Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.C(N(CC)CC)C>C1COCC1.O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][N:7]1[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]1
Reactant: FC(F)(F)C1CCNCC1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1CCC(C(F)(F)F)CC1
Yield: 99.7 %

Procedure:
To a solution of 4-trifluoromethylpiperidine hydrochloride (1 g, 5.3 mmol) in THF (20 mL) was added methylbromoacetate (0.52 mL, 5.5 mmol) and triethylamine (2.2 mL, 15.8 mmol). The reaction was heated at reflux for 4 h and then diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester as a brown oil (1.19 g, 98%). MS 226 (M+H)+. To a solution of (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester (1.19 g, 5.3 mmol) in THF (15 mL) at 0° C. was added portion wise lithium aluminium hydride (0.4 g, 10.6 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4-trifluoromethylpiperidin-1-yl)-ethanol as a brown oil (1.0 g, 99%). MS 198 (M+H)+. To a solution of diisopropylazodicarboxylate (0.58 mL, 2.28 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (1.14 g, 3.4 mmol). The reaction was stirred at RT for 10 mins. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0.47 g, 2.3 mmol) and 2-(4-trifluoromethylpiperidin-1-yl)-ethanol (0.45 g, 2.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (548 mg, 62%). MS 386 (M+H)+. To a solution of 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (548 mg, 1.42 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 2.84 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 358 (M+H)+ which was used directly for coupling with H2N-Leu-P1.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][O:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: COCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (84 mg, 84%), MS (ISP) m/z=401.5 [(M+H)+], mp 156° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and methoxy-acetic acid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[C:24]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([C:4]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:2]([NH:35][CH2:34][CH2:33][CH2:32][NH:31][C:24](=[O:25])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:3]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Yield: 96 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (1.6 g, 1 eq), N-Boc-1,3-diaminopropane (0.9 g, 1.2 eq) and potassium carbonate (1.35 g, 2 eq) in acetonitrile (80 ml) is heated under reflux for 5 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (100 ml) and water (40 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 6:4) produces the expected compound in the form of a yellow oil (2.2 g; 96% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[Cl:27][CH2:23][CH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:12]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2C(CO)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCl)CCC2c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
A stirred mixture of (2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol (1.25 g, 3.58 mmol) and thionyl chloride (2 ml) was heated for 4 h at 80° C. aqueous work-up and crystallization from ethyl acetate/hexane yielded the title compound as an off-white solid (1.12 g, yield 85%), m.p. 130° C. and MS: m/e=367 (M+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[BrH:15].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:15][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Br
Reactant: Nc1ccc(Sc2ccccc2)cn1
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc(Sc2ccccc2)cn1
Reaction time: 1 h

Procedure:
2-Amino-5-(phenylthio)pyridine (16.9 g., 0.1 mole) is added to 40 ml. of 48% hydrobromic acid, cooled to 10° C in an ice bath. While maintaining a temperature of 0°, the resultant hydrobromide salt is treated with 37.5 g. of bromine dropwise. The temperature is reduced and maintained at -10° while 14.0 g. of sodium nitrite in 200 ml. of water is added dropwise. After 1 hour at 0° C, the pH of the reaction mixture is adjusted to pH7 with 30% aqueous sodium hydroxide. Following the same workup as for the 2-chloro ananlogue, there is obtained 2-bromo-5-(phenylthio) pyridine.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C.[Cl-].[Na+]>C1COCC1>[CH:19]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1)=[O:20]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C#N
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-bromo-2-methylbenzonitrile (4.0 g, 20 mmol) in 100 mL of anhydrous THF was added BuLi (1.6 M, 12.8 mL) dropwise at −78° C. under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at −78° C. and dry DMF (2.2 mL) then added dropwise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (100 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 4-formyl-2-methylbenzonitrile. MS m/z: 146 (M+1)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[N:11](COCC[Si](C)(C)C)[CH:10]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([CH3:50])(=[O:48])=[O:49])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccc(NS(C)(=O)=O)cc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 464.4 %

Procedure:
(S)—N-(3-Methoxy-4-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (159 mg, 0.02 mmol) was treated with boron tribromide (1M in dichloromethane, 0.61 ml, 0.61 mmol) in dichloromethane (1 ml) as a solvent and then with a solution of ammonia (7N in methanol, 4 ml, 28 mmol) according to the method described in Example 41 to give 53 mg (46% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9].[OH:15]O>>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9])=[O:15]
Reactant: CCCCc1c[nH]c(SC)c1[N+](=O)[O-]
Reactant: OO
Product: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Yield: 40.2 %

Procedure:
2-Methylthio-3-nitro-4-n-butylpyrrole (3.7 g) was suspended in glacial acid (50 ml) and 30% hydrogen peroxide (1.62 g) was added. The mixture was heated to 80° for 7 hours, and it was then evaporated to a brown oil. The crude product was purified by column chromatography using silica gel, eluted with benzene and chloroform, to give an oil which crystallized on standing. This was recrystallised from 2-propanol to give 2-methylsulphinyl-3-nitro-4-n-butylpyrrole (1.6 g), m.p. 133°-4°.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH2:28][C:29]([OH:31])=[O:30])=[CH:18][CH:17]=1>>[CH2:1]([O:31][C:29](=[O:30])[CH2:28][C:23]1[C:24]([CH3:27])=[N:25][O:26][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl bromide (0.491 mL, 4.13 mmol) and cesium carbonate (1.68 g, 5.16 mmol) were added to [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid (1.02 g, 3.44 mmol) and the reaction stirred at room temperature. After two hours, a second aliquot of benzyl bromide (0.100 mL) was added. When the reaction was complete by analytical LCMS it was submitted to standard aqueous workup to obtain the title compound.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(=O)C.[Na+]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]([NH2:17])[S:16][C:2]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C(C)Br)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)sc2C)cc1
Yield: 66.8 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 4 hours, followed by post-treatment to give a crude product, which was recrystallized with anhydrous ethanol to obtain a product as a white solid in a yield of 66.8%, mp: 139-140 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.37 (3H, s, ArCH3), 3.84 (3H, s, OCH3), 5.09 (2H, br, NH2), 6.93 (2H, d, J=8.68 Hz, ArH), 7.50 (2H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 220.1 (M+, 100), 205.1 (18), 163.1 (31); HREI-MS Calcd. for C11H12N2OS: 220.0670. found: 220.0672. Anal. Calcd. for C11H12N2OS: C, 59.98; H, 5.49; N, 12.72. found: C, 59.90; H, 5.52; N, 12.55.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C@@H:20]1[CH2:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]1[OH:28]>CN(C)C=O.O>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:19][C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]2[OH:28])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a solution of 4-amino-6-chloro-5-nitropyrimidine (320 mg, 1.83 mmol) in N,N-dimethyl formamide (5 mL) and triethylamine (512 μL, 3.67 mmol) was added (1R,2S,3R,5R)-3-Amino-5-hydroxymethyl-cyclopentane-1,2-diol (293 mg, 2.02 mmol). The mixture was stirred at room temperature and monitored by thin layer chromatography until starting material was no longer detected. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (2×10 mL). The organic extract was washed with saturated aqueous sodium chloride (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was recrystallized from hot methanol/water to give a 298 mg of (1R,2S,3R,5R)-3-(6-amino-5-nitro-pyrimidin-4-ylamino)-5-hydroxymethyl-cyclopentane-1,2-diol as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[N:7]=[C:8]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:9]2[O:10][CH:11]([NH2:17])[C:12](=[O:16])[NH:13][C:14]=2[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:3]([CH2:2][N:13]1[C:12](=[O:16])[CH:11]([NH2:17])[O:10][C:9]2[C:8]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:7][C:6]([CH3:5])=[N:15][C:14]1=2)#[N:4]
Reactant: N#CCCl
Reactant: Cc1nc(CCN2CCOCC2)c2c(n1)NC(=O)C(N)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1nc(CCN2CCOCC2)c2c(n1)N(CC#N)C(=O)C(N)O2
Yield: 91.3 %

Procedure:
0.25 g of chloroacetonitrile dissolved in 50 ml of methyl ethyl ketone is dropped within 15 minutes to a suspension containing 0.88 g of 2-methyl-4-[2-(4-morpholinyl)-ethyl]-amino-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one base (e.g. prepared as described in Example 23) and 0.5 g of anhydrous potassium carbonate in 15 ml of methyl ethyl ketone under boiling and stirring. The mixture is further boiled under stirring for 8 hours, the precipitate is filtered as hot and washed with methyl ethyl ketone. The filtrate is evaporated and the residue is triturated with diisopropyl ether. After filtering, the solid is washed with diisopropyl ether and dried to give 0.91 g (91%) of the product, m.p.: 126°-128° C.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(C)(C)C.[F-:27].[CH2:28]([N+:32]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>O1CCCC1.C(OCC)C>[F:22][C:21]([S:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]2)=[CH:19][CH:18]=1)([F:24])[F:23].[F-:27].[CH2:41]([N+:32]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:42][CH2:43][CH3:44]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ccc(SC(F)(F)F)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@H]1CC[C@H](Nc2ccc(SC(F)(F)F)cc2)CC1
Temperature: 40 °C

Procedure:
[Trans-4-(tert-butyl-dimethyl-silyloxy)-cyclohexyl]-(4-trifluoromethylsulfanyl-phenyl)-amine (180 mg, 0.44 mmol, prepared in accordance with Example 28) was dissolved in tetrahydrofuran (3 mL). A molar solution of tetrabutylammonium fluoride (500 μL, 5 mmol) was then added. The resulting mixture was heated to 40° C. and then maintained at that temperature for 4 hr. After cooling to room temperature, the mixture was diluted with diethylether (20 mL), washed with water (10 mL), and washed with saturated aqueous hydrogencarbonate (10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The oily residue obtained was purified by column chromatography on silica gel (dichloromethane and then dichloromethane/methanol, 95:5). The desired product was isolated as a colorless oil with traces of tetrabutylammonium fluoride.
Reaction SMILES: C[Si](C)(C)Cl.C(N(CC)CC)C.C(O)(=O)C.[CH3:17][Si:18]([CH3:36])([CH3:35])[N:19]1[C@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:21]([O:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]1=[O:34]>>[CH3:17][Si:18]([CH3:36])([CH3:35])[N:19]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]([O:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]1=[O:34]
Reactant: C[Si](C)(C)O[C@@H]1C(=O)N([Si](C)(C)C)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C[Si](C)(C)OC1C(=O)N([Si](C)(C)C)C1c1ccccc1

Procedure:
A one-pot procedure for the synthesis of previously unreported N-trimethylsilyl beta-lactam from the trimethylsilyl-2-trimethylsiloxy-acetate has been discovered to be an efficient economical method not requiring cryogenic cooling. To a magnetically stirring solution of hexamethyldisilazane (390 g, 2.42 mol) in dry 1,2-dimethoxyethane (505 mL) under nitrogen with a circulation chiller at 0° C. was added a 2.5 M solution of n-butyllithium (840 mL, 2.1 mol) at a rate so as to control the exothermic reaction temperature to <30° C. (over 45 min) to generate the required LHMDS base in situ. Once the LHMDS solution temperature has reached <10° C., a neat mixture of TMSCl (119.5 g, 1.1 mol) and the trimethylsilyl-2-(trimethylsiloxy)acetate (240 g, 1.1 mol) was added over 15 minutes to give the tris(trimethylsiloxy)ethene in situ. Then neat benzaldehyde (106.12 g, 1.0 mol) was added at a rate so as to control the exothermic reaction temperature to <25° C. to give the N-trimethylsilyl-benzaldimine in situ. The mixture was allowed to react at ambient temperature (22° C.) until 1HNMR monitoring indicated that the disappearance of the ketene acetal resonance at 5.4 ppm (CDCl3) occurred at 12 h of reaction time. The reaction mixture was quenched with trimethylchlorosilane (TMSCl, 108.64 g, 1.0 mol), triethylamine (25.3 g, 0.25 mol) followed by acetic acid (6.0 g, 0.1 mol) while keeping the exothermic reaction temperature to <22° C. The mixture was diluted with hexanes (500 mL) and the resulting lithium chloride salt was filtered off through a pad of celite (200 g) followed by filter cake washing with hexanes (250 mL). The filtrate was concentrated under rotary vacuum evaporation to a residue. The residue was taken up in hexanes (500 mL) and allowed to stand at −25° C. to induce crystal formation. The white crystals were collected by vacuum filtration, washed with cold −20° C. hexanes (200 mL), and dried to a constant weight of 152 g. The filtrate was concentrated to a residue, taken up in hexanes (200 mL), and recrystallized as previous to give a second crop of 32 g. The crops were combined (184 g, 60% yield) after HNMR analysis to be pure cis-N-trimethylsilyl-3-trimethylsiloxy-4-phenyl-azetidin-2-one. Mp: 53 to 55° C. 1H NMR (400 MHz, CDCl3) δ (ppm): 0.11 (s, 9H), 0.14 (s, 9H), 4.63 (d, J=5.01 Hz, 1H), 5.06 (d, J=5.01 Hz, 1H), 7.31 (m, 5H).
Reaction SMILES: [F:1][C:2]1([C:8]2[S:9][C:10]([C:13]3[CH:14]=[C:15]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][N:12]=2)[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.[OH2:31].[OH2:32].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>C(Cl)Cl.CO.[O-]S([O-])(=S)=O.[Na+].[Na+].O>[F:1][C:2]1([C:8]2[S:9][C:10]([C:13]3[CH:14]=[C:15]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][N:22]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:4][S:5](=[O:32])(=[O:31])[CH2:6][CH2:7]1
Reactant: O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(F)CCSCC3)s2)c1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=S([O-])([O-])=S
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(F)CCS(=O)(=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
N-{3-[2-(4-fluorotetrahydro-2H-thiopyran-4-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 132, 140 mg, 0.308 mmol) was dissolved in a 2:1 v/v CH2Cl2/MeOH mixture (6 mL) and magnesium monoperoxyphthalate hexahydrate (286 mg, 0.462 mmol) was added. The reaction was stirred at room temperature for 2 hrs, diluted with aqueous 10% Na2S2O3 and water and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Column chromatography on silica (gradient elution, 0 to 50% EtOAc in hexanes) afforded the title compound (0.118 g, 0.243 mmol, 79% yield) as a white solid. MS ESI: [M+H]+ m/z 487.0. 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.84 (d, J=4.9, 1H), 8.14 (d, J=2.7, 1H), 8.04 (bs, 1H), 7.48 (bs, 1H), 7.29 (d, J=4.9, 1H), 7.22 (bs, 1H), 3.48-3.40 (m, 2H), 3.28-3.24 (m, 2H), 2.75-2.60 (m, 4H), 2.32 (s, 3H). rhSYK activity=+++.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:10].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C1(C)C=CC=CC=1>[Br:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[NH:1][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N#Cc1ccc(N)c(Br)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(C#N)cc1Br)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 5.00 g (25.4 mmol) 4-amino-3-bromobenzonitrile in 30 mL of toluene was added 8.23 g (38.1 mmol) of diethyl ethoxymethylenemalonate (2a). The mixture was then heated to reflux for overnight with a condenser open to the air. The resulting solution was cooled down to room temperature and poured into 100 mL of hexanes. The white precipitate was collected and washed with hexanes (30 mL×3) to yield 11.9 g of an off-while solid as the desired product. MS ESI (m/z) 367 (M+1)+.