Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][C:15]=1[O:30][CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][CH2:54][NH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N+:57]=1[O-:62]>C1COCC1>[CH3:31][O:30][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([CH3:28])([CH3:29])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:19][C:14]=1[O:13][CH2:52][CH2:53][CH2:54][NH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N+:57]=1[O-:62]
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(O)c(OC)c1
Reactant: [O-][n+]1ccccc1NCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])c(OC)c1
Reaction time: 0.25 h

Procedure:
A solution of diethyl azodicarboxylate (174 mg, 1.0 mmol) in 3 ml THF was added to a solution of the product of STEP 6 (18 mg, 0.676 mmol) and triphenylphosphine (262 mg, 1.0 mmol) in 7 ml THF at room temperature and stirred for 15 min. 2-(3-Hydroxypropylamino)pyridine N-oxide (168 mg, 1.0 mmol) was added. The reaction was stirred at room temperature for 18 h. THF was evaporated and the residue purified by chromatography (on silica gel, C2HC2I/CH3OH/NH4OH=97.5/2/0.5) to afford a pale brown oil in 81.5 mg). NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(OCC)C>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(C(C)(C)C)ccc2[nH]1
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(C)(C)C)ccc2n1Cc1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of 1 g (4.08 mmol) of ethyl 5-t-butyl-1H-indole-2-carboxylate is added dropwise to a suspension of 0.33 g (8.15 mmol) of 60% sodium hydride in 10 ml of dimethylformamide, stirred at 0° C. under argon. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled and 1.06 g (4.08 mmol) of 4-bromomethylpyridine hydrobromide are added portionwise. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled again to 0° C. and a further 0.33 g (8.15 mmol) of 60% sodium hydride in 10 ml of dimethylformamide is added. After 30 minutes at 0° C., 1.06 g (4.08 mmol) of 4-bromomethylpyridine hydrobromide are added portionwise. The reaction mixture is then stirred for 20 hours at 20° C. After this time, the mixture is poured into a solution of 100 ml of ice-water and 70 ml of ethyl ether. The organic phase is separated out and the aqueous phase is re-extracted with 50 ml of ethyl ether. The organic phases are combined, washed with 50 ml of water and then dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane/acetone). 0.7 g of expected product is obtained in the form of an oil, which is used without further purification in the subsequent synthesis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].C(O)(=O)C.[N+:27]([O-])([OH:29])=[O:28]>O>[N+:27]([C:13]1[CH:12]=[C:11]([O:14][CH3:15])[C:10]([O:16][CH3:17])=[CH:9][C:8]=1[C:6]([C:5]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:7])([O-:29])=[O:28]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A mixture of 2.93 g (9.7 mmol) of 3,3',4,4'-tetramethoxybenzophenone (prepared according to Example 1), 9 g of glacial acetic acid and 1.88 g (19.4 mmol) of 65 percent strength nitric acid was stirred at room temperature for 7.5 h. 22 ml of water was then added dropwise, and the resulting precipitate was filtered off, washed 2×6 ml of water and dried to give 2.41 g of a beige solid. The yield of the product was 71.5 percent of theory. Further data concerning the product was:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:30])[NH:28][CH2:27][CH2:26][NH:25][C:24]1=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:29])[C:23]3([CH3:30])[CH3:22])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)NCCNC1=O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3-dimethylpiperazin-2-one hydrochloride (CAN 1104383-07-4) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=395.4 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Cl:19][C:20]1[C:25]([O:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:18]=[CH:17][C:5]=4[N:6]=3)=[CH:15][CH:14]=2)=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: Clc1nccnc1Cl
Reactant: Oc1ccc(Nc2nc3ccc(F)cc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2nc(Nc3ccc(Oc4nccnc4Cl)cc3)sc2c1
Temperature: 80 °C

Procedure:
To a solution of 4-(6-fluorobenzo[d]thiazol-2-ylamino)phenol (7.5 g, 0.028 mol) and 2,3-dichloropyrazine (5.0 g, 0.034 mol) in DMSO (35 mL) was added cesium carbonate (11.0 g, 0.034 mol). The mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT and diluted with water (350 mL). The aqueous layer was extracted with EtOAc (4×300 mL). The combined organic extract was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (silica 100-200 mesh; 30-60% ethyl acetate in hexane) to give N-(4-(3-chloropyrazin-2-yloxy)phenyl)-6-fluorobenzo[d]thiazol-2-amine as a white solid. [M+H]=372.8. IC50 (uM) +.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=2)[CH2:25][NH:26]C(=O)OC(C)(C)C)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]([CH3:48])[C:45](=[O:47])[CH3:46])=[CH:40][CH:39]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:26][CH2:25][C:24]1[CH:23]=[C:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([N:44]([CH3:48])[C:45](=[O:47])[CH3:46])=[CH:42][CH:43]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(CNC(=O)OC(C)(C)C)c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(CN)c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Yield: 8.4 %

Procedure:
A solution of tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzylcarbamate (306 mg, 0.580 mmol), N-(4-aminophenyl)-N-methylacetamide (190 mg, 1.16 mmol) and trimethylsilyl chloride (0.100 mL, 0.791 mmol) in nBuOH (5 mL) was stirred at 116° C. for 20 h. The mixture was then purified by HPLC to give N-(4-(4-(3-(aminomethyl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (27 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4][NH:3]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4][N:3]1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: O=C1NOCc2ccccc21
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(OCCN2OCc3ccccc3C2=O)cc1
Yield: 66.6 %

Procedure:
##STR34## The title compound (370 mg, 66%) was prepared from 4-oxo-3,4-dihydro-1H-2,3-benzoxazine (280 mg, 1.87 mmol) (prepared according to the procedure described in Tetrahedron, 22 (1966) 2107) and 4-(2-bromoethoxy)benzaldehyde (430 mg, 1.87 mmol) and K2CO3 (520 mg, 3.74 mmol). mp: 102° C.
Reaction SMILES: C(OC(=O)[N:7]([CH:20]1[CH2:23][N:22]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:21]1)[CH2:8][C@H:9]([OH:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([N:22]2[CH2:21][CH:20]([NH:7][CH2:8][C@H:9]([OH:19])[CH2:10][O:11][C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[CH2:23]2)(=[O:25])=[O:26])=[CH:32][CH:31]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOc1ccc(S(=O)(=O)N2CC(N(C[C@H](O)COc3ccc(O)cc3)C(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1ccc(S(=O)(=O)N2CC(NC[C@H](O)COc3ccc(O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111 %

Procedure:
To a solution of [1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl]-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propyl]-carbamic acid tert-butyl ester (0.11 g, 0.2 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.15 ml, 2 mmol). The mixture was stirred at room temperature for 2 h, and then quenched with saturated sodium carbonate solution and extracted with dichloromethane. The organic solution was washed with brine, dried over sodium sufate, and evaporated to give 0.10 g of a white solid; m.p. 55-58° C.; MS (ES) m/z 451 (MH+); HRMS (CI) Calcd. for C22H31N2O6S (MH+): 451.1903, Found: 451.1882.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[OH:14][C:8]1[C:6]2[O:7][C:3]([C:1]3[N:2]=[N:32][NH:33][N:34]=3)=[C:4]([C:18](=[O:31])[C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[C:5]=2[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(=O)c2c(C#N)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2c(-c3nn[nH]n3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Mixture of 2-cyano-7-acetoxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-benzo[b]furan (15 mg, 0.04 mmol) ammonium chloride (11 mg, 0.2 mmol) and sodium azide (13 mg, 0.2 mmol) in dry DMF (400 μL) was stirred at 110° C. for 4 hours. More sodium azide (15 mg, 0.23 mmol) was added and stirring was continued for 1 hour (tlc), quenched with saturated ammonium chloride solution and extracted with ethyl-acetate (10 mL×2). The organic layer was dried over magnesium sulfate and solvent was distilled and the crude was purified by silica gel plate to afford the title compound as creamy solid; (3.5 mg, 21%; 1H NMR (300 MHz, CDCl3) δ: 7.85 (1H, NH), 7.26 (d, J=8.54 Hz, 1H), 7.02 (s, 2H, benzoyl Hs), 6.95 (d, J=8.54 Hz, 1H), 5.74 (b, 1H, OH), 3.97 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.82 (s, 6H, 2×OMe).
Reaction SMILES: [C@@H:1]12[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]1[CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:2]2.FC(F)(F)C(O)=O>C(Cl)Cl>[C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(C(=O)OCc3ccccc3)C[C@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Yield: 39.8 %

Procedure:
The product of Example 38I (1.0 g, 6.92 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (5 mL) at room temperature for 1 hour. The mixture was concentrated and the residue was diluted with CHCl3 (50 mL). The brown chloroform solution was washed with saturated aqueous NaHCO3 (2×20 mL, pH=8-9) and brine (5 mL), dried (MgSO4), filtered, and the filtrate concentrated to provide the title compound as a brown oil (0.64 g, 97% yield) which was used in the next step without purification. 1H NMR (MeOH-d4, 300 MHz) δ 3.30-3.16 (m, 3H), 3.36 (m, 1H), 3.80 (m, 3H), 4.45 (dd, J=6.4 Hz, 4.8 Hz, 1H), 5.16 (s, 2H), 7.36 (m, 5H); MS (DCI/NH3) m/z 250 (M+NH4)+, 233 (M+H)+.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].Br[CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[C:13](=[O:17])[CH2:12]1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCN1CCN(C(=O)OCc2ccccc2)CC1=O
Reaction time: 1 h

Procedure:
Amine preparation: to 4-CBZ-piperazin-2-one (1.95 g) in DMF (5 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 660 mg) in several aliquots. After stirring for 1 h, 2-bromoethylacetate (1.38 ml) was added. The reaction mixture was stirred at room temperature overnight; it was then diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The resulting residue was purified using flash chromatography to yield 4-(2-acetoxy-ethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (925 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][O:53][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][OH:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CO
Solvent: CC(=O)Cl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 6k (2.32 g, 2.69 mmol) was dissolved in 12 mL methanol, followed by addition of acetyl chloride (16 μL, 0.40 mmol). The reaction mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 6m (1.22 g, pale yellow grease), yield: 60.7%. 1H NMR (400 MHz, CD3OD): δ 7.54-7.52 (m, 2H), 7.41 (d, 1H), 7.32-7.22 (m, 13H), 7.18 (d, 2H), 7.08-7.04 (m, 4H), 4.91-4.85 (m, 3H), 4.75 (d, 1H), 4.52 (d, 1H), 4.17-4.09 (m, 3H), 4.00 (d, 1H), 3.94-3.83 (m, 3H), 3.75-3.69 (m, 2H), 3.09 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[Sn](C)(C)C.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Cn1cccc1[Sn](C)(C)C
Product: Cn1cccc1-c1ccccc1[N+](=O)[O-]
Yield: 68.6 %

Procedure:
1-Methyl-2-(trimethylstannyl)-1H-pyrrole (3.94 g, 14.7 mmol) and 1-bromo-2-nitrobenzene (3.22 g, 15.9 mmol, 1.08 eq) were coupled as in Example 75 to give 2.04 g of 1-methyl-2-(2-nitrophenyl)-1H-pyrrole, which was reduced as in Example 64 to give 1.53 g of 2-(1-methyl-1H-pyrrol-2-yl)aniline.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:19].C(Cl)(Cl)Cl>C(C(C)=O)C.Cl>[O:19]=[C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=2)[N:5]1[CH2:4][CH:3]=[O:2]
Reactant: COC(Cn1c(=O)ccc2ncc(C(F)(F)F)cc21)OC
Agent: Cl
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: O=CCn1c(=O)ccc2ncc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of 90 mg of 1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one in 0.72 mL of methyl ethyl ketone, 38 μL of concentrated hydrochloric acid was added, and the mixture was heated under reflux while stirring for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, thereto were added chloroform and a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 67 mg of (2-oxo-7-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:23][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH3:22])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc([C@@H](C)N)cc1
Reactant: COc1ccc(C(=O)O)cc1C
Product: COc1ccc([C@@H](C)NC(=O)c2ccc(OC)c(C)c2)cc1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1-(R)-(4-methoxy-phenyl)-ethylamine. MS (M+H, 300.1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([O-:30])(=[O:29])=[O:28])=[O:17])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:31]=[C:20]1[N:19]2[CH2:25][C@@H:22]([CH2:23][CH2:24][C@H:18]2[C:16]([NH:15][O:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:17])[N:21]1[O:26][S:27]([OH:30])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO[C@H]1CCCNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium ({[(2S,5R)-2-({[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 20 (0.23 g, 0.32 mmol) in DCM (15 mL) was added trifluoroacetic acid (0.64 mL, 8.32 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-7-oxo-N-[(3S)-piperidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 4 (Table 1) (0.008 g, 6.8%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH3:24])[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[CH2:20][C@@H:19]1[CH3:33])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH:19]([CH3:33])[CH:20]=[C:21]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:22][CH:23]1[CH3:24])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@H]1C=C(OS(=O)(=O)C(F)(F)F)C[C@H](C)N1C(=O)OC(C)(C)C
Reactant: Nc1ccc(B(O)O)cc1
Product: CC1C=C(c2ccc(N)cc2)CC(C)N1C(=O)OC(C)(C)C
Yield: 56.9 %

Procedure:
The title compound was then prepared according to the Suzuki coupling procedure of Example 35, step (b) using 4-aminophenylboronic acid (219 mg, 1.00 mmol) and cis/trans-2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared above, 321 mg, 1.00 mmol). Silica gel chromatography (10-20% EtOAc/hexanes) afforded 4-(4-amino-phenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (172 mg, 57%): Mass spectrum (ESI, m/z): Calcd. for C18H26N2O2, 303.2 (M+H) found 303.1.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([Cl:11])=[CH:9][NH:8][C:7](=[O:12])[CH:6]=1)(=[O:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([O:4][C:5]1[C:10]([Cl:11])=[CH:9][N:8]=[C:7]([O:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)Oc1cc(=O)[nH]cc1Cl
Product: CC(=O)Oc1cc(OC(=O)c2ccccc2)ncc1Cl
Yield: 93 %

Procedure:
The general procedure of Example 20 was repeated using 500 mg of 4-acetoxy-5-chloro-2-pyridone and 0.37 ml of benzoyl chloride to produce 720 mg of the title compound in a yield of 93%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:17][C:18]([C:20]1[CH:39]=[CH:38][C:23]2[N:24]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:25]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[N:26][C:22]=2[CH:21]=1)=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([CH3:16])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([CH2:51][C:52](Br)([CH3:56])[C:53]([O-:55])=[O:54])(C)(C)C>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:17][C:18]([C:20]1[CH:39]=[CH:38][C:23]2[N:24]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[C:25]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[N:26][C:22]=2[CH:21]=1)=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:52]([C:53]([OH:55])=[O:54])([CH3:56])[CH3:51])[CH:13]=2)[N:8]([CH3:16])[CH:7]=1
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: CC(C)(C)CC(C)(Br)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@H](Cc1cn(C)c2ccc(OC(C)(C)C(=O)O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound of example 114 (0.097 g, 0.18 mmol) was dissolved in acetone (1.5 mL). Cesium carbonate (0.175 g, 0.54 mmol) and tert-butylbromoisobutyrate (0.080 g, 0.36 mmol) were added and the mixture stirred at 60° C. overnight in a sealed tube. The reaction mixture was then diluted with water (10 mL) and the product extracted with EtOAc (50 mL). The organic phase was dried (MgSO4), concentrated and the residue purified by flash chromatography using 60-80% EtOAc in hexane as eluent. The purified diester was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added. After stirring at room temperature for 1.5 h, volatiles were removed under a stream of nitrogen and the residue purified by preparative C18 reversed-phase HPLC to give the title compound of example 115.