Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:3]=1.[CH:14]1([O:20][N:21]2[C:26]([CH3:28])([CH3:27])[CH2:25][CH:24]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:23][C:22]2([CH3:35])[CH3:34])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-:36].[Na+]>C1(C)C(C)=CC=CC=1>[CH:14]1([O:20][N:21]2[C:22]([CH3:34])([CH3:35])[CH2:23][CH:24]([N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[C:2]3[N:7]=[C:6]([N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:24]4[CH2:23][C:22]([CH3:34])([CH3:35])[N:21]([O:36][CH:19]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:26]([CH3:28])([CH3:27])[CH2:25]4)[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:3]=3)[CH2:25][C:26]2([CH3:27])[CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCCCNc1nc(Cl)nc(Cl)n1
Reactant: [OH-]
Reactant: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCNc1nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1
Yield: 43.9 %

Procedure:
A mixture of 5.0 g (22.5 mmol) of 2,4-dichloro-6-n-butylamino-1,3,5-triazine, 21.1 g (67.8 mmol) of 1-cyclohexyloxy-4-n-butylamino-2,2,6,6-tetramethylpiperidine, 100 ml of xylene, and 5.4 g of 50% aqueous sodium hydroxide is heated at reflux for 16 hours. The reaction mixture is partitioned between ether and water. The ether layer is washed with 1N HCl (2×100 ml), saturated sodium bicarbonate (100 ml) and saturated sodium chloride (100 ml), then dried over magnesium sulfate and concentrated. The crude product is purified by flash chromatography (heptane) and crystallized from ethanol to afford 7.6 g (44% yield) of the title compound, a glass, m.p. 80°-86° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.CN(C)C1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([O:29][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-(4-methyl-3-oxopiperazin-1-yl)fluorobenzene (2.94 g) was dissolved in dry DMF (40 ml) under argon, and the solution cooled to -20° C. N,N-Dimethylaniline (2.1 ml) was added, followed by benzyl chloroformate (2.07 ml), and the mixture stirred for 10 minutes at -20° C. The temperature was allowed to rise to ambient over 16 hours. The mixture was diluted with ethyl acetate, and washed twice with water, and then brine. After drying (MgSO4) and evaporation of solvent, the residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 5-benzyloxycarbonylamino-2-(4-methyl-3-oxopiperazin-1-yl)fluorobenzene (4.6 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>C(Cl)Cl>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:26][CH2:25]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
To a solution of crude 1-(bromomethyl)-2-(trifluoromethyl)-4-nitrobenzene (13.7 mmol, 60% pure) in CH2Cl2 (20 mL) was added Et3N (1.5 g, 15 mmol) and 4-methylpiperazine (1.5 g, 15 mmol). After stirring for 5 hrs at rt, 50 mL H2O was added, and the mixture was extracted with 50 mL CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluent: 10% MeOH in CH2Cl2) to give the product (67.4%, 2.8 g). 1H NMR (300 MHz, CDCl3) δ: 8.52 (1H, s), 8.37-8.40 (1H, d, J=9.0 Hz), 8.00-8.03 (1H, d, J=9.0 Hz), 3.85 (2H, s), 3.09-3.15 (2H, m), 2.90-2.93 (2H, m), 2.80-2.83 (2H, m), 2.67 (3H, s), 2.53-2.59 (2H, m).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].ON1C(=O)CCC1=O.C(=O)(SC(C)(C)C)OC(OC(=O)C(C)C)C.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([O:53]O)=[O:52])[CH:46]=1>C(Cl)Cl.CCOCC>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:44][C:45]1[CH:46]=[C:47]([CH:48]=[CH:49][CH:50]=1)[C:51]([OH:53])=[O:52]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: CC(OC(=O)SC(C)(C)C)OC(=O)C(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In still another alternative synthesis of (10), N-hydroxysuccinimide (230 mg, 2 mmol) was added to a solution of compound (8) (248 mg, 1 mmol) in CH2Cl2 (10 mL) was added and the reaction mixture cooled to 0° C. m-Chloroperbenzoic acid (670 mg, 3 mmol, commercial grade: 77% in water) was added over a period of 10 min and the mixture allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ether (50 mL) and washed with water (2×10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (10) together with m-chlorobenzoic acid. The crude product mixture was purified by column chromatography on silica gel, eluting with 4:6 EtOAc:hexane. Residual m-chlorobenzoic acid was removed by repeated crystallizations from a mixture of tert-butyl methyl ether and hexane which resulted in analytically pure product (30 mg, 11%).
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:15]1([CH2:21][N:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH:24]2[CH2:26][O:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CO.C1(C)C=CC=CC=1>[C:28]1([CH2:27][N:22]([CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:23][CH:24]([OH:25])[CH2:26][N:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:3]2=[O:2])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ncccn1
Reactant: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1ncccn1CC(O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 55 °C
Yield: 45 %

Procedure:
A solution of 2-hydroxypyrimidine hydrochloride (1:1) (0.075 mol) in methanol (150 ml) was stirred for 30 minutes and then added to a solution of sodium carbonate (0.075 mol) in methanol (20 ml). The mixture was stirred and refluxed for 15 minutes, and cooled to 55° C. A solution of N,N-bis(phenylmethyl)oxiranmethanamine (0.075 mol) in toluene (160 ml) was added dropwise and the reaction mixture was stirred at 50° C. overnight. Water (75 ml) was added and the mixture was stirred at 55° C. for 15 minutes. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH3OH/CH2Cl2 97/3). The pure fractions were collected and the solvent was evaporated, yielding 11.8 g (45%) of (±)-1-[3-[bis(phenylmethyl)amino]-2-hydroxypropyl]-2(1H)pyrimidinone (interm. 2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH3:31][CH2:30][CH2:29][CH2:28][S:27][C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][C:23]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: CCCCSc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCSc1ccccc1-c1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
In toluene/ethanol/water (10/1/1.2 ml) was dissolved methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (730 mg), and to the solution were added 4-(butylthio)phenyl borate (780 mg) and potassium carbonate (620 mg). The mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (127 mg), and the mixture was stirred at 90° C. for 16 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give methyl 7-[(4-butylthio)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (680 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4]C=[C:2]1[CH2:6]C(OCC[Br:12])=O.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.CC(C)=[O:23]>>[Br-:12].[C:2]([S:1][CH2:5][CH2:4][N+:14]1([CH3:13])[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)(=[O:23])[CH3:6]
Reactant: CN1CCN(C)CC1
Reactant: CC(C)=O
Reactant: O=C(Cc1cccs1)OCCBr
Product: CC(=O)SCC[N+]1(C)CCN(C)CC1
Product: [Br-]
Temperature: 25 °C

Procedure:
A solution of 2-bromoethyl thiolacetate *(2.20 g, 0.012 mol) and 1,4-dimethylpiperazine (1.95 mL, 0.014 mol) in acetone (4 mL) was stirred at 50° C. for 65 h. After cooling to 25° C., the liquid phase was decanted from the gum which was triturated twice in diethyl ether; a hygroscopic yellowish powder, 3.2 g (90%) was obtained; ir (Nujol) νmax : 1685 (C=O of thioester) cm-1 ; 1Hmr (D2O) δ: 2.37, 2.39 ##STR122##
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH2:37][C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[OH:39][C@@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:37][CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: NCC[C@@H](O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)NCC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (1R)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 94% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: O(CC(O)=O)C1C=CC=CC=1.[CH3:12][C:13]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:14]=1[O:15][CH2:16][C:17](O)=O.[CH2:25]([NH:28][CH:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[O:39][CH3:40])[CH2:30]1)[CH2:26][CH3:27]>>[CH3:40][O:39][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:36]=1[CH2:37][CH2:38][CH:29]([N:28]([CH2:17][CH2:16][O:15][C:14]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:13]=1[CH3:12])[CH2:25][CH2:26][CH3:27])[CH2:30]2
Reactant: Cc1ccc(C)c(OCC(=O)O)c1
Reactant: CCCNC1CCc2c(cccc2OC)C1
Agent: O=C(O)COc1ccccc1
Product: CCCN(CCOc1cc(C)ccc1C)C1CCc2c(cccc2OC)C1

Procedure:
In Example 29, phenoxyacetic acid was replaced by 2,5-dimethylphenoxyacetic acid and (-)-2-(N-n-propylamino)-5-methoxytetralin was replaced by (+)-2-(N-n-propylamino)-5-methoxytetralin. The crude mixture was subjected to flash chromatography (Silica: 9:1 pet ether/EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.1-6.6(m, 6H), 4.0(t, 2H), 3.8(s, 3H), 2.3(s, 3H), 2.15(s, 3H), 0.9(t,3H).
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:12]C1C=CC=C(C(OO)=O)C=1.C(Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[C:9]([OH:11])[N:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1[nH]ccc2cccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Oc1nccc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In accordance with Scheme 3, the compound of formula X, 1-oxy-7H-[1,7]naphthyridin-8-one can be prepared as follows: The compound of formula IX, 7H-[1,7]naphthyridin-8-one (which can be prepared from commercially available starting product in accordance with literature Chemical & Pharmaceutical Bullentin (1985), 33(2), 626-33) was stirred for about 70 hours at room temperature in chloroform with 3-chloroperbenzoic acid to obtain the compound of formula X. To a suspension of 1-oxy-7H-[1,7]naphthyridin-8-one in dry N,N-dimethylformamide was added drop wise oxalyl chloride at 0° C. After completed addition, the mixture was allowed to warm to room temperature and stirred for about 30 minutes to obtain the compound of formula XI, 2-chloro-[1,7]naphthyridin-8-ol. To a solution of 2-chloro-[1,7]naphthyridin-8-ol in pyridine was added trifluoromethanesulfonic anhydride at about −10° C. The reaction mixture was allowed to warm to room temperature and stirred for about 1 hour to obtain the compound of formula XII, trifluoro-methanesulfonic acid 2-chloro-[1,7]naphthyridin-8-yl ester. Furthermore, the compound of formula XII and a compound of formula R2NH2, for example 2-amnio-4-methylthiazole are dissolved in dry dioxane. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, cesium carbonate and tri(dibenzylideneacetone)dipalladium chloroform complex are added and the reaction mixture is stirred for about 20 hrs at about 130° C. to obtain a compound of formula XIII. The desired compound of formula I can be prepared as follows: To a compound of formula XIII in dry tetrahydrofuran were added tetrakis(triphenylphosphine)palladium and a about 1.0 M solution of diethylzinc in n-hexane. The reaction mixture was heated at reflux for about 1 hour to obtain a compound of formula I.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:25][C:26]([Cl:31])([Cl:30])[C:27](Cl)=[O:28].O>O1CCCC1>[Cl:25][C:26]([Cl:31])([Cl:30])[C:27]([NH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:5])=[O:28]
Reactant: COc1cccc(C(=O)c2ccccc2N)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)c2ccccc2NC(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 2.89 g (12.7 mmol) of 2-amino-3′-methoxybenzophenone and 2.13 ml (15.2 mmol) of triethylamine in 16 ml of tetrahydrofuran (THF), 1.56 ml (14 mmol) of trichloroacetyl chloride were added dropwise under ice-cooling and stirred for 2 hours. Water was added to the reaction mixture, which was followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give 4.51 g (12.1 mmol) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>>[CH3:15][O:16][CH:17]([O:21][CH3:22])[CH:10]1[CH2:9][CH:8]([CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:14][CH2:13][CH2:12][NH:11]1
Reactant: c1cn(CCC2CCCNCC2)cn1
Reactant: COC(OC)N(C)C
Product: COC(OC)C1CC(CCn2ccnc2)CCCN1
Temperature: 100 °C

Procedure:
A mixture of hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine (6.0 g, 0.031M) and dimethylformamide dimethylacetal (33 ml) was heated at 100° C. for 4 hrs. The reaction was stripped to dryness to give hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine carboxaldehyde dimethylacetal. The solution of the hexahydroazepine carboxaldehyde dimethylacetal in methylene chloride (40 ml) was added to the mixture of 6-aminopenicillanic acid (5.7 g, 0.026M) and diisopropylethylamine (3.15 ml) in methylene chloride (150 ml) at 0° C. and stirred at 0° C. for 1 hr, room temperature for 3 hrs. The solvent was removed and water (100 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[hexahydro[2-(1H-imidazol-1-yl)ethyl]- 1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.2 molar hydrochloride hydrate (diastereomers) (4.0 g, 32% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:18]=[N:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:19].[F:20][C:21]([F:27])([F:26])[S:22]([NH2:25])(=[O:24])=[O:23].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:20][C:21]([F:27])([F:26])[S:22]([NH:25][CH2:13][C:12]1[CH:15]=[CH:16][N:17]=[CH:18][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:19])[N:2]([CH3:1])[C:6]=2[CH:7]=1)(=[O:24])=[O:23]
Reactant: Cn1c(=O)oc2ccc(-c3cnccc3C=O)cc21
Reactant: NS(=O)(=O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)oc2ccc(-c3cnccc3CNS(=O)(=O)C(F)(F)F)cc21
Temperature: 70 °C
Reaction time: 15 h
Yield: 22.2 %

Procedure:
A mixture of 3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)isonicotinaldehyde (128 mg, 0.5 mmol), trifluoromethanesulfonamide (94 mg, 0.63 mmol), acetic acid (60.5 mg, 1 mmol) and 4° A molecular sieves in 1,2-dichloroentane (2 mL) heated at 70° C. under nitrogen for 6 h. The suspension was cooled to room temperature and sodium triacetoxyborohydride (excess amount) was added. The reaction mixture was further stirred at room temperature for an additional 15 h. The mixture was diluted with dichloromethane (20 mL) and filtered through a pad of celite. The filter cake was thoroughly washed with an additional 30 mL of dichloromethane. The combined filtrates were washed with NaHCO3 (saturated solution). The aqueous phase was extracted with dichloromethane (2×50 mL). The organic phases were combined, dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (0-100% ethyl acetate in heptane, v/v) and yielded 43 mg of 1,1,1-trifluoro-N-((3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-4-yl)methyl)methane-sulfonamide as colorless solid ESI-MS m/z; 388.0 [M+1]+, Retention time 1.19 min; 1HNMR (MeOD, 400.342 MHz): δ 3.43 (s, 3H), 4.41 (5, 2H), 7.12 (dd, J=8.2, 1.8 Hz, 1H), 7.15 (s, 1H), 7.21 (d, J=1.6 Hz, 1H), 760 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.60 (d, J=8.2 Hz, 1H); and 5-(4-(hydroxymethyl)pyridin-3-yl)-3-methylbenzo[d]oxazol-2(3H)-one 37 mg as pinkish solid ESI-MS m/z: 257.0 [M+1]+, Retention time 0.84 min; 1HNMR (MeOD, 400.342 MHz): δ 3.3 (s, 3H), 4.41 (s, 2H), 7.12 (dd, J=1.76, 8.2 Hz, 1H), 7.21 (d, J=1.56 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.60 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.60 (d. J=5.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([OH:19])=O)[CH2:11]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:19])[CH2:11]2)[CH:3]=1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C)n1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 0 °C
Yield: 105.5 %

Procedure:
To a suspension of (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (2.2 g, 7.73 mmol) in CH2Cl2 (30 mL) at room temperature was added Hunig's base (1.75 mL, 10.04 mmol, 1.3 equiv) and benzylamine (1.01 mL, 9.27 mmol, 1.2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (3.23 g, 8.50 mmol, 1.1 equiv) in one portion, and the resulting suspension was stirred in the ice bath for 30 minutes. LCMS showed conversion complete. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. Silica gel column chromatography using a gradient elution of 1% EtOAc in CHCl3 to 40% EtOAc in CHCl3 afforded the title compound (3.05 g) as a gum. LC-MS (ES) m/z=374 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][CH2:5][C:6]2[C:11](C=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(=O)(O)[O-:14].[Na+].[CH3:18][OH:19]>ClCCl>[CH:18]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])=[O:19]
Reactant: COC1=Cc2ccccc2CC1
Reactant: O=C([O-])O
Reactant: CO
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCc1ccccc1C=O
Yield: 90 %

Procedure:
A suspension of 4.5 g of 3-methoxy-1,2-dihydronaphthalene, 1 g of sodium bicarbonate, 20 mL of methanol and 80 mL of dichloromethane was stirred and cooled in a dry ice-acetone bath. A rapid stream of ozone was bubbled into the suspension until a persistent blue coloration was visible. The mixture was flushed with nitrogen and 3.5 mL of methyl sulfide was added. The mixture was stirred in an ice-acetone bath for 1 hour and then 2 hours at room temperature. The organic solution was washed with water, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether to provide 5.0 g (90%) of the desired title intermediate. NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[BrH:10].[Br:11]Br>>[NH2:1][C:2]1[C:3]([Br:11])=[CH:4][C:5]([C:8]#[N:9])=[N:6][C:7]=1[Br:10]
Reactant: BrBr
Reactant: Br
Reactant: N#Cc1ccc(N)cn1
Product: N#Cc1cc(Br)c(N)c(Br)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-amino-2-cyanopyridine (2 g) was added to a 48% aqueous hydrogen bromide solution (14 mL). Bromine (2.2 mL) was added to the solution at 0° C. The reaction mixture was warmed to room temperature and stirred for six hours. The precipitated solid was collected by filtration to give the title compound (4.5 g).