Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1I)[CH3:2].[CH3:11][Si:12]([CH3:16])([CH3:15])[C:13]#[CH:14].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:14]#[C:13][Si:12]([CH3:16])([CH3:15])[CH3:11])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCc1nc(N)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(N)ccc1C#C[Si](C)(C)C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 18 g (72.6 mmol) 6-ethyl-5-iodo-pyridin-2-ylamine and 14.4 mL (102 mmol) 1-trimethylsilyl-ethyne using 1.38 g (7.3 mmol) CuI, 5.1 g (7.3 mmol) PdCl2(PPh3)2 and 101 mL (726 mmol) triethylamine in 100 mL dry THF. For the work-up the solvent is removed under reduced pressure, the crude product is taken up in ethyl acetate and the organic phase is extracted with water. The product is purified twice by chromatography on silica gel using a cyclohexane/ethyl acetate gradient. Yield: 12.73 g (80%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-])=O)[CH:10]=2)[CH2:3]1>C(O)C.CO.[Pd]>[NH2:17][C:11]1[CH:10]=[C:9]([N:4]2[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@@H]1CN(c2ccc(C#N)c([N+](=O)[O-])c2)C[C@H](C)N1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: C[C@@H]1CN(c2ccc(C#N)c(N)c2)C[C@H](C)N1
Reaction time: 16 h

Procedure:
A solution of the product of Step 1 (186 mg, 0.71 mmol) in ethanol (14 ml) and methanol (3-4 ml) was treated with palladium on charcoal (37 mg, 10% paste) and stirred under an atmosphere of hydrogen for 16 hours. The mixture was then filtered through celite, washing with ethanol and the then evaporated in vacuo. Purification of the residue by mass directed autoprep HPLC gave the title compound (D20) as the formic acid salt. MS (ES+) m/e 231 [M+H]+.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[Na].[O:11]=[C:12]1[CH:17]([CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16](=[O:33])[O:15][C:14]([CH3:35])([CH3:34])[O:13]1.O>O1CCCC1>[Br:7][C:17]1([CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12](=[O:11])[O:13][C:14]([CH3:35])([CH3:34])[O:15][C:16]1=[O:33]
Reactant: CC1(C)OC(=O)C(CCn2cccc2C(=O)c2ccccc2)C(=O)O1
Agent: [Na]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)C(Br)(CCn2cccc2C(=O)c2ccccc2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridinium bromide perbromide (11.51 g, 36 mmoles) in tetrahydrofuran (25 ml) was added dropwise at 0°-5° C. to a vigorously stirred suspension of the sodium salt of 1-[2-(4,6-dioxo-2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-2-benzoylpyrrole (VI, prepared as described above, 13.5 g, 37.2 mole). The mixture was stirred for 1 hour at 0°-5° C. The mixture was then poured into water (600 ml) and extracted three times with diethyl ether (100 ml, then 2×50 ml). The organic phase was separated and washed with two 200 ml portions of water, dried over magnesium sulfate and evaporated to afford crystalline 1-[2-(5-bromo-4,6-dioxo-2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-2-(benzoyl)pyrrole (VIIa). The product could be recrystallized from ethyl acetate/hexane to give material with the following properties: m.p. 89°-91° C. 1H NMR (CDCl3): delta 1.81 (s, 3H); 2.00 (s, 3H); 3.19 (t, 2H); 4.58 (t, 2H); 6.19 (dd, 1H); 6.71 (dd, 1H); 6.89 (dd, 1H); 7.4-7.55 (m, 3H); 7.78 (dd, 2H). 13C NMR (CDCl3): delta 26.8, 28.9, 39.7, 43.5, 45.8, 107.3, 123.5, 127.9, 129.2, 130.3, 131.4, 139.1, 163.0, 186.9.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.O.NN.[OH-].[K+].Cl>C(O)COCCO>[NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=C1CCCNc2ccccc21
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc2c(c1)CCCCN2
Yield: 47.8 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-benzo[b]azepin-5-one (5) (1.58 g, 9.80 mmol), hydrazine monohydrate (1.92 mL, 40.0 mmol), and KOH (3.3 g, 58.8 mmol) in diethylene glycol (50 mL) was heated to reflux for 6 hr under a N2 atmosphere. After cooling, the reaction was poured onto ice-cold water, neutralized with 1N HCl, and extracted with EtOAc. All the organics were washed with water and saturated NaCl. Dried over MgSO4, filtered, and concentrated to yield compound 6 (0.69 g). This crude material was used in the next step with out further purification.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:46])[NH:36][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([CH3:39])[CH3:38])[CH:30]=2)=[CH:27][C:12]2[C:13]([C:23]([NH:25][CH3:26])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1>N1C=CC=CC=1>[CH:1]1([S:4]([NH:8][C:9]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:46])[NH:36][C:37]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([CH3:39])[CH3:38])[CH:30]=3)=[CH:27][C:12]3[C:13]([C:23]([NH:25][CH3:26])=[O:24])=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)[O:15][C:11]=3[CH:10]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(=O)(=O)C3CC3)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Cyclopropanesulfonyl chloride (8 μL, 0.058 mmol) was added to a stirring solution of 6-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (20 mg, 0.038 mmol) in Pyridine (0.5 mL) at rt. It was allowed to stir for 2 hours. The mixture was concentrated purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (17 mg, 70%). 1H NMR (500 MHz, CD3OD) δ ppm 8.41 (1H, br. s.), 7.91-8.01 (3H, m), 7.78-7.86 (2H, m), 7.61-7.71 (2H, m), 7.58 (1H, t, J=7.63 Hz), 7.41-7.49 (2H, m), 7.24-7.33 (4H, m), 7.18 (1H, t, J=6.87 Hz), 2.94 (3H, s), 2.34-2.43 (1H, m), 1.77 (6H, s), 0.80-1.03 (4H, m). LC-MS retention time: 1.53 min; m/z (MH+): 626. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=15.40 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=12.65 min, purity=99%.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([N:23]([CH3:34])[S:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+]>CO.O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([N:23]([CH3:34])[S:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)COc1ccc(C(C)N(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(c1ccc(OCC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
To a solution of methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(4-fluoro-N-methylphenylsulfonamido)ethyl)phenoxy)acetate (19) in MeOH/H2O (4/1) was added lithium hydroxide (2 eq) and the mixture was stirred at room temperature for 2 h. After concentrating in vacuo, the residue was purified via semi-preparative HPLC to give 21.9 mg, (15.2% from Intermediate 18) of 2-(2-(3-trifluoromethylphenyl)-4-(1-(4-fluoro-N-methylphenylsulfonamido)ethyl)phenoxy)acetic acid (Example 22) as white solid. 1HNMR (CDCl3, 400 MHz): δ 7.61 (s, 1H), 7.53 (m, 3H), 7.31 (m, 1H), 7.25 (m, 1H), 7.22 (m, 1H), 7.03 (m, 2H), 6.72 (d, 1H), 5.01 (m, 1H), 4.14 (s, 2H), 2.38 (s, 3H), 1.06 (d, 3H). MS (ES-API): M=323.1 (main fragment). HPLC (Method B) tR=3.43 min.
Reaction SMILES: [O:1]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])S(C(F)(F)F)(=O)=O.O[C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[Si:9]([O:1][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 59 %

Procedure:
tert-Butyldimethylsilyl triflate (1.44 ml) was added to a stirred solution of 1-tert-butyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.03 g) and triethylamine (1.76 ml) in DCM (50 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours and then the mixture was washed with saturated aqueous potassium hydrogensulfate, dried (Na2SO4), and concentrated in vacuo to give a clear oil. Purification by column chromatography, using 0-30% ethyl acetate in hexane as eluent, gave 1-tert-butyl 2-methyl (2R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate as a clear oil (891 mg, 59%); NMR spectrum (CDCl3) 4.43-4.32 (m, 2H), 3.75-3.72 (m, 2H), 3.65-3.56 (m, 1H), 3.43-3.31 (m, 1H), 2.21-2.15 (m, 1H), 2.07-1.98 (m, 1H), 1.47 (s, 3H), 1.42 (s, 6H), 0.88 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](\[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)/[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](\[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C. for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from acetone-diisopropyl ether to obtain E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetic acid (427 mg, yield 88%) as colorless crystals. m.p. 130-131° C. (decomposition)
Reaction SMILES: [OH:1][C:2]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][C:20]=2[Cl:27])=[O:17])[CH3:13])[CH2:8][CH2:7]1)=[O:4].OC(C1SC=CC=1)(C1SC=CC=1)C(O[C@H]1CC[C@H](N(CCC(NC2C=C(OC)C(C=O)=CC=2Cl)=O)C)CC1)=O>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[OH:1][C:2]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][C:20]=2[Cl:27])=[O:17])[CH3:13])[CH2:8][CH2:7]1)=[O:4]
Reactant: CN(CCC(=O)Nc1ccc(CO)cc1Cl)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Agent: [Mn+4]
Agent: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1C=O
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN(CCC(=O)Nc1ccc(C=O)cc1Cl)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1

Procedure:
Obtained as a light brown oil (94%) starting from trans-4-((3-(2-chloro-4-(hydroxy-methyl)phenylamino)-3-oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2-thienyl)-acetate (intermediate 49; 0.06 g, 0.11 mmol) and manganese (IV) oxide (0.098 mg, 1.13 mmol) in chloroform (1.4 mL) following the experimental procedure as described for intermediate 43.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][NH2:14]>CCO>[CH3:9][O:8][C:7]1[C:2]([NH:14][CH3:13])=[N:3][CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: CN
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Solvent: CCO
Product: CNc1ncc([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-3-methoxy-5-nitropyridine (8.00 g, 43.4 mmol) was added portion-wise to a 35% solution of methylamine in EtOH (14 mL). After standing for 10 min the mixture was cooled to 0° C. and further 35% methylamine in EtOH (14 mL) was added. After stirring at rt for 20 min ice/water (˜28 mL) was added. The mixture was cooled to 0° C., stirred vigorously and then allowed to stand for 15 min. The resulting solids were isolation by filtration, washed with H2O and dried to yield crude 3-methoxy-N-methyl-5-nitropyridin-2-amine (7.81 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([OH:20])[CH2:3][N:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]3N=N[N:19]=[C:8]3[C:7]=2[N:6]=[CH:5]1>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:19][C:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:3][C:2]([CH3:21])([CH3:1])[OH:20])[C:16]=2[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: CC(C)(O)Cn1cnc2c1c1ccccc1n1nnnc21
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)Cn1cnc2c(N)nc3c(c21)CCCC3
Reaction time: 48 h
Yield: 82.3 %

Procedure:
A catalytic amount of platinum (IV) oxide was added to a solution of α,α-dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol (0.40 g, 1.4 mmole, Example 1) in trifluoroacetic acid (10 mL). The mixture was hydrogenated at 50 psi (3.44×105Pa) for 48 hours. The catalyst was removed by filtration and washed with ethanol. The filtrate was concentrated under vacuum using heptane to azeotrope the trifluoroacetic acid. The resulting oil solidified on standing. The solid was dissolved in water containing enough hydrochloric acid to form a salt of the product. The aqueous solution was filtered through charcoal. The filtrate was made basic with ammonium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0.3 g of 4-amino-α,α-dimethyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-ethanol as a white solid, m.p. 259.8°-261.3° C. Analysis: Calculated for C14H20N4O: % C, 64.59; % H,7.74; % N, 21.52; Found % C, 64.49; % H, 7.63; % N, 21.41.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[OH-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([S:19][C:18]([Cl:22])([Cl:21])[Cl:17])[C:3]1=[O:14]
Reactant: Cn1c(=O)[nH]n(-c2ccccc2)c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)n(SC(Cl)(Cl)Cl)n(-c2ccccc2)c1=O
Yield: 99 %

Procedure:
To a solution of 38.2g (0.2 mole) 4-methyl-1-phenyl urazole in 200 ml water was added a solution of 8g (0.2 mole) sodium hydroxide in 20 ml water. A mixture of 37.2g (0.2 mole) trichloromethylsulfenyl chloride and 3g of an emulsifier solution (as in example 1) in 25 ml water was then added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that formed was filtered and the filter cake washed with water. After drying and recrystallizing from benzene there was obtained 67g (99% 4-methyl-1-phenyl-2-(trichloromethylthio)urazole having a melting point of 214° C.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[Cl:23][C:19]1[C:18]([F:24])=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:25].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)NCc1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (6.35 g, 17.22 mmol) in CH2Cl2 (60 mL) was added TFA (13.18 mL, 172 mmol) and the solution was stirred at RT for 3 h. The crude reaction mixture was concentrated under vacuum, Et2O was added and the white precipitate was filtered off to give the desired compound as a TFA salt. MS (LC/MS): 287.0 [M+H]+, 285.1 [M−H]−; tR (HPLC conditions f) 1.27 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[S:17][C:18]=1[Cl:19]>>[Br:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[S:17][C:18]=1[Cl:19]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Br)c(Cl)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromo-5-chlorothiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (40.9 mg) with purity >90%. MS pos) m/z 445.0, 447.0.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[C:4]=1[C:29]1[S:30][C:31]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:32]=2[N:33]=1.Cl>>[N:9]1([C:7]2[NH:8][C:3](=[O:2])[C:4]([C:29]3[S:30][C:31]4[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][C:32]=4[N:33]=3)=[C:5]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[N:6]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(C(F)(F)F)ccc2s1
Agent: Cl
Product: O=c1[nH]c(N2CCOCC2)nc(N[C@@H]2CCCNC2)c1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
(3R)-tert-butyl 3-(6-methoxy-2-morpholino-5-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)pyrimidin-4-ylamino)piperidine-1-carboxylate (40.0 mg, 0.07 mmol, 1.00 equiv) was added to concentrated hydrochloric acid (3.0 mL, 12N). The resulting solution was stirred for 2 h at 80° C. in an oil bath. After concentrated under reducing pressure, the residue was washed with 30 mL of methanol. The solid was collected by filtration and dissolved in 5 ml of water. After adjusted the pH value to 11 with 1N sodium hydroxide (aq.), the solid was collected by filtration and dried in vacuo to provide the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ ppm 1.58-1.86(m, 3H), 1.95-1.96(m, 1H), 2.58-2.67(m, 2H), 2.78-2.81(m, 1H), 3.11-3.13(m, 1H), 3.65-3.67 (m, 8H), 4.08-4.12(m, 1H), 7.445-7.466(d, J=8.4 Hz, 1H), 7.943-7.980(d, J=14.8 Hz, 1H), 8.072-8.092 (d, J=8.0 Hz, 1H), 10.347-10.364(m, 1H); MS m/z [M+H]+ (ESI): 481. IRAK4 IC50=70 nM
Reaction SMILES: [CH2:1]1COCC1.[C:6]1([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].CI>O>[CH3:1][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(-c2ccccc2)cc2ccccc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
A solution of dry THF containing 2-phenylindole (1 mmole) was added NaH (1.1 mmole) and MeI (1.2 mmole, dropwise), and the reaction mixture was stirred at 65° C. for 3 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ether. The extracts was dried (MgSO4) and evaporated under reduced pressure to give yellow-orange solid. Further purification by column chromatography on silica gel with hexane as an eluent gave a pale yellow solid of 1-methyl-2-phenylindole (79% yield). The solid product (0.7 mmole) was dissolved in DMF (10 ml), a mixture of POCl3(0.09 mmole) and DMF (0.09 mmole) was added dropwise. After stirring at 75° C. for 1 h, the reaction mixture was added into saturate NaHCO3solution. The precipitated solid was collected by filtration and washed with ethanol to give a pale gray solid of 1-methyl-2-phenylindole-3-carboxaldehyde (85% yield). A dry DMF solution of the aldehyde (2 mmole) was added o-aminothiophenol (2.1 mmole) and Ac2O (0.5 ml) at room temperature. The mixture was stirred at 60° C. for 3 h. The reaction mixture was poured into stirred water and the precipitated solid was collected by filtration. The crude solid was washed with MeOH and recrystallized from benzene to afford compound 1-2 (38% yield). 1H-NMR (CDCl3, TMS) δ(ppm)=3.6 (s, 3H, —CH3), 7.3-7.8, 8.1, 8.9 (m, d, m, 13H, aromatic H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[N:8]1([C:6]2[N:7]=[C:2]([C:33]3[CH:34]=[C:29]([C:26](=[O:28])[CH3:27])[CH:30]=[CH:31][CH:32]=3)[CH:3]=[C:4]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(N3CCOCC3)n2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(-c2cc(Nc3ccc(OC(F)(F)F)cc3)nc(N3CCOCC3)n2)c1
Temperature: 30 °C
Yield: 49.7 %

Procedure:
To a mixture of compound (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.3 g, 0.8 mmol) and 3-acetyl benzene boronic acid (0.13 g, 0.79 mmol) in DMF (10 mL) was added palladium tetrakis triphenyl phosphine (0.027 g, 0.023 mmol) and 2M Na2CO3 soln (0.67 g, 6.32 mmol) at room temperature. The reaction mixture was then heated for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to temperature in the range of 20-40° C., diluted with water, extracted with ethyl acetate (3×10 mL). Combined organic layers were concentrated and the residue was purified by column chromatography using 15% ethylacetate in pet-ether to afford the desired compound (0.18 g, 49%) as a brown solid.