Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:24]2[CH2:25][CH2:26][O:27][CH:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)[CH2:23]2)=[CH:4][CH:3]=1
Reactant: c1cncc(C2CNCCO2)c1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCOC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
5.632 g of 4-Bromobenzyl bromide and 3.819 g of 2-Pyridin-3-yl morpholine oxalate (Array) in 50 mL of acetonitrile were stirred at room temperature and 6.229 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification is done by flash chromatography to afford product. Wt: 211 mg; 16% yield. ES MS m/z 334
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:16][CH2:17][O:18][C:19](=[O:23])[C:20]([O-])=[O:21]>C(Cl)Cl>[O:21]=[C:20]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:19]([O:18][CH2:17][CH3:16])=[O:23]
Reactant: Nc1cccnc1
Reactant: O=C([O-])C(=O)OCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution 3-aminopyridine (3.00 g, 27.0 mmol) in methylene chloride (110 mL) at 23 ° C. was added triethylamine (7.53 mL, 54.0 mmol) and N,N-dimethylarninopyridine (330 mg, 2.70 mmol). The solution was cooled to 0° C. and chloroethyloxalate 4.42 g, 32.4 mmol) was added in a dropwise fashion. The reaction mixture was stirred at 0° C. for 2 hours and then quenched with water (30 mL) and partitioned. The organic portion was washed with 10% sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 4.30 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCC(NS(=O)(=O)c1ccc(Br)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCC(NS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 9.4 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)hexanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (554.2 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.6 ml) and 1-methyl-2-chloropyridinium iodide (875.4 mg) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (123.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Li+].CC([N-]C(C)C)C.[C:19](=[O:21])=[O:20]>C1COCC1.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:19]([OH:21])=[O:20]
Reactant: COc1cncc(OC)c1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cncc(OC)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A solution of 3,5-dimethoxypyridine (600 mg, 4.3 mmol) (prepared according to the method of Testaferri, L. et al Tetrahedron, 1985, 41, 1373) in THF (2.6 ml) was added to a solution of LDA [generated from n-BuLi (1.9 ml, 2.5 M in hexane, 4.73 mmol) and diisopropylamine (0.6 ml, 5.16 mmol)] in THF (2.6 ml) at −78° C. under nitrogen. The reaction mixture was stirred for 30 minutes at −78° C., transferred via cannula to a suspension of crushed solid CO2 (30 g) in toluene (100 ml) under vigorous stirring and warmed to room temperature. The reaction is quenched by addition of water (20 ml) to and 1M NaOH (10 ml) and the aqueous layer separated, acidified to pH 4 with glacial acetic acid and extracted with 10% MeOH in dichloromethane (3×50 ml). The combined organic layers were dried (MgSO4) and the solvent removed under vacuum to give the title compound (502 mg, 63%) as a white solid.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[NH2:25]N.O.Cl>CO>[NH:25]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccn[nH]1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (2.70 g, 8 mmol) and NH2NH2.H2O (1.94 mL, 40 mmol) in MeOH (25 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from AcOEt to give the title compound (0.969 g, 40% yield) as an off-white solid: mp 192-194° C.; 1H NMR (300 MHz, CDCl3): δ ppm 6.82 (1H, d, J=7.9 Hz), 7.03 (1H, d, J=1.9 Hz), 7.69 (1H, d, J=1.9 Hz), 7.72-7.76 (2H, m), 7.83-7.89 (1H, m), 7.91-7.93 (1H, m), 8.33 (1H, d, J=7.9 Hz), 12.85 (1H, brs). LC-MS (ESI) m/z 307 [M+H]+. Anal. Calcd for C14H9F3N4O: C, 54.91; H, 2.96; N, 18.29. Found: C, 54.92; H, 2.99; N, 18.33.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=2)[C:12]([OH:14])=O)=[CH:6][CH:5]=1.[F:33][CH:34]([F:37])[CH2:35][NH2:36]>>[F:33][CH:34]([F:37])[CH2:35][NH:36][C:12](=[O:14])[CH:11]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:19][CH:18]=1)[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:32])([F:31])[F:1])=[CH:9][CH:8]=1
Reactant: NCC(F)F
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCC(F)F)c1ccc(OCCC(F)(F)F)cc1
Yield: 80.9 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 3-[4-(trifluoromethoxy)phenyl]-2-{[4-(3,3,3-trifluoropropoxy)benzoyl]amino}propanoic acid (233 mg) prepared in Example 70 (70a) and 2,2-difluoroethylamine (49 mg) to give 214 mg of the title compound (white powder).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[Si](N=C=S)(N=C=S)(N=C=S)[N:18]=[C:19]=[S:20].Cl>C1C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:19](=[S:20])[NH2:18])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: S=C=N[Si](N=C=S)(N=C=S)N=C=S
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: c1ccccc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (1.43 g, 0.01 mole) in benzene (20 ml) was treated with n-butyl-lithium (15% w/w, 4.5 ml, 0.01 mole) and the solution was allowed to stand at room temperature for 0.5 h. The solution was then treated with a suspension of silicon tetraisothiocyanate (1.3 g, 0.005 mole) in benzene (5 ml) at 0° C. After 10 min., water (50 ml) was added and the mixture was stirred for 0.5 h at room temperature and then acidified with conc. HCl. The aqueous layer was separated, washed with ethyl acetate and the pH was adjusted to 10 with solid Na2CO3. The basic mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with n-hexane to give 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.2 g, 10%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[NH2:14][C:15]1[C:27]([Cl:28])=[CH:26][C:18]2[C:19](=[O:25])[N:20]([CH3:24])[CH2:21][CH2:22][O:23][C:17]=2[CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:28][C:27]1[C:15]([NH:14][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=2)=[CH:16][C:17]2[O:23][CH2:22][CH2:21][N:20]([CH3:24])[C:19](=[O:25])[C:18]=2[CH:26]=1
Reactant: CN1CCOc2cc(N)c(Cl)cc2C1=O
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc3c(cc2Cl)C(=O)N(C)CCO3)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 6.5 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.5 g, 2.36 mmol), 8-amino-7-chloro-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (0.38 mmol) and p-toluene sulphonic acid (0.49 g, 2.6 mmol) in dioxane (10 mL) was heated at 100° C. for 2 h. The mixture was cooled, filtered and the solid washed with dioxane. The solid was dried in a vacuum oven and purified via silica gel column chromatography (20-100% ethyl acetate/isohexane) gave 7-chloro-4-methyl-8-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one as a white solid (10 mg, 28%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=402 at 3.04 min. 1H NMR δ (ppm)(400 MHz, CDCl3): 8.41 (1H, s), 8.22 (1H, s), 7.97 (1H, s), 7.77-7.67 (1H, m), 5.29 (1H, s), 4.47-4.39 (2H, m), 3.61-3.51 (2H, m), 3.21-3.18 (3H, m), 3.20-3.07 (3H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9]O)=[CH:2]1.C(N(CC)CC)C.C1(C)C=CC(S([Cl:39])(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:39][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCN(CCCCCCc1ccccc1)Cc1ccoc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCCN(CCCCCCc1ccccc1)Cc1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.533 g (8.470 mmol) of 2-[(3-furylmethyl)-(6-phenylhexyl)amino]ethanol, 1.77 ml (12.7 mmol) of triethylamine and 30 mg of 4-dimethylaminopyridine in 50 ml of dichloromethane, 1.94 g (10.2 mmol) of p-toluenesulfonyl chloride was added at room temperature, followed by overnight stirring at room temperature. The solvent was distilled off under reduced pressure; the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield the desired product.
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH2:11][CH3:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH2:11]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]=1[CH2:3][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1)[CH3:12]
Reactant: CCc1cncc(F)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cncc(F)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
A mixture of 4-(bromomethyl)-3-ethyl-5-fluoropyridine hydrobromide (9.7 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.7 g, 12 mmol), and triethylamine (3.5 mL, 25 mmol) in absolute ethanol (100 mL) was stirred at overnight room temperature. The mixture was evaporated. Water (100 mL) and EtOAc (100 mL) were added. The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude mixture was purified by flash chromatography (0-5% MeOH/CH2Cl2), affording the title compound (250 mg, 9% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.21 (t, 3H, J=7.5 Hz), 2.23 (s, 3H), 2.83 (q, 2H, J=7.5 Hz), 4.51 (s, 2H), 6.07 (s, 1H), 8.33 (s, 1H), 8.41 (s, 1H); M+ 280.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C(N)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1C=CC=CC=1>[C:16]([O:20][C:21]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:15])[CH2:11]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1CNCCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)ON=C(C(N)=O)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1

Procedure:
A mixture of 1-(phenylmethyl)piperazinone (XIV, Example 40, 19.0 g., 0.1 mole) and 2-(t-butoxycarbonyloxyimino)-2-phenylacetamide (30.0 g., 0.12 mole) in benzene (200 ml.) is heated under reflux for 1 hour. The benzene is removed under reduced pressure, the residual oil is dissolved in ethyl acetate:SSB (1:1) and chromatographed on silica gel. The column is eluted with ethyl acetate, the appropriate fractions are pooled, concentrated and the product is crystallized from ethyl acetate:SSB (1:10) to give the title compound, m.p. 89°-90°.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8])C.Cl.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[NH:20])([O-:15])=[O:14]>>[CH:7]([C:6]1[N:21]=[C:19]([C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[N:20]=[C:4]([OH:11])[CH:5]=1)([CH3:8])[CH3:9]
Reactant: N=C(N)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: Cl
Product: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 4-methyl-3-oxo-pentanoic acid ethyl ester and 3-nitro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 1.25 (d, J=6.9 Hz, 6H), 2.80-2.92 (m, 1H), 6.37 (s, 1H), 7.83 (t, J=8.0 Hz, 1H), 8.40 (dd, J=7.5, 2.3 Hz, 2H), 8.62 (d, J=7.5 Hz, 1H) 9.01 (s, 1H), 12.50 (br s, 1H); MS: m/z (ESI) 260 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[S:8][C:9]3[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([O:18]C)[C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Ce+4].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[CH:1]1([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH:14]=[CH:13][C:12](=[O:18])[C:10]=3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(OC)c2sc(C3CCCCC3)nc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1C=CC(=O)c2sc(C3CCCCC3)nc21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
1 g (3.61 mmol) of 2-cyclohexyl-4,7-dimethoxy-1,3-benzothiazole is put into suspension in an acetonitrile/water mixture (3/1) at 0° C. then 4.36 g (7.96 mmol; 2.2 eq.) of cerium (IV) and ammonium nitrate are added to the suspension. The reaction mixture is maintained for 15 hours under stirring at ambient temperature, then 0.78 g (yield=88%) of 2-cyclohexyl-1,3-benzothiazole-4,7-dione is obtained after filtration, washing with cold water and drying under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:16]=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[N:7][C:6]=2[CH:26]=1.BrC1[S:31][CH:32]=[CH:33][N:34]=1>C(N(CC)CC)C.[Pd](Cl)Cl.[Cu]I>[S:31]1[CH:32]=[CH:33][N:34]=[C:16]1[C:11]#[C:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=2[N:7]=1
Reactant: Brc1nccs1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1nccs1)c1nc2ccccc2o1
Yield: 210.7 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mmol), 2-bromothiazole (1.13 ml, 95%, 12 mmol), bistriphenylphosphine)palladium(II) dichloride (21.1 mg, 30 μmol), and copper (I) iodide (1.2 mg, 6 μmol) in triethylamine (12 ml) was heated at 90 EC, under argon, for 3 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (70 ml) and water (30 ml). The organics were washed with 1 N HCl (30 ml) and saturated sodium hydrogen carbonate (30 ml), dried (Na2SO4) and evaporated--to give 2.86 g (100%) of crude thiazolylethynylbenzoxazole, which was purified by flash chromatography (SiO2 ; dichloromethane). The product was crystallized and recrystallized from methanol to give 1.43 g (50.4%) of the title compound (mp 137-41 EC).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.7 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), isobutyl bromide (0.64 g, 4.6 mmol) and potassium carbonate (0.57 g, 4.1 mmol) and DMF (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.08 g, 19%).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:7]([C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)=[O:9])[CH:16]=1)[CH3:11]
Reactant: O=C(O)c1csc(Cl)n1
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2csc(Cl)n2)c1

Procedure:
2-Chloro-thiazole-4-carboxylic acid (79) (70 mg, 0.43 mmol) was coupled with ethyl ester (6) (77 mg, 0.43 mmol) following Method C to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:7]([NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])=[O:8])=[N+:2]=[N-:3].O.O=[C:32]1O[C@H:37]([C@H](CO)O)[C:35]([O-])=[C:33]1[OH:34].[Na+]>CC(O)(C)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:33]([C:35]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:23][CH2:24][CH3:25])[CH:21]=2)[C:7]([NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[O:8])[CH:37]=1)(=[O:34])[CH3:32]
Reactant: CCCN(c1cc(N=[N+]=[N-])cc(C(=O)N[C@H](C)c2ccc(F)cc2)c1)S(C)(=O)=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)=O)nn2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 1025.5 %

Procedure:
To a solution of 0.15 g (0.36 mmol) 3-azido-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide in 2 mL t-BuOH was added 1 mL water and 0.004 g (0.018 mmol) copper(II) sulfate hydrate and 0.007 g (0.036 mmol) sodium ascorbate. The heterogeneous reaction mixture was stirred at rt for 24 h, then diluted w. 75 mL EtOAc, washed with 50 mL water, 50 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica gel cartridge 20-100% EtAOc/hex over 15 min) afforded 0.18 g (100%) 3-(4-acetyl-1H-1,2,3-triazol-1-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl) (propyl)amino]benzamide as a foam. 1H NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.11 (br t, J=1.83 Hz, 1H), 7.93 (t, J=2.02 Hz, 1H), 7.89 (br t, J=1.64 Hz, 1H), 7.38 (m, 2H) 7.06 (m, 2H), 6.52 (br d, J=7.50 Hz, 1H), 5.32 (quint, J=7.15 Hz, 1H), 3.74 (t, J=7.14 Hz, 2H), 2.93 (s, 3H), 2.76 (s, 3H), 1.64 (d, J=6.96 Hz, 3H), 1.54 (m, 2H), 0.93 (t, J=7.32 Hz, 3H). LCMS [M+H]+=488.1
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([NH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[O:17])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].O1CCCC1.O.[OH-].[Li+]>O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([NH:15][C:7]12[CH2:13][CH:11]3[CH2:10][CH:9]([CH2:14][C:5]([C:3]([OH:4])=[O:2])([CH2:12]3)[CH2:6]1)[CH2:8]2)=[O:17]
Reactant: COC(=O)C12CC3CC(CC(NC(=O)c4ccccn4)(C3)C1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC12CC3CC(C1)CC(C(=O)O)(C3)C2)c1ccccn1
Temperature: 25 °C
Reaction time: 25 h
Yield: 93.3 %

Procedure:
To a round bottom flask was added 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester (24.8 g, 78.9 mmol), tetrahydrofuran (250 mL), water (250 mL) and lithium hydroxide monohydrate (14.9 g, 355 mmol) and the mixture was stirred vigorously at room temperature for 25 hours. The crude mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran, then the aqueous solution was diluted with water (200 mL) and the pH was adjusted to about 3-4 by adding solid citric acid monohydrate. A voluminous white precipitate appeared which was filtered, washed with water and dried under high vacuum at 50° C. to afford 22.1 g (93%) of the title compound, 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid, as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 8.18 (d, J=7.7 Hz, 1H), 7.97 (br s, 1H), 7.85 (td, J=7.8, 1.8 Hz, 1H), 7.42 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 2.35-2.31 (m, 2H), 2.31-2.25 (m, 2H), 2.25-2.09 (m, 4H), 2.00-1.86 (m, 4H), 1.80-1.64 (m, 2H). ESI-MS m/z: 301.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:38]([O:40]C)=[O:39])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:34](=[O:37])[CH:35]=[O:36])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:33])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:34](=[O:37])[CH:35]=[O:36])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:33])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3cccs3)C2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3cccs3)C2=O)cc1)C(=O)O
Reaction time: 7 h
Yield: 74.7 %

Procedure:
2-[3-{4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-(2-thienyl)acetic acid (0.480 g.) was dissolved in methanol (3 ml.), and to the solution, there was added 1 N aqueous sodium hydroxide (2 ml.) under ice-cooling. The mixture was stirred at the same temperature for 7 hours while adjusting to pH 9.0 to 9.5 with 1 N aqueous sodium hydroxide. After the reaction, the reaction mixture was adjusted to pH 7.0 with dilute hydrochloric acid and evaporated to dryness under reduced pressure on a water bath. The resultant residue was dissolved in a small amount of water, and the aqueous solution was adjusted to pH 5.5 with dilute hydrochloric acid and then washed with ethyl acetate. The aqueous solution was adjusted to pH 4.0 to 4.5 with dilute hydrochloric acid and then extracted with ethyl acetate. This extract was evaporated to dryness under reduced pressure to give 2-[3-{4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloylamino}-2 -oxo-1-azetidinyl]-2-(2-thienyl)acetic acid (0.350 g.).