Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].O.Br.Br.Br.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[N:28]=[CH:29][S:30][CH:31]=3)[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[S:30]1[CH:31]=[C:27]([CH2:26][N:25]2[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=[C:21]2[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:15][CH2:16]2)[N:28]=[CH:29]1
Reactant: c1ccc2c(c1)nc(NC1CCNCC1)n2Cc1cscn1
Reactant: CCOC(=O)NCCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2cscn2)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 5.4 parts of ethyl (2-chloroethyl)carbamate, 19 parts of N-(4-piperidinyl)-1-(4-thiazolylmethyl)-1H-benzimidazol-2-amine trihydrobromide monohydrate, 15 parts of sodium carbonate, 0.2 parts of sodium iodide and 90 parts of N,N-dimethylacetamide was stirred overnight at about 75° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 14 parts of ethyl [2-[4-[[1-(4-thiazolylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]carbamate as an oily residue (intermediate 133)
Reaction SMILES: [Cl:1][CH:2]([Cl:33])[C:3]([NH:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:31])[CH2:26][O:27]C(=O)C)[CH2:21][CH2:20]3)=[C:15]([F:32])[CH:14]=2)[CH2:8]1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:33][CH:2]([Cl:1])[C:3]([NH:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:31])[CH2:26][OH:27])[CH2:23][CH2:24]3)=[C:15]([F:32])[CH:14]=2)[CH2:8]1)=[O:4]
Reactant: CC(=O)OCC(=O)N1CCC(c2ccc(N3C[C@H](CNC(=O)C(Cl)Cl)OC3=O)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NC[C@H]1CN(c2ccc(C3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(−)-2,2-dichloro-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-4-piperidinyl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 32, 110 mg) and anhydrous potassium carbonate (60 mg) in methanol (8.8 mL) is stirred under N2 at ambient temperature for one hour and then concentrated under reduced pressure and chromatographed on silica gel (70-230 mesh, 10 g), eluting with methanol/chloroformn (10/90). Pooling and concentration of those fractions with an Rf=0.41 by TLC (methanol/chloroform, 10/90), repurification by radial chromatography (2000 m silica gel plate) eluting with methanol/methylene chloride, and trituration with chloroform/diethyl ether gives the title compound, NMR (CDCl3, 400 MHz) 7.46, 7.39, 7.15, 5.99, 4.84, 4.74, 4.22, 4.09, 3.77, 3.61, 3.10, 2.79, 1.89, 1.65δ.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][C:39]([OH:44])=[CH:40][CH:41]=3)[O:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][C:39]([O:44][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)=[CH:40][CH:41]=3)[O:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ccc2c(c1)OCC(c1cccc(F)c1)C2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2cccc(F)c2)C3)nc1

Procedure:
2-[3-(3-Fluorophenyl)chroman-7-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 125 mg of 3-(3-fluorophenyl)-chroman-7-ol. The product was recrystallised from ethanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.0, 2.8 Hz), 7.33 (m, 1H), 7.16 (d, 1H, J 8.9 Hz), 6.95-7.06 (m, 4H), 6.69-6.71 (m, 2H), 4.38 (dd, 1H, J 10.6, 4.3 Hz), 4.06 (t, 1H, 10.6 Hz), 3.30 (m, 1H), 3.06 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[O:20]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:35][CH:34]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(Oc5ccccc5)cc4)ccc3o2)C1

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.034 g, 0.131 mmol), 4-phenoxy-benzoic acid (0.042 g, 0.196 mmol), HATU (0.050 g, 0.131 mmol), polystyrene-bound diisopropylamine (0.327 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Concentrate the solution in vacuo. Dilute with CH2Cl2, wash with 1.0M NaOH (2×25 mL), dry over Na2SO4, filter, and concentrate in vacuo. Subject the residue to silica gel flash column chromatography on an ISCO Companion (4 g column, eluting with 10% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white oil. Dissolve in CH2Cl2 and add n-hexane. Re-concentrate to yield the desired product as a white solid (0.031 g, 52%). mass spectrum (m/e): 457.3 (M+1), 455.3 (M−1). 1H NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 8.01-7.99 (m, 2H), 7.70-7.68 (m, 1H), 7.49-7.42 (m, 2H), 7.35-7.32 (m, 2H), 7.25-7.20 (m, 1H), 7.13-7.07 (m, 4H), 3.52-3.47 (d, J=8.0 Hz, 2H), 3.12 (s, 3H), 2.66-2.55 (m, 1H), 2.55-2.47 (m, 2H), 2.43-2.35 (m, 1H), 2.55-2.47 (m, 2H), 2.43-2.35 (m, 1H), 2.28-2.24 (m, 1H), 2.23 (s, 3H), 1.93-1.83 (m, 1H), 1.49-1.39 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:6]2=[CH:7][C:8]=1[OH:9].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:15][CH:17]2[CH2:18][O:19]2)=[CH:7][C:6]2[O:10][C:11](=[O:12])[CH:13]=[CH:14][C:5]=2[CH:4]=1
Reactant: COc1cc2ccc(=O)oc2cc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ccc(=O)oc2cc1OCC1CO1

Procedure:
25.0 g (130 mmol) of scopoletine, 15.3 ml (196 mmol) epichlorohydrin, 36.0 g (260 mmol) potassium carbonate and 2.5 g of potassium iodide are agitated in 500 ml DMF under nitrogen for 3 h at 80° C. After vacuum evaporation and repeated extraction with hot ethanol re-evaporation was performed. 21.2 g (66%); fusion point 143°-145° C. (from ethanol).
Reaction SMILES: [O:1]([CH:9]1[CH2:13][CH2:12][C:11]([C:14]2[C:15]([F:29])=[C:16]3[O:20][C:19]([CH:21]4[CH2:23][CH2:22]4)=[N:18][C:17]3=[C:24]([C:27]#[N:28])[C:25]=2[CH3:26])=[CH:10]1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH:21]1([C:19]2[O:20][C:16]3[C:17](=[C:24]([C:27]#[N:28])[C:25]([CH3:26])=[C:14]([C:11]4[CH2:12][CH2:13][CH:9]([OH:1])[CH:10]=4)[C:15]=3[F:29])[N:18]=2)[CH2:23][CH2:22]1
Reactant: Cc1c(C2=CC(O[Si](C)(C)C(C)(C)C)CC2)c(F)c2oc(C3CC3)nc2c1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(C2=CC(O)CC2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
6-[3-(tert-Butyldimethylsiloxy)cyclopent-1-enyl]-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-304) (275 mg, 0.67 mmol) was dissolved in tetrahydrofuran (6 ml), and at 0° C., tetra-n-butylammonium fluoride (1.0 M tetrahydrofuran solution, 1.0 ml, 1.0 mmol) was added. After stirring at room temperature under nitrogen atmosphere for 16 hours, aqueous saturated ammonium chloride solution was added to the solution at 0° C., followed by stirring at the same temperature for 5 minutes. This was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=1:1, v/v) to obtain the entitled compound (91 mg, 46%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15]OC1C(C)=CC(C)=CC=1C.[C-:26]#[N:27].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][C:26]#[N:27]
Reactant: [C-]#N
Reactant: COc1ccccc1C1CCCCC1COc1c(C)cc(C)cc1C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1C1CCCCC1CC#N
Temperature: 100 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
Combine 2-[2-(2-methoxy-phenyl)-cyclohexylmethoxy]-1,3,5-trimethyl-benzene (0.810 g, 2.71 mmol), sodium cyanide (2.13 g, 43.4 mmol), and d6-DMSO (10.0 mL) at rm temperature. Heat and stir at 100° C. under nitrogen for 18 hours. Cool to room temperature and add ethyl acetate then add water and wash 5× with brine. Separate layers and dry over anhydrous sodium sulfate. Concentrate and flash chromatography using 0 to 30% ethyl acetate/hexanes to yield the titled compound (0.346 g, 56%). TLC Rf=0.43 in 20% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.2 (m, 1H), 7.0 (m, 1H), 6.9 (m, 2H), 3.8 (s, 3H), 3.3 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 2.1 (m, 1H), 1.8 (m, 6H), 1.4 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](C(O)=O)[CH:9]=2)[N:4]=1.C([O:18][C:19](C1C=C2C(C=CC=[N+]2[O-])=CC=1)=[O:20])C>>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([C:19]([OH:20])=[O:18])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Reactant: CNc1ccc2cc(C(=O)O)ccc2n1
Product: CNc1ccc2ccc(C(=O)O)cc2n1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 20, using 7-(ethoxycarbonyl)quinoline 1-oxide. 1H NMR (400 MHz, DMSO-d6, δ): 8.08 (s, 1H), 7.90 (d, 1H), 7.71-7.62 (m, 2H), 7.21 (s, 1H), 6.84 (d, 1H), 2.91 (d, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[CH2:8][NH2:9]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1-c1nccs1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccccc1-c1nccs1
Temperature: 70 °C
Yield: 79.9 %

Procedure:
To a stirred solution of (2-(thiazol-2-yl)phenyl)methanol (0.95 g, 5.1 mmol) in THF (15 mL) was added phthalimide (1.12 g, 7.65 mmol), triphenylphosphine (2.0 g, 7.65 mmol). The mixture was cooled in an ice-water bath and diisopropyl azodicarboxylate (3.1 g, 15.3 mmol) was added dropwise. After the addition, the mixture was stirred at 0° C. for 30 min, and at rt for 18 h. The mixture was then filtered and the filtrate was evaporated. The residue was purified by column chromatography to yield 2-(2-(thiazol-2-yl)benzyl)isoindoline-1,3-dione (1.1 g) as a white solid. To a stirred solution of 2-(2-(thiazol-2-yl)benzyl)isoindoline-1,3-dione (400 mg, 1.25 mmol) in ethanol (10 mL) was added dropwise hydrazine hydrate (160 mg, 3.1 mmol). The mixture was heated at 70° C. for 1 h. After cooling to rt, the mixture was filtered, and the filtrate was evaporated. The residue was purified by column chromatography to yield (2-(thiazol-2-yl)phenyl)methanamine (190 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][C:3]=1[C:12]([NH2:14])=[O:13].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:11][C:8]1[CH:7]=[CH:6][C:5]2[NH:4][C:3]3[C:12](=[O:13])[NH:14][C:16](=[O:15])[NH:1][C:2]=3[C:10]=2[CH:9]=1
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)c2[nH]c3ccc(Br)cc3c2[nH]1
Temperature: 25 °C
Yield: 98 %

Procedure:
1.3 g (5.1 mmol) 3-amino-5-bromo-1H-indole-2-carboxylic acid amide was suspended in 50 ml dioxan and, after the addition of 670 μl (5.5 mmol) diphosgene, refluxed for 2 h. Having cooled down to room temperature, 2 ml water was carefully added and thereafter the precipitate was sucked off. 1.4 g (94%) 8-bromo-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 278, 280 [M−H]−
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:15]([O:19]CC)OCC)=[N:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.[C:29](=[O:31])=[O:30]>CCOCC>[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[C:5]2[CH:22]=[CH:23][C:2]([C:29]([OH:31])=[O:30])=[CH:3][C:4]=2[O:8][N:7]=1)=[O:19]
Reactant: O=C=O
Reactant: CCOC(OCC)c1ccccc1-c1noc2cc(Br)ccc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccccc1-c1noc2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-bromo-3-(2-(diethoxymethyl)phenyl)benzo[d]isoxazole (Compound 5) (50 g) in dry ether (330 mL) under nitrogen at −78° C. was added a 2.5M solution of n-butyl lithium in hexanes (55.8 mL) was added dropwise and stirring continued at −78° C. for 45 min. The thick brown suspension was transferred via cannula to a mechanically stirred mixture of solid carbon dioxide pellets in ether (250 mL, under nitrogen and cooled in acetone/dry ice bath) and the resulting reaction mix topped up with further carbon dioxide pellets and left stirring in cold bath under nitrogen whilst warming to room temperature overnight. The reaction was quenched with 2N HCl (100 mL) and the ether removed under reduced pressure and ethanol (300 mL) added. The resultant yellow suspension was stirred on at 60° C. for 15 min, then cooled to room temperature and stirred in ice bath for 30 min and resulting yellow solid isolated by filtration and dried in vacuum oven at 45° C. to give the title product (29.76 g).
Reaction SMILES: O=C1NC=C([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)C=C1C(O)=O.[NH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=[O:23]>N1C2C(=CC=CC=2)C=CC=1>[N:12]1[CH:11]=[CH:16][N:15]([C:21]2[CH:20]=[CH:19][C:18](=[O:23])[NH:17][CH:22]=2)[CH2:14][CH:13]=1
Reactant: O=c1cccc[nH]1
Reactant: O=C(O)c1cc(-c2cnccn2)c[nH]c1=O
Solvent: c1ccc2ncccc2c1
Product: O=c1ccc(N2C=CN=CC2)c[nH]1
Temperature: 25 °C

Procedure:
1,2-Dihydro-2-oxo-5-(2-pyrazinyl)nicotinic acid (72.5 g) is added as a fine powder to 800 ml of stirred quinoline heated to just below boiling. The reaction mixture is refluxed for 24 hours, allowed to cool to RT and then placed in an ice bath, and the solid crystallized out. The solid is filtered, washed with ether, dried and recrystallized from isopropanol (first treating with charcoal and filtering while hot) yielding the desired decarboxylated pyridone.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=1.O[N:32]1[C:36]2[CH:37]=CC=C[C:35]=2N=N1.C1(N)CC1>ClCCl>[CH3:35][CH:36]([NH:32][C:28]([C:26]1[N:27]=[C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:14]4=[CH:15][C:16]5[O:20][CH2:19][O:18][C:17]=5[CH:21]=[C:13]4[O:12][CH2:11]3)[C:2]2=[O:1])[O:24][CH:25]=1)=[O:30])[CH3:37]
Reactant: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Solvent: ClCCl
Product: CC(C)NC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
A solution of 2-((2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)methyl)oxazole-4-carboxylic acid (0.41 g, 1.0 mmol), N-hydroxybenzotriazole (0.20 g, 1.5 mmol) and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.29 g, 1.5 mmol) in dichloromethane (10 mL) was stirred for 30 min, followed by the addition of cyclopropylamine (0.8 mL). The solution was stirred at ambient temperature for 16 h, diluted with dichloromethane (100 mL), washed with distilled water (2×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (gradient: 50% to 75%) to afford N-(1-methylethyl)-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide (0.40 g, 91%) as a colorless solid: mp 188-191° C.; 1H NMR (300 MHz, CDCl3) δ8.14 (s, 1H), 7.28-7.22 (m, 1H), 7.19 (d, J=6.8 Hz, 1H), 7.07 (dd, J=7.4, 7.4 Hz, 1H), 6.85 (d, J=7.7 Hz, 2H), 6.49 (s, 1H), 6.16 (s, 1H), 5.85 (ABq, 2H), 5.04 (ABq, 2H), 4.81 (ABq, 2H), 2.82 (m, 1H), 0.85-0.77 (m, 2H), 0.64-0.58 (m, 2H); 13C NMR (75M Hz, CDCl3) δ177.2, 161.3, 158.1, 155.8, 149.0, 142.4, 141.8, 141.0, 136.6, 132.0, 129.1, 124.15, 124.10, 119.2, 108.6, 103.0, 101.6, 93.7, 80.2, 58.2, 37.1, 22.3, 6.60, 6.55; MS (ES+) m/z 446.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[C:32](Br)[CH:31]=[CH:30][N:29]=1>>[NH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:26])[CH3:9])=[CH:4][CH:3]=2)[CH:31]=[CH:30][N:29]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Nc1cc(Br)ccn1
Product: C[C@@H](c1ccc(-c2ccnc(N)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-amino-4-bromopyridine in Step 4. LC-MS Method 2 tR=0.951, m/z=432; 1H NMR (CDCl3) 1.26-1.40 (m, 1H), 1.48 (d, 3H), 1.59-1.63 (m, 1H), 1.83-1.95 (m, 2H), 2.09-2.20 (m, 1H), 2.21-2.37 (m, 2H), 2.86 (m, 1H), 3.50 (m, 2H), 4.54-4.75 (s, 2H), 5.62 (m, 1H), 6.56 (s, 1H), 6.71 (d, 1H), 6.90 (d, 2H), 7.21-7.33 (m, 7H), 8.00 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.CO.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:15])[F:16])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(OC)cc2OC1C(F)(F)F
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
The ester from Step 2 (4 g, 12 mmole) was dissolved in a mixture of THF:MeOH:H2O and LiOH.H2O (4 g, 95 mmole) was added and the mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The mixture was acidified with 10% HCl and extracted with EtOAc. The EtOAc layer was washed twice with H2O, aqueous NH4Cl solution, dried over Na2SO4 concentrated in vacuo and to give 1.3 g (36% yield) of the product: 1H NMR (CDCl3/300 MHz) 7.48 (s, 1), 7.09 (s, 1H), 6.47 (s, 1H), 5.56 (q, 1H, J=6.9 Hz), 3.79 (s, 3H); ESHRMS m/z 307.0012 (M−H, C12H7ClF3O4, Calc'd 306.9985).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5].[CH2:19]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C>>[CH:2]([C:3](=[CH2:19])[C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])([CH3:18])[CH3:1]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Cc1cccc(-c2csc(C(=O)CC(C)C)c2)c1
Solvent: CC(=O)OC(C)=O
Product: C=C(C(=O)c1cc(-c2cccc(C)c2)cs1)C(C)C
Temperature: 110 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
3-methyl-1-(5-methyl-4-phenyl-(2-thienyl))butan-1-one (106 g, 0.411 mol), urotropin (161.2 g, 1.15 mol), and acetic anhydride (151.1 g, 1.48 mol) were mixed in a 1 L flask, sparged with nitrogen, and stirred for 24 h at 110° C. The dark mixture was cooled to 70° C. and poured into 700 mL of a 2 N aqueous solution of NaOH. The organic fraction was extracted with 50/50 (v/v) dichloromethane/hexane (3×250 mL), washed with 1 N HCl, saturated aqueous solution of NaHCO3, and dried (MgSO4). Evaporation of solvents gave 98 g of crude product (70% product by GC/MS) used without further purification. 1H-NMR δ (CDCl3): 7.5 (s, 1H), 7.2–7.38 (m, 5H), 5.6 (s, 1H), 5.45 (s, 1H), 2.9 (m, 1H), 2.41 (s, 3H), 1.05 (d, 6H). EIMS: m/z (%) 270 (M+, 65), 255 (100), 237 (11), 201 (89), 171 (11), 129 (38).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25](=[O:55])[C@@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH:52]=O)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:17]([O:24][C:25](=[O:55])[C@@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC1CCN(c2ccc(C(=O)N[C@@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.0.093 g, 0.4 mmol), (2S)-2-{[4-(4-(formyl)piperidin-1-yl)benzoyl]amino}butanedioic acid dibenzyl ester (0.4 mmol) and glacial acetic acid (0.022 g, 0.4 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.025 g, 0.4 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give the product (0.074 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH:18]=[CH:17][CH:16]=[C:14]([OH:15])[C:12]=1[OH:13])[OH:11].C(Cl)Cl>C(N(CC)CC)C.O1CCCC1>[C:1]([O:11][C:10]1[CH:18]=[CH:17][CH:16]=[C:14]([O:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]=1[O:13][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(O)c1O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1cccc(OC(=O)c2ccccc2)c1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
A 500 ml three-necked round-bottom flask equipped with a magnetic stirrer was charged with 20.0 g (0.142 mol) of benzoyl chloride, 6.2 g (0.05 mol) of pyrogallol, 400 ml of methylene chloride, and 50 ml of tetrahydrofuran (THF). Triethylamine (TEA; 15.3 g, 0.15 mol) was added drop-wise via an addition funnel over a period of 10 min. After the addition of TEA, the solution was stirred for an additional 15 min and subsequently transferred to a 1000 ml separatory funnel. The solution was washed with 150 ml of a 1.0 M solution of HCl (1×), 100 ml of 0.1 M solution of NaOH (2×), 100 ml of 1.0 M solution of HCl (1×), and 100 ml of deionized water (3×). The methylene chloride layer was extracted, dried over MgSO4 for 1 hour, and filtered. The methylene chloride was removed in vacuo, and a viscous oil was recovered. The viscous oil was placed into a minimal amount of methylene chloride and crystallized from hexanes after 2-3 weeks time (slow evaporation of solvent occurred during crystallization) to afford a white, crystalline solid. The solid was filtered and dried in vacuo (30 mm Hg) overnight.