Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:14]([O:16]C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(#N)C>[CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCOCOCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCOCOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 84.6 %

Procedure:
(Step 3) To methyl (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoate (190 mg, 0.52 mmol) obtained in Step 2, acetonitrile (10 mL) and an aqueous sodium hydroxide solution (0.5 mol/L, 5.2 mL, 2.58 mmol) were added, and the resulting mixture, was stirred at room temperature for 5.5 hours. To the reaction mixture, Dowex 50 (registered trademark) (Muromachi Technos, 50WX8, 50-100 mesh, H+ form) was added thereto to neutralize the mixture, and the insoluble matter was removed by filtration, and then, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and then, the solvent was evaporated under reduced pressure, whereby (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoic acid (156 mg) was obtained.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1>N1C=CC=CC=1>[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:21]=[C:22]([NH:26][C:5](=[O:7])[CH3:6])[CH:23]=[CH:24][CH:25]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)cc(N)n(Cc2cccc(N)c2)c1=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(Cn2c(N)cc(=O)n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Using the general procedure for Intermediate 1, (3-nitrobenzyl)-urea [J. Med. Chem. 1996, 39, 1924 ] is converted into 6-amino-3-methyl-1-(3-nitro-benzyl)-1H-pyrimidine-2,4-dione, [M−H]− 275. A suspension of this compound (4.88 g, 17.7 mmol) and 10% Pd/C (0.484 g) in ethanol (200 ml) is hydrogenated at 1 atmosphere for 1.5 hours. The reaction mixture is filtered through a celite plug and evaporated to give 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt [M−H]− 245. Acetic anhydride (1.85 ml, 19.57 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (5.01 g, 16.35 mmol) in pyridine (50 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[3-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, 1H NMR (400 MHz, DMSO): δ: 2.00 (s 3H), 3.09 (s 3H), 4.72 (s 1H), 5.02 (s 2H), 6.75 (s 2H), 6.88 (d J 6 1H), 7.25 (t J 6 1H), 7.30 (s 1H), 7.55 (d J 6 1H). Using the general procedure for Intermediate 1, this compound is converted into N-[3-(5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide [MH]+ 304.
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH3:3].C(=O)([O-])O.[Na+].[C:17](#[N:19])[CH3:18]>>[CH3:18][C:17]1[O:6][C@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:4]([CH2:1][CH2:2][CH3:3])[N:19]=1
Reactant: CCC[C@H]1O[C@@H]1C(=O)OCC
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC[C@@H]1N=C(C)O[C@@H]1C(=O)OCC
Temperature: 5 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
Acetonitrile (5 ml) was added to ethyl (2S,3R)-3-propyl-2-oxiranecarboxylate (0.8 g, 5 mmol). The mixture was cooled to 5° C., and boron trifluoride diethyl ether complex (0.4 g, 5.5 mmol) was gradually added dropwise thereto. The mixture was stirred at room temperature for 6 hours, and then saturated aqueous solution of sodium hydrogencarbonate (15 ml) was added thereto. The mixture was concentrated, and was extracted with ethyl acetate (20 ml). The organic layer was washed twice with water (10 ml), and the solvent was evaporated away under reduced pressure. The concentrated matter was purified by silica gel column chromatography to obtain the title compound as a colorless oil (0.69 g, yield: 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][N:19]=2)[CH:15]=[CH:14][N:13]=1.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>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([F:11])[CH:17]=3)=[N:19][CH:20]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: NCc1ccc(-c2ccnc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-bromopicolinic acid 38-3 (309 mg, 1.53 mmol), (2′-fluoro-2,4′-bipyridin-5-yl)methanamine 38-2 (312 mg, 1.53 mmol) and HATU (582 mg, 1.53 mmol) in DMF (7 mL) was added DIEA (0.76 mL, 4.59 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol containing ˜7N ammonia in dichloromethane to give 5-bromo-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)picolinamide 38-4 as yellow solid. MS m/z 387.1 (M+1)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([C:24]2[C:25]([C:33]3[CH:34]=[C:35]([NH:39][C:40](=[O:49])[C:41]4[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=4[F:48])[CH:36]=[CH:37][CH:38]=3)=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)[CH:21]=[CH:20][N:19]=1>>[F:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:41]=1[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:25]2[C:24]([C:22]3[CH:21]=[CH:20][N:19]=[C:18]([NH:16][C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:11]=4)[N:23]=3)=[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]3[N:26]=2)[CH:34]=1)=[O:49]
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCOCC4)c3)n2)c1)c1c(F)cccc1F

Procedure:
The title compound was prepared from (3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)-amine and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide in a manner analogous to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.55 (s, 1H), 8.84 (d, 1H), 8.48 (d, 1H), 8.27 (d, 1H), 8.01 (s, 1H), 7.81 (d, 1H), 7.59 (m, 1H), 7.49 (m, 3H), 7.35 (d, 1H), 7.25 (m, 3H), 7.13 (t, 2H), 6.51 (d, 2H), 4.0 (m, 2H), 3.54 (m, 4H), 2.64 (m, 2H), 2.41 (m, 4H). HRMS calculated C36H32F2N7O3 [M+H]+ 648.2535, found 648.2528.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH3:6][C:7]([CH3:9])=[O:8]>>[C:1]([O:4][CH2:6][CH:7]1[CH2:9][O:8][C:7]([CH3:9])([CH3:6])[O:8]1)(=[S:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC([O-])=S
Agent: [K+]
Product: CC(=S)OCC1COC(C)(C)O1

Procedure:
A mixture of 13.3 g of the above product and 7.2 g of potassium thioacetate in 300 ml of acetone was refluxed for 10 hours. The resulting mixture was filtered, most of the solvent evaporated off under vacuum and the remaining solution poured into diethyl ether. The solution was washed with water, the organic solvent removed under vacuum and the residue distilled under vacuum, giving (±)2,2-dimethyl-1,3-dioxolan-4-ylmethyl thioacetate, having a boiling point between 83° C. and 87° C. at a pressure of 0.1 mm Hg.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:27]([O:31][C:32]([N:34]1[CH2:43][CH2:42][C:41]2[C:36](=[C:37]([C:44](O)=[O:45])[CH:38]=[CH:39][CH:40]=2)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([C:44]([C:37]4[CH:38]=[CH:39][CH:40]=[C:41]5[C:36]=4[CH2:35][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:43][CH2:42]5)=[O:45])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecane dihydrochloride (F-09) (0.49 g, 1.62 mmol) was dissolved in DMF and triethylamine (0.45 g, 3.25 mmol), and 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (0.45 g, 1.62 mmol) (available commercially from Ennova, for example) was added, followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.93 g, 2.11 mmol) and 4-methylmorpholine (0.53 g, 4.87 mmol). The reaction mixture was stirred for 15 h at RT, and then the solvent was removed in vacuo. The residue was taken up in ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with sat. sodium hydrogen carbonate solution and sat. sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol 20:1+ammonia solution (25% aq.)). Yield: 0.78 g (98%).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:30][CH:31]=[CH2:32])[C@H:19]([CH2:27][CH2:28][CH3:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].[CH3:35][C:36]1[CH:37]=[C:38](Br)[CH:39]=[CH:40][C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(#N)C>CN(C)C=O>[CH3:34][C:2]([CH3:1])([CH3:33])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:30]/[CH:31]=[CH:32]/[C:38]1[CH:39]=[CH:40][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:36]([CH3:35])[CH:37]=1)[C@H:19]([CH2:27][CH2:28][CH3:29])[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5]
Reactant: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@H](CCC)C(=O)OC(C)(C)C
Reactant: Cc1cc(Br)ccc1-c1ccccc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCC[C@H](C(=O)OC(C)(C)C)[C@@H](C/C=C/c1ccc(-c2ccccc2)c(C)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 62.6 %

Procedure:
According to the method of Preparation 3, tert-butyl (2S, 3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-(1-propyl)hex-5-enoate (543 mg, 1.15 mmol) was reacted with 3-methyl-4-phenylbromobenzene (356 mg, 1.44 mmol) under palladium catalysis in a mixture of anhydrous acetonitrile and dimethylformamide (2:5, 7 mL) at 90° C. for 17 h. The mixture was concentrated under reduced pressure, poured into ethyl acetate (100 mL) and washed with water (2×100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate) to give mainly tert-butyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]-2-(1-propyl)hex-5-enoate as a colourless gum (460 mg, 63%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see c, below).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[C:16]1([CH:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:24]2[CH2:25][CH2:26][O:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:15])=[CH:4][N:3]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCOC(c4ccccc4)C3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-phenylmorpholine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [CH3:1][C:2]([Mg]Br)=[CH:3][CH3:4].[F:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[F:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][CH2:13][C:14]2[N:15]=[CH:16][CH:17]=[C:18]3[C:3]([CH3:4])=[C:2]([CH3:1])[NH:20][C:19]=23)=[CH:10][CH:9]=1
Reactant: CC=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1COc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(COc3ccc(F)cc3)nccc2c1C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
1-Methyl-1-propenyl magnesium bromide (0.5 M in tetrahydrofuran solution, 1.7 ml, 0.851 mmol) was added at −78° C. to a solution of 2-(4-fluorophenoxymethyl)-3-nitropyridine (71 mg, 0.284 mmol) prepared in Preparation 1 in anhydrous tetrahydrofuran (5 ml). The reaction mixture was stirred overnight and a saturated ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate (15 ml). The organic layer washed with water (5 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 15 mg of the titled compound as brown oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:25][C:23]1([CH2:22][C:21]([O:27][CH2:28][CH3:29])=[O:26])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3
Reactant: CCOC(=O)CC(C)=O
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture consisting of 5-benzyloxytryptophol (4.5 g, 0.017 mol), benzene (200 mL), ethyl acetoacetate (3.4 g, 0.026 mol) and p-toluenesulfonic acid (0.5 g) is refluxed for 2.5 hours using a Dean-stock trap to remove the water. The reaction mixture is cooled to room temperature and washed with 5% sodium bicarbonate, (1×200 mL), water (200 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated to give 8.0 g of crude product as a thick oil, which is flash chromatographed on silica gel using 20% ethyl acetate/hexane as an eluent to afford 5.5 g oil which solidifies upon standing, m.p. 96°-98° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([S:10]([NH2:13])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([NH:32][C:33]2[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=2)[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1)([O-:16])=[O:15].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[N+:14]([C:17]1[CH:22]=[C:21]([C:2]2[S:6][C:5]([C:7]([S:10]([NH2:13])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=2)[CH:20]=[C:19]([NH:32][C:33]2[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=2)[CH:18]=1)([O-:16])=[O:15]
Reactant: CC(C)(c1ncc(Br)s1)S(N)(=O)=O
Reactant: CC1(C)OB(c2cc(Nc3nccc(C(F)(F)F)n3)cc([N+](=O)[O-])c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(c1ncc(-c2cc(Nc3nccc(C(F)(F)F)n3)cc([N+](=O)[O-])c2)s1)S(N)(=O)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
The product of Step 5 (174 mg, 0.61 mmol), N-[3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 12, 250 mg, 0.61 mmol), and PdCl2(dppf).CH2Cl2 (44.6 mg, 0.061 mmol) were combined in a flask, sealed, and purged with nitrogen (2×). Dioxane (3.6 mL) and 2 M Na2CO3 (0.91 mL, 1.83 mmol) were added, and the reaction was purged again with nitrogen (2×). The mixture was stirred in an oil bath at 100° C. for 4 h. The dark brown reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (dry load, 20-100% ethyl acetate in hexanes) afforded 220 mg (74%) of 2-[5-(3-nitro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propane-2-sulfonamide as a yellow solid. ESI: [M+H]+ m/z 489.0. 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.94 (d, J=4.9, 1H), 8.72 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.43 (d, J=4.9, 1H), 7.10 (s, 2H), 1.81 (s, 6H). rhSYK activity=++
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32]([S:34][CH3:35])=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.O.[OH:37]OS([O-])=O.[K+]>CO>[OH:1][C:2]1([C:29]2[S:33][C:32]([S:34]([CH3:35])=[O:37])=[N:31][CH:30]=2)[CH2:3][CH2:4][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:6][CH2:7]1
Reactant: CSc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
N-({1-[4-Hydroxy-4-(2-methylsulfanyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 45a, 100 mg, 0.19 mmol) in MeOH (1 mL) and water (1 mL) was treated with OXONE (Aldrich, 230 mg, 0.38 mmol) at room temperature for 6 hours. The reaction mixture was partitioned between DCM and saturate NaHCO3. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compounds as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.[CH:11]1([CH:14]=[O:15])[CH2:13][CH2:12]1.O>C1COCC1>[Cl:10][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:14]([CH:11]2[CH2:13][CH2:12]2)[OH:15])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)ccnc1Br
Reactant: O=CC1CC1
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Cl)ccnc1C(O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
2-bromo-4-chloro-3-methoxy-pyridine (2.97 g, 13.4 mmol) was added to THF (dry) (100 ml) and cooled to 0° C. Isopropylmagnesium chloride-lithium chloride complex (13.5 ml, 17.6 mmol) was added and the reaction mixture stirred for 0.5 h at room temperature. The mixture was cooled to 0° C., cyclopropanecarboxaldehyde (1.297 ml, 17.4 mmol) was added and the reaction mixture stirred for 1 h at room temperature. The mixture was cooled to 0° C., water (72.3 ml, 4 mol) was added and the reaction mixture stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (3×75 mL), the organic phase dried over sodium sulfate, filtered and evaporated to dryness to obtain crude product which was purified over silica gel using 0:1 to 1:0 ethyl acetate in heptane to obtain (4-chloro-3-methoxy-2-pyridyl)-cyclopropyl-methanol as a yellow oil (2.4 g, 70%)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH2:45][CH2:46][CH3:47])[C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH2:45][CH2:46][CH3:47])[C:35]([NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCCC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CCCC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-n-butylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>C1(C)C=CC=CC=1>[C:14]([CH2:16][C:17]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:18])([OH:15])=[O:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)Nc1ccc(C(=O)O)cc1
Yield: 92.1 %

Procedure:
4-Aminobenzoic acid (0.50 g, 3.6 mmol) was added to a solution of Meldrum's acid (0.63 g, 4.4 mmol) in toluene (5.0 mL) and treated according to Procedure 1. 4-[(Carboxyacetyl)amino]benzoic acid (0.74 g, 91%) was obtained as a colourless solid; δH (400 MHz, DMSO-d6) 3.38 (br s, 2H, CH2), 7.68 (t, J2,3=J5,6=8.0 Hz, 1H, H2, H6), 7.89 (d, J2,3=J5,6=8.0, 1H, H3, H5), 10.44 (s, 1H, NH), 12.70 (br s, 1H, CO2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:30]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:30])[C:18]([NH:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:24][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A suspension of trans (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4-methanesulfonyl-cyclohexyl)-amine (585 mg, 1.20 mmol) and ethanol (4 mL, IMS grade) was treated with water (1.3 mL) followed by ammonium chloride (393 mg, 7.30 mmol) and iron powder (274 mg, 4.90 mmol). The mixture was heated to 80° C. for 45 minutes. The resulting solid was isolated and washed repeatedly with ethanol/water. The filtrate was partially concentrated under vacuum and then diluted with DCM and water. The phases were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum to give 505 mg (92%) of trans 1-benzenesulfonyl-N*4*-(4-methanesulfonyl-cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine as a pale brown solid that was used without further purification. 1H NMR (400 MHz, DMSO) δ: 8.01 (dd, 2H), 7.70-7.64 (m, 1H), 7.55 (m, 3H), 7.47 (d, 1H), 6.76 (d, 1H), 5.13 (d, 1H), 3.72 (br s, 1H), 3.06 (m, 1H), 2.93 (s, 3H), 2.09 (m, 4H), 1.63 (m, 2H), 1.33 (m, 2H).