Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:11]=[CH2:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:29]12([CH2:39][NH:40][C:41](=[O:50])[C:42]3[C:47]([Cl:48])=[CH:46][N:45]=[C:44](Cl)[CH:43]=3)[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>O.CN(C)C=O>[C:29]12([CH2:39][NH:40][C:41](=[O:50])[C:42]3[C:47]([Cl:48])=[CH:46][N:45]=[C:44]([CH2:12][CH2:11][CH2:10][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:43]=3)[CH2:30][CH:31]3[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]3)[CH2:36]1)[CH2:38]2
Reactant: C=CCO[Si](C)(C)C(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: 60 °C
Yield: 248.6 %

Procedure:
A solution of 9-borabicyclo[3.3.1]nonane at 0.5 M in tetrthydrofuran (2.78 mL, 1.39 mmol) was added to neat (allyloxy)(tert-butyl)dimethylsilane (0.15 mL, 0.69 mmole). The mixture was heated to 60° C. for 2 hours under nitrogen. The reaction was subsequently cooled to room temperature and a solution of potassium phosphate (0.37 g) in water (1 mL) was added slowly. A solution of N-(1-adamantylmethyl)-2,5-dichloroisonicotinamide (0.20 g, 0.59 mmol; prepared as described in WO 01/94338) in dimethylformamide (3 mL) was added followed by tetrakis(triphenyphosphine)palladium (0) (7 mg). The solution was heated to 70° C. for 2 hours; allowed to cool to room temperature then partitioned between ethyl acetate (20 mL) and brine (10 mL). The aqueous phase was further extracted with ethyl acetate (2×20 mL) and the combined organics were washed with brine (20 mL); dried over magnesium sulphate; filtered and evaporated under vacuum to give the crude product (0.70 g) as a yellow oil, which was used, as such, without any further purification.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.O.[C:12](=O)([O-])[O-].[Na+].[Na+].CI>O.C(O)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([S:1][CH3:12])=[CH:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CI
Product: CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Mercapto-5-nitro pyridine (20.0 g, 128 mmol) was suspended in water/ethanol (43 mL/13 mL). Sodium carbonate monohydrate (17.49 g, 141 mmol, dissolved in 86 mL of water) was added to the above slurry dropwise. Methyl iodide (20.0 g, 141 mmol) was added to the above mixture and the mixture was stirred at room temperature for one hour. The solid was filtered and washed with water and ethanol to provide the title compound in quantitative yield.
Reaction SMILES: C([O:5][C:6](=[O:56])[C:7]([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:48]C(OC(C)(C)C)=O)[S:46][CH:47]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:33](=[O:42])[CH2:34][N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:48][C:45]1[S:46][CH:47]=[C:43](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:56])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][NH:32][C:33](=[O:42])[CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[N:28]=[N:27]2)=[O:14])[N:44]=1
Reactant: CN1CCN(CC(=O)NCc2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N3S(=O)(=O)O)nn2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CC(=O)NCc2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c4csc(N)n4)C(=O)N3S(=O)(=O)O)nn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.3 %

Procedure:
To a slurry of (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((2-(4-methylpiperazin-1-yl)acetamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (120 mg, 0.13 mmol) In DCM (1.3 mL) at 0° C. was added TFA: DCM (1:1, 3.9 mL) followed by triethylsilane (62 μL, 0.39 mmol). The reaction mixture was stirred at 0° C. for 30 min and slowly warmed to room temperature. After 2 h at rt it was concentrated in vacuo and triturated with MTBE: Heptane (1:2) whereupon a solid was observed. The crude solid was purified by reverse phase prep HPLC (C18 column, ACN-water solvent system with 0.1% formic acid modifier) to afford the title compound (9 mg). LCMS: m/z=669.75 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J=8.7 Hz, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.33 (s, 2H), 6.71 (s, 1H), 5.29 (dd, J=8.7, 5.6 Hz, 1H), 4.88-4.60 (m, 2H), 4.34 (d, J=5.7 Hz, 2H), 4.24 (q, J=5.3 Hz, 1H), 3.20-2.87 (m, 8H), 2.77 (s, 3H), 1.34 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[C:21]([C:23]3[CH:27]=[CH:26][O:25][C:24]=3[CH3:28])[CH:20]=[CH:19][N:18]=2)[CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:20]1[C:21]([C:23]2[CH:27]=[CH:26][O:25][C:24]=2[CH3:28])=[CH:22][C:17]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[N:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1occc1-c1ccnc(N2C[C@@H](C)O[C@@H](C)C2)c1
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1cc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (133 mg, 0.749 mmol) was added portionwise to a solution of cis-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-2-pyridinyl]morpholine (204 mg, 0.749 mmol) in chloroform (6 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. Crude LC/MS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate and washed with water, brine, water and brine. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜5 ml) and purified on silica by a Biotage SP4 chromatographic system (25+M cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound (295 mg, 0.798 mmol, 107% yield) as a colourless oil. LC/MS [M+H]+=351/353.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[C:3]1=[N:33]NC1C=CC=CC=1>C(O)(=O)C.[Zn]>[NH2:33][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]1=[O:32]
Reactant: CC(C)N(C(=O)Cn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2)c2ccccc21)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)N(C(=O)CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 0 °C
Yield: 100.9 %

Procedure:
Zinc powder (9.1 g) was added in portions to a slurry of 2-[2,4-dioxo-5-phenyl-3-(phenylhydrazono)-2,3,4,5-tetrahydro benzo[b][1,4]-diazepin-1 -yl]-N-isopropyl-N-phenylacetamide (7.5 g), in glacial acetic acid, cooled to 0° C. The reaction was allowed to warm to R.T. and stirred an additional hour. The zinc was filtered through a celite pad and the glacial acetic acid was evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and washed with 10% aqueous sodium carbonate (2×100 ml) and water (2×100 ml), dried (Na2SO4) and evaporated to a tan oil. Trituration with hexane and ethyl acetate provided the title compound as a light tan powder (6.3 g). 1H-NMR (300 MHz, CDCl3): d 7.6-6.8 (m, 14H), 5.05 (m, 1H), 4.3-4.0 (m, 3H) 1.05 (d, 6H); MS (FAB) =448 (MH+); TLC, Rf=0.25 (chloroform:methanol, 9:1 ).
Reaction SMILES: Cl.[CH2:2]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]>CO.O1CCCC1>[CH2:2]([O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
Conc. hydrochloric acid (0.9 g) was added at ambient temperature to a solution of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(2.4 g) in a mixture of methanol (16.8 ml) and tetrahydrofuran (4.8 ml) and the mixture was stirred for 3 hours at 30° C. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with conc.hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.72 g).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[O:22]1[C:26]2([CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1>C1COCC1>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:29]3([OH:32])[CH2:30][CH2:31][C:26]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:27][CH2:28]3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: Nc1ncnn2c(Br)ccc12
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Nc1ncnn2c(C3(O)CCC4(CC3)OCCO4)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (9.20 g, 35.41 mmol) was dissolved in THF (105 mL) under argon at room temperature. Chlorotrimethylsilane (9.08 mL, 7.77 g, 70.82 mmol, 2 eq.) was added, and the mixture was stirred at room temperature for 3 h. It was then cooled to 0° C., and 2-propyl magnesium chloride (74 mL of a 2.0 M solution in THF, 149 mmol, 4.2 eq.) was added. The mixture was stirred for further 3 h while warming up to room temperature. Then, 1,4-dioxaspiro[4.5]decan-8-one (8.38 g, 53.12 mmol, 1.5 eq.) was added, and stirring was continued for another 16 h. The reaction was quenched with a 1:1 mixture of concentrated aqueous ammonium chloride solution and ice until the pH value reached 6-7. The mixture was extracted with two portions of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium carbonate and concentrated to dryness. The title compound was crystallized from diethyl ether. Yield: 6.05 g (58% of th.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:41][CH2:40][CH2:39]1>>[N:38]1([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and azetidine according to conditions described in general procedure C. Mp: 196-197° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.17-2.25 (m, 2 H), 3.23-3.30 (m, 6 H), 3.75-3.78 (m, 4 H), 3.87 (s, 1 H), 6.14 (d, J=5.5 Hz, 1 H), 7.03-7.06 (m, 1 H), 7.25 (d, J=8.8 Hz, 1 H), 7.40-7.63 (m, 5 H), 7.84-7.86 (m, 1 H), 7.99-8.01 (m, 1 H), 8.22 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:37][C:38](=[NH:55])[C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[CH:42][N:43]2[CH2:48][CH2:49][C:50]([O:52]CC)=[O:51]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:55]=[C:38]([C:39]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:40]=3[CH:41]=[CH:42][N:43]4[CH2:48][CH2:49][C:50]([OH:52])=[O:51])[N:37]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CCC(=O)O)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.8 %

Procedure:
3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D4) (117 mg) was added to EDCI (114 mg) and HOBT (81 mg) dissolved in DMF (2.5 ml). This was stirred at RT for 10 minutes and then ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D57) (150 mg) in DMF (2.5 ml) was added and stirring continued at RT for 2 hours then at 80° C. overnight. The reaction mixture was evaporated to dryness and extracted from H2O (25 ml) with EtOAc (2×25 ml). The combined organics were evaporated and treated with 2 M aq. NaOH (10 ml) and EtOH (10 ml), stirred at 50° C. for 2 hours then evaporated to remove the EtOH. The remaining solution was acidified, filtered and the precipitate washed with EtO/H2O then recrystallised from hot EtOH/H2O then from DMSO. Washing with Et2O and MeOH gave the title compound (46 mg) as a white solid. δH (d6-DMSO, 400 MHz): 1.37 (6H, d), 2.81 (2H, t), 4.50 (2H, t), 4.89 (1H, septet), 7.08 (1H, d), 7.35 (1H, apparent t), 7.46 (1H, d), 7.60 (1H, d), 7.81 (1H, d), 7.94 (1H, d), 8.15 (1H, dd), 8.23 (1H, d). MS (ES−): C22H2035ClN3O4 requires 425; found 424 (M−H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH:25]=[O:26]>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:25]([C:24]4[CH:23]=[C:22]([F:21])[CH:29]=[C:28]([F:30])[CH:27]=4)[OH:26])=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: COC(=O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Yield: 69 %

Procedure:
Methyl 10-bromo-3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with 3,5-difluorobenzaldehyde to afford 291 mg (69% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:22])[S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[NH2:23][CH2:24][C:25]1[C:30]([CH2:31][CH3:32])=[N:29][C:28]2[N:33]([CH2:36][CH3:37])[N:34]=[CH:35][C:27]=2[C:26]=1[NH:38][CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:22])[S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:23][CH2:24][C:25]2[C:26]([NH:38][CH:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[C:27]3[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]3=[N:29][C:30]=2[CH2:31][CH3:32])=[O:18])(=[O:11])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CN(Cc1cccc(Br)c1)S(=O)(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)N(C)Cc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To 3-{[[(3-bromophenyl)methyl](methyl)amino]sulfonyl}benzoic acid (150 mg, 0.390 mmol) in DCM 7.8 mL) was added 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (133 mg, 0.390 mmol), HBTU (163 mg, 0.429 mmol), and TEA (0.163 mL, 1.171 mmol). This mixture was stirred at room temperature for 2 h. The reaction mixture was washed with H2O (2×3 mL), dried over Na2SO4, filtered, and concentrated. The crude product was further purified by CombiFlash flash chromatograph to afford the title compound (0.2453 mg, 94%). LC-MS m/z 669 (M+H)+.
Reaction SMILES: [Si](O[C@H:9]([C@H:32]1[CH2:36][C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.C(OC([N:55]1[CH2:59][C@H:58]([O:60][CH2:61][CH2:62][CH3:63])[CH2:57][C@@H:56]1[C@@H:64]([O:87][Si](C(C)(C)C)(C)C)[C@@H:65]([NH:75][C:76]([C:78]1[CH:79]=[C:80]([CH:84]=[CH:85][CH:86]=1)[C:81]([OH:83])=O)=[O:77])[CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCCC>ClCCl>[CH2:10]([N:20]([CH3:21])[C:81](=[O:83])[C:80]1[CH:84]=[CH:85][CH:86]=[C:78]([C:76]([NH:75][C@@H:65]([CH2:66][C:67]2[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=2)[C@H:64]([OH:87])[C@H:56]2[CH2:57][C@@H:58]([O:60][CH2:61][CH2:62][CH3:63])[CH2:59][NH:55]2)=[O:77])[CH:79]=1)[CH2:9][CH2:32][CH3:36]
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(N)=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCN(C)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](OCCC)CN2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Step 3 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid (Step 1 (C), 66 mg, 0.10 mmol) in dichloromethane (2 mL) were added HATU (46 mg, 0.12 mmol) and N-methylbutan-1-amine (12 mg, 0.13 mmol) and the reaction mixture was stirred at rt overnight. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% to 80% EtOAc/Hexane step gradient) to give 60 mg of the title compound (80% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.75 (2H, m), 0.83 (9H, s), 0.88 (3H, m), 0.93-0.96 (2H, m), 1.12 (1H, m), 1.35-1.41 (1H, m), 1.48-1.53 (11H, m), 1.61 (1H, m), 2.01-2.06 (1H, m), 2.19 (1H, d, J=10 Hz), 2.66 (1H, m), 2.89-2.93 (3H, m), 3.04 (1H, s), 3.21 (1H, brd s), 3.27-3.36 (3H, m), 3.51 (1H, brd s), 3.75 (1H, dd, J=5, 15 Hz), 3.97 (1H, m), 4.05-4.11 (2H, m), 4.60 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.41-7.48 (2H, m), 7.87 (2H, s), 8.13 (1H, brd s). MS (ESI) (M+H)+ 746.36.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>S1(CCCC1)(=O)=O>[CH2:19]([O:8][C:7]1[CH:9]=[C:2]([C:1]([O:11][CH3:12])=[O:10])[C:3]([OH:4])=[CH:5][CH:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of methyl gentisate (16.8 g) and anhydrous potassium carbonate (7.0 g) in dry sulpholane (150 ml) was treated, with stirring, with benzyl chloride (12.7 g), and the mixture was stirred and heated at 100° C. for 4 hours. The mixture was then poured into water (800 ml) and the separated solid was filtered off and recrystallized from ethanol (with the aid of charcoal) to give methyl 5-benzyloxysalicylate (10.7 g), m.p. 108°-112° C. This ester (9.2 g) was heated at 150° C. for 3 hours with a mixture of anhydrous potassium carbonate (2.5 g) and benzyl chloride (4.52 g) in dry sulpholane (100 ml) and the mixture was then cooled and poured into a mixture of ice and water (700 ml), and the mixture was extracted with diethyl ether (2 × 300 ml). The ether extracts were combined and evaporated, the residual oil was triturated with water (100 ml), the oil was separated and the aqueous layer was extracted with diethyl ether (25 ml). The combined oil and extracts were washed with brine, dried over magnesium sulphate and evaporated to give crude methyl 2,5-dibenzyloxybenzoate (12.7 g). This ester (12.4 g) was heated at reflux with aqueous sodium hydroxide solution (2N; 400 ml) for 2 hours and allowed to cool. The separated sodium salt was filtered off and ground with hydrochloric acid (6N; 100 ml), the mixture was heated at reflux for 5 minutes and then cooled. The solid which separated was filtered off, washed with water and dried to give 2,5-dibenzyloxybenzoic acid (8.2 g), m.p. 107°-108.5° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[C:9](=[O:12])[CH2:10][Cl:11].[Cl-].[NH4+].Cl>CCOCC>[Cl:11][CH2:10][C:9]([C:8]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:7]=1[Cl:6])([OH:12])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: [Li]CCCC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCC(O)(CCl)c1ccc(Cl)cc1Cl

Procedure:
Into a 500 ml four-necked flask equipped with a thermometer, a condenser, a mechanical stirrer, an addition funnel, and a nitrogen inlet tube are placed 102 ml (0.2 m, 1.97 M solution in hexane) of n-butyllithium. This solution is cooled to -60° with an acetone-dry ice bath. 2,4-Dichlorphenacyl chloride (44.7 g, 0.2 m) dissolved in 250 ml of ether is then added dropwise. The temperature is maintained below -55° throughout the reaction. After the addition, the reaction is allowed to warm gradually to -10° and then poured into a mixture containing 250 ml of saturated ammonium chloride and 250 ml of 10% hydrochloric acid solution. The layers are separated and the aqueous layer is extracted with 100 ml of ether. The combined ether extracts are washed with 10% hydrochloric acid, saturated sodium chloride solution, and dried over MgSO4. Solvent is evaporated to give 52 g of a pale yellow oil. Vacuum distillation (100°-120°/0.2 mm) affords 44 g of pure product.
Reaction SMILES: NC1C=C(C=CC=1O)C[N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:7]1.C1CCNCC1.C(OC(=O)C)(=O)C>ClCCl>[C:30]([O:29][C:27]([NH:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[C:17]([NH:16][CH2:15][C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1)=[O:35])=[O:34])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 143.6 %

Procedure:
To a mixture of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (27 mg, 0.049 mmol), (piperidinomethyl)polystyrene (2.7 mmol/g, 60 mg, 0.15 mmol) and dichloromethane (2 mL) was added acetic anhydride (0.12 mmol) in dichloromethane (0.12 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to give 1-(3-acetylamino)-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (30 mg, quant.): ESI/MS m/e 590.4 (M++H, C29H37F2N5O6).