OH2:21]>Cl>[Cl:1][C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:21])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: CC(C)(C#N)c1ncccc1Cl
Agent: Cl
Agent: Clc1cccnc1Cl
Product: CC(C)(C(N)=O)c1ncccc1Cl
Temperature: 92.5 °C

Procedure:
A crude mixture of 2-(3-chloropyridin-2-yl)-2-methylpropionitrile and 2,3-dichloropyridine (0.171 g) was dissolved in concentrated hydrochloric acid (4 mL) and the solution was heated to 90-95° C. for 5.5 hours. Upon cooling, it was diluted with water and extracted twice with dichloromethane. The aqueous phase was basified with sodium hydroxide (with cooling) to pH of 8 and extracted twice with dichloromethane. The organic extracts were washed with water and dried over anhydrous magnesium sulfate. Filtration and evaporation gave 2-(3-chloropyridin-2-yl)isobutyramide (64 mg). 1H-NMR (DMSO-d6): δ 8.48 (dd, 4.6, 1.5 Hz), 7.83 (dd, 7.95, 1.5), 7.325 (dd, 7.95, 4.6), 6.97 and 6.93 (2 s, CONH2), 1.50 (s, 6H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[C:16]([C:22](=[O:38])[NH:23][CH:24]3[CH:31]4[CH2:32][CH:27]5[CH2:28][C:29]([S:34]([CH3:37])(=[O:36])=[O:35])([CH2:33][CH:25]3[CH2:26]5)[CH2:30]4)[CH:15]=[N:14]2)=[CH:9][CH:8]=1.O>CO>[CH3:37][S:34]([C:29]12[CH2:33][CH:25]3[CH2:26][CH:27]([CH2:32][CH:31]([CH:24]3[NH:23][C:22]([C:16]3[CH:15]=[N:14][N:13]([C:10]4[CH:9]=[CH:8][C:7]([C:6]([OH:39])=[O:5])=[CH:12][CH:11]=4)[C:17]=3[S:18][CH2:19][CH2:20][CH3:21])=[O:38])[CH2:30]1)[CH2:28]2)(=[O:35])=[O:36]
Reactant: CCCSc1c(C(=O)NC2C3CC4CC2CC(S(C)(=O)=O)(C4)C3)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCSc1c(C(=O)NC2C3CC4CC2CC(S(C)(=O)=O)(C4)C3)cnn1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
Lithium hydroxide monohydrate (27.5 mg, 0.65 mmol) was added to a suspension of 4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoic acid methyl ester (Intermediate#105) (116 mg, 0.22 mmol) in methanol (4 mL)/water (2 mL) at ambient temperature. The resulting suspension was stirred at ambient temperature for 18 hours. The bulk of the organic solvent was removed in vacuo and the resulting solution was diluted with water (10 mL) and washed with ether (10 mL). The aqueous layer was acidified to ˜pH4 with 2M HCl then extracted with EtOAc (3×25 ml). The EtOAc layers were combined, washed sequentially with water (5 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoic acid (113 mg, 100%) as a white solid.