Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[CH2:4][O:3]1.C(O)C.Cl[CH:21]([CH:27]=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:16])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][N:15]=[C:11]3[CH:10]=2)[CH2:4][O:3]1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CC1(C)OCC(COc2ccnc(N)c2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(OCC3COC(C)(C)O3)ccn12
Temperature: 60 °C

Procedure:
4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine (5.6 g, 0.025 mol) was mixed with ethanol (60 mL) in a reaction flask under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene; 93 mL; Commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 2 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (200 mL) and sodium bicarbonate solution (100 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (50 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica gel, eluting with ethyl acetate to give ethyl 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (5.76 g).
Reaction SMILES: [Br:1][C:2]1([Br:20])[C:4]2([CH2:8][C@@H:7]([C:9]([O:11]C)=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]2)[CH2:3]1>C1COCC1.CO.O>[Br:20][C:2]1([Br:1])[C:4]2([CH2:8][C@@H:7]([C:9]([OH:11])=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:5]2)[CH2:3]1
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OC(C)(C)C)CC2(Br)Br
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(C[C@H]1C(=O)O)CC2(Br)Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (6S)-5-tert-butyl 6-methyl 1,1-dibromo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (3.05 g, 7.39 mmol) in THF-MeOH-water (35 mL, 14 mL and 14 mL respectively) was added LiOH monohydrate (930 mg, 3 eq). The mixture was stirred at room temperature for 1.5 hr before being evaporated off. The aqueous residue was acidified with 1M HCl, extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated to give the title compound (quantitative yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3): 10.45 (br s, 1H), 4.65-4.45 (m, 1H), 3.99-3.86 (m, 1H), 3.53-3.31 (m, 1H), 2.87-1.95 (m, 2H), 1.86-1.73 (m, 2H), 1.49, 1.48 and 1.44 (3 s, 9H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:7][CH2:8][CH3:9].[C:19](=[O:21])=[O:20].CCOCC>C1COCC1>[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([F:18])[C:14]([C:19]([OH:21])=[O:20])=[C:15]([F:17])[CH:16]=1)[CH2:7][CH2:8][CH3:9]
Reactant: O=C=O
Reactant: CCCCOc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCOc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.5M in hexane; 3.60 ml, 0.038 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 16 (7.00 g, 0.038 mol) in dry THF (35 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured onto a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide which was then acidified with 36% hydrochloric acid. The product was filtered off and dried (CaCl2) in vacuo to give a colourless solid.
Reaction SMILES: Br[CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5].[N-:8]=[N+:9]=[N-:10].[Na+]>CS(C)=O>[N:8]([CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5])=[N+:9]=[N-:10]
Reactant: O=C(O)C(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
KY-740 3-bromo-2-oxopropanoic acid (1.66 gr, 10 mmol) was added to a solution of sodium azide (0.715 gr, 11 mmol) in DMSO (20 ml) which was prepared by stirring the sodium azide in DMSO at room temperature for 40 min. the mixture reaction was stirred for 2 h at room temperature. It was quenched with water (50 ml). The mixture was extracted with Et2O (3×100 ml). The combined organic layers were washed with water, dried with Na2SO4, filtered, and concentrated in vacuo. Yield 1.1 gr (85%). 1HNMR (400 MHz, DMSO-d6) δ 6.3 (s, 2H). 13C-NMR δ 113.52, 136.31, 165.3.
Reaction SMILES: [CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16](O)=[O:17])=[C:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>ClCCl>[CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16]([N:42]([O:43][CH3:44])[CH3:41])=[O:17])=[C:12]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CNOC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2.83 h

Procedure:
To a solution of (E)-3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-acrylic acid (2.0 g, 6.0 mmol) in dichloromethane (25 ml) at −5° C. is added triethylamine (0.668 g, 6.6 mmol).and pivaloyl chloride (0.725 g, 6.0 mmol). After stirring at 0° C. for 170 min, N,O-dimethyl-hydroxylamine hydrochloride (0.59 g, 6.0 mmol) and triethylamine (1.22 g, 12.0 mmol) are added. After stirring in an ice bath for 90 min, and at room temperature for 30 min, more N,O-dimethylhydroxylamine hydrochloride (0.177 g, 1.8 mmol) is added and the reaction is stirred at room temperature for 17 h. After quenching with 0.2M citrate buffer pH5 (25 ml), the organic phase is separated and washed with 0.2M citrate buffer pH5 (25 ml), 0.2M phosphate buffer pH7 (25 ml) and water (25 ml). The water phases are extracted with dichloromethane (2×20 ml). Combined organic phases are dried over magnesium sulphate, evaporated, and the crude product chromatographed on silica gel (hexane/ethyl acetate 2:1) to afford (E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-N-methoxy-N-methyl-acrylamide (7). MS (ES): [M+H]+ 377, Mp. 155-156° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([N+:20]([O-:22])=[O:21])[C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=2)=[C:4]([N+:20]([O-:22])=[O:21])[C:3]=1[C:23]#[N:24]
Reactant: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
To a biphasic solution of methyl 5-chloro-4-cyano-3-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (3.60 g, 9.26 mmol) and (3-fluorophenyl)boronic acid (1.42 g, 10.2 mmol) in toluene (80 mL) was added saturated NaHCO3 (80 mL) and then the reaction was bubbled with N2 to degas. Tetrakis(triphenylphosphine)palladium(0) (0.535 g, 0.463 mmol) was added. The resulting mixture was bubbled with N2 for 5 minutes and then heated at 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified on silica gel column, eluting with ethyl acetate/hexane, 0-30%, to give the desired product (1.23 g, 40%). LCMS calculated for C15H9ClFN2O4 (M+H)+: m/z=335.0; Found: 335.1. 1H NMR (CDCl3, 400 MHz) δ 8.14 (1H, s), 7.40 (1H, m), 7.20 (1H, m), 6.97 (1H, m), 6.93 (1H, m), 3.66 (3H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9])=[C:4]([CH3:17])[CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8]([OH:10])=[O:9])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(F)ccc1OC(C)(C)C(=O)O
Reaction time: 8 h

Procedure:
A solution of 4-fluoro-2-methylphenol (10 g, 79.28 mmol), ethyl 2-bromoisobutyrate (23.2 mL, 158.6 mmol), potassium carbonate (21.9 g, 158.6 mmol), and DMSO (80 mL) was stirred at room temperature for 72 hours. Water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to afford ethyl 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoate. To a solution of ethyl 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoate (13.3 g, 55.44 mmol) in tetrahydrofuran (40 mL) and methanol (10 mL) was added NaOH (6.66 g, 166.32 mmol) in water (14 mL) and stirred overnight. The volatiles were removed in vacuo and acidified with concentrated HCl. The milky white solution was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoic acid (658) as a yellow solid.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:37][CH2:38][C:39]1([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:9]([O:8][C:6]([NH:1][CH2:2][C:3]([N:42]1[CH2:43][CH2:44][C:39]([CH2:38][OH:37])([C:45]([O:47][CH3:48])=[O:46])[CH2:40][CH2:41]1)=[O:5])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C1(CO)CCNCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(CO)CCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of Boc-Gly-OH (331 mg, 1.89 mmol, 1.1 equiv.) in DMF (1 mL) was added HBTU (718 mg, 1.89 mmol, 1.1 equiv.), followed by addition of methyl 4-(hydroxymethyl)piperidine-4-carboxylate (1.72 mmol, 1 equiv.) and DIEA (749 μL, 4.30 mmol, 2.5 equiv.) at rt. The reaction mixture was stirred for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed by saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by column chromatography to give methyl 1-(2-(tert-butoxycarbonylamino)acetyl)-4-(hydroxymethyl)piperidine-4-carboxylate (560 mg, 98%, two steps). LRMS (M-Boc+H+) m/z 231.1.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.Cl.Cl.[OH:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([C@@H:63]2[CH2:67][C@H:66]([SH:68])[CH2:65][NH:64]2)[CH2:59][CH2:58]1>C(#N)C>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:68][C@@H:66]3[CH2:65][NH:64][C@H:63]([CH:60]4[CH2:59][CH2:58][N:57]([CH2:56][CH2:55][OH:54])[CH2:62][CH2:61]4)[CH2:67]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: OCCN1CCC([C@@H]2C[C@H](S)CN2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CN[C@H](C4CCN(CCO)CC4)C3)[C@H](C)[C@H]12
Reaction time: 19 h
Yield: 55.3 %

Procedure:
To a solution of p-nitrobenzyl (1R, 5S, 6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (8.92 g, 15 mmol) in acetonitrile (600 ml), N,N-diisopropylethylamine (10.7 ml, 61.5 mmol) was added under cooling with ice and (2S, 4S)-2-[N-(2-hydroxyethyl)piperidin-4-yl]-4-mercaptopyrrolidine dihydrochloride (4.80 g, 15.8 mmol) was further added in limited amount. After the mixture was stirred at the same temperature for 19 hours, the reaction solution was concentrated to a volume of 300 ml and stirred under cooling with ice for 2 hours. Precipitates were collected by filtration and washed with acetonitrile, followed by drying to obtain p-nitrobenzyl (1R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-2-[(2S, 4S)-2-[N-(2-hydroxyethyl)piperidin-4-yl]pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (4.77g, yield: 55.4%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38])#[N:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([C:32]#[N:33])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Yield: 96.2 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 69 mg (0.514 mmol) of 3-cyanobenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (250 mg, 96%) is obtained as white foam. TLC: methylene chloride/methanol/cone. ammonia (700:50:1) Rf =0.53, FD-MS: M+ =556.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:13][O:14][CH:15]([O:19][CH3:20])N(C)C>>[CH3:13][O:14][CH:15]([O:19][CH3:20])[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:8][CH2:9]1
Reactant: c1cn(CC2CCNCC2)cn1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(Cn2ccnc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[(1H-imidazol-1-yl)methyl]-piperidine (5 g, 0.03M) and dimethylformamide dimethylacetal (40 ml) was heated at 100° C. for 8 hrs. Removal of the excess of dimethylformamide dimethylacetal gave 4-[(imidazol-1-yl)methyl]-1-piperidine carboxaldehyde dimethylacetal (6.33 g) which was dissolved in methylene chloride (25 ml) and added to the mixture of 6-aminopenicillanic acid (5.15 g, 0.024M) and diisopropylethylamine (3.14 ml) in methylene chloride (90 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs. The solvent was then removed and water (80 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-1-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-6 -oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (5.2 g, 55% yield).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][C@@H:62]([CH2:76][C:77]1[CH:82]=[C:81]([F:83])[CH:80]=[C:79]([F:84])[CH:78]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1>C(Cl)Cl>[F:83][C:81]1[CH:82]=[C:77]([CH:78]=[C:79]([F:84])[CH:80]=1)[CH2:76][C@H:62]([NH:61][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:25][CH2:26][CH3:27])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:63]([OH:75])[CH2:64][NH:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][CH3:74])[CH:68]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccn2COCC)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2nccn2COCC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-[(dipropylamino)carbonyl]-5-[1-(ethoxymethyl)-1H-imidazol-2-yl]benzoic acid (177 mg, 0.47 mmol), diisopropylethylamine (651 mg, 0.5 mmol), and HBTU (209 mg, 0.55 mmol) in methylene chloride (5 mL) is added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (196 mg, 0.48 mmol) and diisopropylethylamine (130 mg, 1.0 mmol) in methylene chloride (5 mL). The reaction mixture is stirred at room temperature for 15 h and concentrated under reduced pressure. The residue is diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 methanol/methylene chloride) provides the title compound. APCI MS m/z 690.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][C:5]([NH2:17])=[C:4]([N+:18]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: Nc1cc(OCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(OCCN2CCCCC2)cc1N
Yield: 95.9 %

Procedure:
443 mg of 4-fluoro-2-nitro-5-(2-piperidin-1-ylethoxy)-phenylamine in solution in 20 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 44 mg of palladium-on-charcoal at 25° C. for 10 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 380 mg of 4-fluoro-5-(2-piperidin-1-ylethoxy)benzene-1,2-diamine are obtained in the form of a black lake. The compound is used without any other purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:24][CH3:25])=[N:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[C:18]([Si](C)(C)C)[N:17]=[N:16]3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.N(CC1C=C(C2C=CC=C(Cl)C=2)C(OC)=NC=1)=[N+]=[N-].C([Si](C)(C)C)#C.C(N(C(C)C)CC)(C)C>C1COCC1.O.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:24][CH3:25])=[N:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(Cn2cc([Si](C)(C)C)nn2)cc1-c1cccc(Cl)c1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Agent: COc1ncc(CN=[N+]=[N-])cc1-c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(Cn2ccnn2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
3-(3-Chlorophenyl)-2-methoxy-5-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine. To a solution of 5-(azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (directly used from previous reaction) and ethynyltrimethylsilane (75.1 mg, 0.77 mmol) in THF (3 mL), water (1 mL), was added copper (I) iodide (19.4 mg, 0.10 mmol) and diisopropylethylamine (132 mg, 1.02 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted in to DCM. The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification (FCC, SiO2, 0-50% EtOAc/hexanes) afforded the title compound (92 mg, 48%). [M+H]=373.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:26])([F:25])[CH2:12]OC1C=C(S([O-])(=O)=O)C=CC=1C.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][C:11]([F:26])([F:25])[F:10]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1OCC(F)(F)F
Reactant: Oc1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 110 °C

Procedure:
To a solution of 2-bromo-4-fluorophenol (4 g) and 2,2,2-trifluoroethoxy-p-toluene sulphonate (5 g) in dimethylformamide (40 ml) was slowly added sodium hydride (1 g, 60% in oil) and the mixture then heated at 110° C. for 12 h. The solution was cooled, diluted with water (500 ml) and the product extracted into ethyl acetate (2×150 ml). The organic phase was washed with saturated NaHCO3 solution, water, saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue was chromatographed on silica gel (eluting with diethyl ether/hexane (1:5)) to give the title compound as a colourless oil. 1H NMR (250 MHz, CDCl3) δ4.36 (2H, q, J 8 Hz), 6.91-7.05 (2H, m), and 7.33 (1H, dd, J 8, 3 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[N:51]1([C:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[N:60]=[CH:59][N:58]=2)[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:12](=[O:14])[N:54]1[CH2:55][CH2:56][N:51]([C:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[N:60]=[CH:59][N:58]=2)[CH2:52][CH2:53]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Reactant: Cc1ccc(CC(CCNC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(CC(CCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ncnc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution containing 4-tert-Butoxycarbonylamino-2-(4-methylbenzyl)-butyric acid (0.24 g, 0.77 mmol) in 25 mL of DMF under a nitrogen atmosphere was added EDCI (0.16 g, 0.84 mmol), HOBT (130 mg, 0.84 mmol) and NMM (0.28 g, 2.8 mmol.) After stirring at room temperature for 15 minutes, 4-Piperazin-1-yl-quinazoline (200 mg, 0.93 mmol) was added and the reaction allowed to stir at room temperature. The reaction was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate and water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 10% MeOH/DCM gave [3-(4-Methyl-benzyl)-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (0.225 g, 64%) as a white solid. LCMS (APCI+) m/z 504 [M+H]+; Rt: 3.03 min. 1H NMR (CDCl3, 400 MHz) δ 3.8.69 (1H, s), 7.92 (1H, d, J 8.3 Hz), 7.76-7.71 (2H, m), 7.45 (1H, t, J 7.8 Hz), 7.06 (4H, m), 4.53 (1H, br. s), 3.96-3.76 (2H, m), 3.63-3.54 (2H, m), 3.47-3.40 (2H, m), 3.24-2.84 (6H, m), 2.76-2.70 (1H, m), 2.27 (3H, s), 2.09-2.00 (1H, m), 1.73-1.65 (1H, m), 1.40 (9H, s.)