Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH:12]([O:14][CH3:15])[CH2:11][CH2:10][CH:9]1[CH2:16][CH:17]([OH:47])[CH:18]([NH:26][C:27](=[O:46])[CH:28]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:29][S:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:56])C=1>ClCCl>[C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH:12]([O:14][CH3:15])[CH2:11][CH2:10][CH:9]1[CH2:16][CH:17]([OH:47])[CH:18]([NH:26][C:27](=[O:46])[CH:28]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:29][S:30]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=[O:56])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1CCC(CC(O)C(Cc2ccccc2)NC(=O)C(CSc2ccc3ccccc3c2)NS(C)(=O)=O)C(C(=O)NC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC1CCC(CC(O)C(Cc2ccccc2)NC(=O)C(CS(=O)c2ccc3ccccc3c2)NS(C)(=O)=O)C(C(=O)NC(C)(C)C)C1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-2-ylsulfanyl)-propionylamino]-4-phenyl-butyl}-5-methoxy-cyclohexanecarboxylic acid tert-butylamide (80 mg, 0.117 mmol) in dichloromethane (3 ml) was cooled to −10° C. A solution of meta-chloroperbenzoic acid in dichloromethane (2 ml) was added and the mixture stirred at −10° C. for 30 minutes. The solution was then washed with 5% aqueous sodium hydrogen carbonate solution, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give, after purification by flash chromatography on silica gel (dichloromethane/methanol: 97/3 2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-2-sulfinyl)-propionylamino]-4-phenyl-butyl}-5-methoxy-cyclohexanecarboxylic acid tert-butylamide (65 mg, 70%) as a white solid. Mass spectrum, 701 [M+H]+. The following compounds were prepared in a similar manner, by oxidation of the appropriate sulphide:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:25]=[C:26]([C:31](=O)[CH2:32][NH:33][C:34](=O)[CH2:35][CH2:36][C:37]2[N:38](S(N(C)C)(=O)=O)[CH:39]=[C:40]([CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45])[N:41]=2)[CH:27]=[CH:28][C:29]=1[F:30]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([C:31]2[S:10][C:34]([CH2:35][CH2:36][C:37]3[NH:41][C:40]([CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45])=[CH:39][N:38]=3)=[N:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)NCC(=O)c2ccc(F)c(F)c2)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCC(C)(C)Cc1cnc(CCc2ncc(-c3ccc(F)c(F)c3)s2)[nH]1

Procedure:
Lawesson's reagent (50 mg, 0.12 mmol) was added to a solution of N-[2-(3,4-difluorophenyl)-2-oxoethyl]-3-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H -imidazol-2-yl]propanamide (30 mg, 0.06 mmol) in dry toluene (4 mL) at rt. After stirring at reflux for 30 min, volatiles were removed. The resulting residue was dissolved in THF (0.5 mL), and 2M aqueous hydrochloric acid (1.5 mL) was added. After stirring at 80° C. overnight, the volatiles were removed. The aqueous phase was diluted with water and washed with 1:5 ethyl acetate/diethyl ether. The aqueous phase was basified with 1N sodium hydroxide and extracted with ethyl acetate. Combined extracts were washed with brine, dried (sodium sulfate) and concentrated to afford the title compound, which was dissolved in methylene chloride and acidified with 1M hydrogen chloride in diethyl ether. Additional diethyl ether and hexane were added, and concentration afforded the HCl salt of the title compound. LC-MS: m/e 376 (M+H).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:10]([C:12]1[S:13][C:14]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:10]#[N:11])[S:13][C:14]=2[CH:20]=1
Reactant: BrCc1ccccn1
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3ccccn3)cc2s1
Yield: 72 %

Procedure:
(Bromomethyl)pyridine hydrobromide (1.87 g, 7.38 mmol) and 2-cyano-6-hydroxybenzothiazole (1.00 g, 5.68 mmol) were suspended in acetone (50 mL). After introduction of potassium carbonate (1.96 g, 14.2 mmol), the suspension was refluxed for 72 h under nitrogen. After cooling down the mixture and filtering the solids, the filtrate was concentrated and the residue was purified by silica gel chromatography using 50%-75% ethyl acetate in heptane. A yellowish solid was obtained in 72% yield. MS (ESI+): m/z 267.90 (M+H)+; calc'd: 268.05.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32]>C(O)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: Fc1ccc(F)c(/C=C/CCl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(C/C=C/c2cc(F)ccc2F)CC1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
A mixture of tert-butyl piperidin-4-ylcarbamate (248 mg, 1.2 mmol), potassium carbonate (188 mg, 1.4 mmol) and 2-[(1E)-3-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124, 257 mg, 1.4 mmol) in ethanol (7 mL) was heated to 80° C. for 18 hours. The mixture was concentrated under reduced pressure, the residue taken up in dichloromethane (20 mL) and water (20 mL), the aqueous phase was back extracted with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 300 mg (69%) of product as a brown foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:23])([N+:20]([O-])=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:13]=2)[NH:8][CH:7]=1>CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH2:20])([CH3:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:13]=2)[NH:8][CH:7]=1
Reactant: COCCOc1ccc2[nH]cc(CC(C)(C(=O)OC)[N+](=O)[O-])c2c1
Solvent: CO
Product: COCCOc1ccc2[nH]cc(CC(C)(N)C(=O)OC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a stirred solution of (+/−)-3-[5-(2-methoxy-ethoxy)-1H-indol-3-yl]-2-methyl-2-nitro-propionic acid methyl ester (12.7 g, 37.8 mmol) in dry methanol (200 ml) Raney nickel (ca 20 g) is added and the mixture is stirred at room temperature under H2 at atmospheric pressure overnight. The reaction mixture is filtered through a pad of Celite and the solid is washed with methanol. The filtrate is concentrated and the residue is purified by column chromatography (dichloromethane-methanol, 9:1) to give (+/−)-2-amino-3-[5-(2-methoxy-ethoxy)-1H-indol-3-yl]-2-methyl-propionic acid methyl ester (5.98 g, 52%). M.p. 117-118 (from ethyl acetate-light petroleum).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([CH3:12])[CH:6]=1.C(O[C:16]1[O:17][CH2:18][C:19](=[O:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C(O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:16]2[O:17][CH2:18][C:19](=[O:26])[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:12])[CH:6]=1
Reactant: Cc1cc(OCCO)ccc1N
Reactant: CCOC(=O)C1=C(OCC)OCC1=O
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCO)cc2C)OCC1=O

Procedure:
A solution of 4-(2-hydroxyethoxy)-2-methylaniline (0.69 g, 4.1 mmol) and ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.83 g, 4.2 mmol) in ethanol (8.3 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, and ethanol was added to precipitate the product. The precipitate was collected by filtration then dried to afford ethyl 2-{[4-(2-hydroxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.55 g, y. 42%).
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+:2]=[N-:3]>O1C=CCCC1>[OH:10][CH2:9][CH2:8][CH2:4][C:5]1[N:3]=[N:2][N:1]([C:4]2[CH2:5][C@@H:6]3[CH2:23][C:22](=[O:24])[N:7]3[C:8]=2[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:10])[CH:6]=1
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Agent: C1=COCCC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(n2cc(CCCO)nn2)C[C@@H]2CC(=O)N12
Yield: 46.2 %

Procedure:
A solution of p-nitrobenzyl 2-azido-carbapen-2-em-3-carboxylate (27.6 mg, 83.8 micromol) in dihydropyran (1.0 ml) was kept 46 hours at 4° C. and 51 hours at ambient temperature. The reaction mixture was chromatographed on two 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plates developed with 3:1 (v/v) diethyl ether-ethyl acetate. The band centered at Rf 0.10 was eluted with ethyl acetate, and the eluate was evaporated under vacuum to provide 8.0 mg (23%) p-nitrobenzyl 2-(4-[3-hydroxypropyl]-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylate; IR (CDCl3): 3600-3100, 1775, 710, 1610, 1520, 1345, 1290, 1215 cm-1 ; NMR (CDCl3): δ 1.78 m (2H), 2.44 t (J=7.5 Hz, 2H), 2.99 dd (J1 =3 Hz, J2 =17 Hz, 1H), 3.37 dd (J1 =8 Hz, J2 =20 Hz, 1H), 3.57 dd (J1 =5 Hz, J2 =17 Hz, 1H), 3.70 bt (J=6 Hz,2H), 3.85 dd (J1 =10 Hz, J2 =20 Hz, 1H), 4.14 m (1H), 5.31 d (J=14 Hz, 1H), 5.52 d (J=14 Hz, 1H), 7.70 d (J=9 Hz, 2H), 8.31 d (J=9 Hz, 2H), 9.84 s (1H); UV (CH2Cl2) λmax (ε): 272 (6000), 317 (8300) nm.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CC(N(C)C)=O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)#[N:17]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Yield: 38.5 %

Procedure:
A mixture of 4-hydroxybenzoic acid (3.50 g, 25 mmol), 4-fluorobenzonitrile (3.00 g, 35 mmol), and powdered K2CO3 (6.80 g, 49 mmol) were heated in DMAC (50 mL) at 140° C. for 20 hours. The cooled mixture was then acidified with 1N HCl and extracted with EtOAc (3×50 mL). Concentration of the extracts in vacuo left a residue which was chromatographed over silica gel (5% MeOH/CHCl3) to provide 2.30 g (39%) of pure product. MS (FD+) 238.9
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C:15](OCC)=[N:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29]([NH:31][NH2:32])=O>C(O)CCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]2[C:29]([C:21]3[S:20][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=3)=[N:31][N:32]=[C:15]2[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1=NCCN(C(=O)OCc2ccccc2)C1
Reactant: NNC(=O)c1nc2ccccc2s1
Solvent: CCCCO
Product: O=C(OCc1ccccc1)N1CCn2c(nnc2-c2nc3ccccc3s2)C1
Temperature: 25 °C

Procedure:
A mixture of 5-ethoxy-3,6-dihydro-2H-pyrazine-1-carboxylic acid benzyl ester (prepared according to the method of Example 259, Step A, 490 mg, 1.87 mmol) and benzothiazole-2-carboxylic acid hydrazide (360 mg, 1.87 mmol; J. Org. Chem. 1958, 23, 1344) in n-butanol (2 mL) was stirred at reflux overnight, cooled to room temperature, concentrated, and purified by flash column chromatography (1% methanol/chloroform) to give 580 mg of the title compound of Example 259, Step B (contaminated with an equimolar amount of benzothiazole-2-carboxylic acid hydrazide which was removed in the subsequent step) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]=[CH2:5].B.[O:13]1CCCC1.OO>>[F:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][CH2:5][OH:13]
Reactant: C1CCOC1
Reactant: C=CCC(F)CCCCCC
Agent: B
Agent: OO
Product: CCCCCCC(F)CCCO

Procedure:
The title compound was prepared essentially as described in Example 1. R-4-fluoro-1-methanesulfonoxydecane was prepared by copper catalyzed addition of vinyl magnesium bromide to epichlorohydrin to yield 5-chloro-4-hydroxypent-1-ene which was treated with base to give the corresponding epoxide. The epoxide is then ring opened by the addition of propyl magnesium bromide to yield 4-hydroxy-dec-1-ene. This hydroxy compound is converted to 4-fluoro-dec-1-ene as described in Example 1, followed by treatment with borane/tetrahydrofuran and hydrogen peroxide to give 4-fluoro-decanol. This alcohol was treated with methane sulfonyl chloride in the presence of triethylamine to yield the desired intermediate R-4-fluoro-1-methylsulfonoxy decane.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](O)=[O:26]>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][N:30]=[C:22]([O:21][CH3:20])[CH:23]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: COc1cc(C(=O)O)ccn1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)ccn1

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 2-methoxy-isonicotinic acid, the title compound was prepared. MS: m/e=416(M+H+). Following the general method of example 1 the compounds of examples 17 to 34 were prepared.
Reaction SMILES: [OH:1][C@H:2]([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O)[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@@H:31]([O:30][C:15]1[CH:14]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:1][C@@H:2]([CH3:36])[C@@H:3]([CH3:4])[N:5]=3)=[CH:12][CH:11]=2)[CH:18]=[C:17]([O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:27]([CH3:29])[CH3:28])[CH:16]=1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](C)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
N-[(2R,3R)-3-Hydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (722 mg, 1.39 mmol) synthesized in Example (109a) was dissolved in tetrahydrofuran (30 mL), and anhydrous methanesulfonic acid (430 mg, 2.47 mmol) and triethylamine (1.20 mL, 8.61 mmol) were added, and stirring was carried out at 50° C. overnight under nitrogen atmosphere. The reaction solution was brought back to room temperature, and a saturated aqueous ammonium chloride solution (50 mL) was added, followed by extraction with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-70%) to afford the desired compound (700 mg, yield 100%) as a yellow liquid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[C:3]1=[N:9]O.C(=O)([O-])[O-:12].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[NH:9][C:3]1=[O:12]
Reactant: C[C@H]1CCC[C@H](C)C1=NO
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C[C@H]1CCC[C@H](C)C(=O)N1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Into 20 ml of xylene were added 1.3 g of trans-2,6-dimethylcyclohexanone oxime and 6 g of polyphosphoric acid, the mixture was stirred for 10 hours at 100° C. The reaction mixture was cooled to near room temperature, poured into ice-water. Sodium carbonate was added to the mixture, and the mixture was extracted with ethyl acetate three times. The organic layers was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.2 g of trans-3,7-dimethylhexahydro-1H-azepine-2-one.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[C:16]([O-:19])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:24]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>CC#N>[CH2:24]([CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:19][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C([O-])[O-]
Reactant: CCCCC1CCNCC1
Reactant: O=C1COc2ccccc2N1CCCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)COc3ccc(OC)cc32)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A 7 mL vial was charged with 4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (1.0 equiv), K2CO3 (2.0 equiv), NaI (2.0 equiv) and 4-Butylpiperidine (1.05 equiv) in 5 mL dry MeCN and shaken at 60° C. for 48 h. The reaction mixture was evaporated to dryness, diluted with 10 mL H2O, extracted into CH2Cl2 (3×13 mL), and filtered through a PTFF Whatman filter. The combined organic layers were evaporated to dryness and purified by CC (Heptane/EtOAc or CH2Cl2/MeOH) or prep TLC (Heptane/EtOAc or CH2Cl2/MeOH).
Reaction SMILES: Cl.[CH:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)([CH3:4])[CH3:3].C(N(CC)CC)C.ClCCl.Cl[S:27]([C:30]1[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=1)[C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])(=[O:29])=[O:28]>N1C=CC=CC=1>[CH:2]([N:5]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)[S:27]([C:30]1[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=1)[C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:40])[CH3:41])=[O:34])(=[O:28])=[O:29])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@H]1CC[C@H](NC(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](N(C(C)C)S(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 734 mg of methyl trans-4-(isopropylamino)cyclohexane carboxylate hydrochloride, 0.90 mL of triethylamine, and 10 mL of dichloromethane was stirred at room temperature for 30 minutes, and 10 mL of pyridine and 1.00 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate were added thereto in this order, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 311 mg of 2-(trimethylsilyl)ethyl 3-{isopropyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoate as a pale yellow solid. ESI+: 484
Reaction SMILES: [S:1]1[C:5]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.Cl.Cl.[NH2:24][CH:25]1[CH2:32][CH:31]2[N:33]([CH3:34])[CH:27]([CH2:28][CH2:29][CH2:30]2)[CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:34][N:33]1[CH:27]2[CH2:28][CH2:29][CH2:30][CH:31]1[CH2:32][CH:25]([NH:24][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:5]4[S:1][C:2]5[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=5[CH:4]=4)=[N:10][C:9]=13)=[O:17])[CH2:26]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3cc4ccccc4s3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cc5ccccc5s4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.4 %

Procedure:
A mixture of 2-benzo[b]thiophen-2-ylbenzoxazole-4-carboxylic acid (128 mg, 0.43 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (118 mg, 0.52 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (164 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.63 mL, 2.2 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-benzo[b]thiophen-2-yl benzoxazole-4-carboxamide (49 mg, 61%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.97 (d, J=7.0 Hz, 1H), 8.38-8.19 (m, 2H), 7.95 (dd, J=7.5, 1.5 Hz, 2H), 7.71 (dd, J=8.0, 1.0 Hz, 1H), 7.51-7.46 (m, 3H), 4.63-4.55 (m, 1H), 3.14 (d, J=10.0 Hz, 2H), 2.70-2.62 (m, 2H), 2.56 (s, 3H), 2.08-2.00 (m, 2H), 1.66-1.52 (m, 4H), 1.28-1.22 (m, 2H); MS (ESI+) m/z 432 (M+H); HPLC>99% (AUC), tR=14.59 min.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH2:13][CH2:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH3:22][C:23]([CH3:25])=O>[Cl-].[Cl-].[Zn+2]>[CH3:22][C:23]([NH:21][C:18]1[CH:19]=[N:20][C:15]([CH2:14][CH2:13][CH2:12][C:8]2[S:7][CH:11]=[CH:10][N:9]=2)=[CH:16][CH:17]=1)([CH3:25])[C:5]#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: Nc1ccc(CCCc2nccs2)nc1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C#N)Nc1ccc(CCCc2nccs2)nc1
Yield: 97.6 %

Procedure:
TMSCN (3.7 mL, 27.9 mmol) was added to a mixture of the compound 139 (2.04 g, 9.3 mmol), acetone (4.1 mL, 55.8 mmol) and ZnCl2 (122 mg, 0.9 mmol) with stirring. The reaction mixture was stirred at 40° C. for 0.5 h, and concentrated in vacuo. The residue was diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 140 (2.6 g, 99%) as a light yellow oil. The crude product was used directly for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1>[CH:10](=[N:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)cc(N=Cc2ccccc2)c1

Procedure:
To a reaction flask, equipped with a Dean-Stark trap, is added 3,5-dichloroaniline (16.2 g., 0.10 mole), benzaldehyde (10.6 g., 0.10 mole), p-toluenesulfonic acid monohydrate (0.2 g.), and toluene (100 ml.). The reaction mixture is then warmed to reflux and the water (1.65 ml.) collected by azeotroping. The cooled reaction mixture is treated with charcoal and the filtrate reduced in vacuo to give an amber oil that crystallizes on standing to give N-benzylidene-3,5-dichloroaniline which is recrystallized from pentane. m.p. 52°-53° C.