Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3C=CS[C:12]=3[C:16]([OH:18])=[O:17])=[C:4]2[CH:3]=[CH:2]1.N[C:20]1[S:21]C=C[C:24]=1C(OC)=O>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[S:21][CH:20]=[CH:24][C:12]=3[C:16]([OH:18])=[O:17])=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccsc1N
Reactant: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Product: O=C(O)c1ccsc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid using methyl 2-aminothiophene-3-carboxylate instead of methyl 3-aminothiophene-2-carboxylate.). LCMS (ESI) 260 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (1H, br. s.) 10.77 (1H, s) 8.16 (1H, d, J=5.66 Hz) 7.41 (1H, dd, J=3.22, 1.85 Hz) 7.23 (1H, d, J=5.86 Hz) 7.01 (1H, d, J=5.86 Hz) 6.94 (1H, d, J=5.66 Hz) 6.47 (1H, d, J=2.73 Hz)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][S:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11].O.[OH-].[Li+]>O1CCOCC1.O>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][S:8][C:9]([CH3:16])([CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)(C)SC[C@H]1COCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(SC[C@H]1COCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 432 h
Yield: 98.1 %

Procedure:
To a solution of 169 mg (0.68 mmol) of ethyl 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methylpropanoate in THF/water (1/1, 10 mL) are added 102 mg (1.36 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 18 d h. Then additional THF/water (1/1, 10 mL) is added and the reaction is for further 48 h. The reaction mixture is concentrated under reduced pressure. The aqueous residue is washed with diether ether (10 mL), then acidified with 6M aqueous HCl solution and extracted with ethyl acetate (3×10 mL). The combined organic extracts are dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to afford 147 mg of 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methylpropanoic acid. Yield: 86%; ES-MS: m/z 243 [M+Na]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.55 (6H, s), 2.65-2.72 (1H, m), 2.73-2.81 (1H, m), 3.32-3.41 (1H, m), 3.57-3.64 (1H, m), 3.68-3.77 (3H, m), 3.77-3.86 (2H, m)
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[NH2:22])[CH2:12]2)[CH2:8][CH2:7]1)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:27]([N:35]=[C:36]=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:1]([N:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[NH:22][C:36]([NH:35][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[S:37])[CH2:12]2)[CH2:8][CH2:7]1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12
Solvent: ClCCl
Product: CC(C)(C)CN1CCC2(CC1)CN(c1ccccc1NC(=S)NC(=O)c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 20f (118 mg, 0.33 mmol) and benzoylisothiocyanate (63 μL, 0.47 mmol) in DCM (3 mL) was stirred at rt for 3 h. The reaction was concentrated and the residue was purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to give 20g, as yellow solid (156 mg). LC-MS m/z 513.06 [M+H]+.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:5]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: O=C(Cl)C1CCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)C1CCC1
Yield: 56.2 %

Procedure:
Cyclobutanecarbonyl chloride (2.37 g, 20 mmols) was added to a chloroform (30 ml) solution of benzyl alcohol (2.16 g, 20 mmols) and triethylamine (2.2 g, 22 mmols) with cooling with ice, and then heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ether. The organic layer was washed with 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate and the solvent was evaporated. The resulting oil was purified through silica gel column chromatography (developer:hexane/acetone=10/1) and distilled (110° C./1.2 mmHg) to obtain 2.14 g (yield: 56%) of benzyl cyclobutanecarboxylate as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[OH-].[Na+]>>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:20]=[N:21][CH:22]=[C:8]2[CH:7]=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (5.6 g, 13.6 mmol) in IMS (50 mL) was added aqueous sodium hydroxide (27.2 mL, 1M, 27.2 mmol) and the reaction mixture stirred at 65° C. for 2 hours. The reaction mixture was concentrated in vacuo to remove the IMS. The resultant solution was acidified to pH ˜5 by addition of aqueous hydrochloric acid (1M) causing a precipitate to form. The product was collected by filtration and dried under vacuum at 45° C. to yield the title compound as a beige solid (5.4 g, 100%). LCMS (Method B): RT=2.79 min, M+H+=398.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[NH2:19][C:20]1[CH:25]=[C:24](Cl)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>O>[NH2:19][C:20]1[CH:25]=[C:24]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: OCCOCc1ccccc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A solution of 7.5 g. of 2-benzyloxyethanol in 30 ml. of dimethylformamide is treated with 1.2 g. of sodium hydride. When the mixture is homogeneous, 3.5 g. of 2-amino-4-chloro-1-nitrobenzene is added and the mixture heated at 110°-120° for 4 hours. The mixture is cooled, diluted with water and extracted with benzene. The crude product is treated with charcoal and isolated by precipitation with cyclohexane to afford 2-amino-1-nitro-4-(2-benzyloxyethoxy)benzene.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)C.CCOCC>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1cnc2cnc(Cl)cc2c1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CCOCC
Solvent: CCO
Product: N#Cc1cnc2cnc(Cl)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To the above 600 mg of 4,6-dichloro-[1,7]naphthyridine-3-carbonitrile in 20 mL of absolute ethanol was added 1 mL of 3-bromoaniline. After refluxing the reaction under an inert atmosphere for 4 hours, the reaction mixture was cooled to ambient temperature, diluted with ether, and the product was filtered and washed with ether. Drying in vacuo yielded 790 mg of 4-(3-bromo-phenylamino)-6chloro-[1,7]naphthyridine-3-carbonitrile as an off-white solid: mp=220-223° C.; mass spectrum (m/e): M+H 359.0, 361.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>[Pt](=O)=O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)NCc1ccnc(Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-4-cyanopyridine (1.9 g), platinum dioxide (0.3 g), acetic anhydride (50 ml) and acetic acid (50 ml) was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between chloroform and dilute aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated to give N-(2-chloropyrid-4-ylmethyl)acetamide (1.5 g), as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Br.[CH3:11][C:12]1([CH3:21])[CH2:17][CH2:16][C:15](B(O)O)=[CH:14][CH2:13]1.C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:15]1[CH2:16][CH2:17][C:12]([CH3:21])([CH3:11])[CH2:13][CH:14]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: N#Cc1ccc(N)c(Br)c1
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: [Na+]
Product: CC1(C)CC=C(c2cc(C#N)ccc2N)CC1

Procedure:
The title compound was prepared from 4-amino-3-bromo-benzonitrile (as prepared in the previous step, 1.0 g, 5.0 mmol), 4,4-dimethylcyclohexen-1-yl boronic acid (938 mg, 6.07 mmol), Pd(PPh3)4 (585 mg, 0.506 mmol) and 2M Na2CO3 (20.2 mL, 40.5 mmol) according to the procedure in Example 44, step (b) (284 mg, 25%). Mass spectrum (ESI, m/z): Calcd. for C15H18N2, 227.1, found 227.3.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:9](O)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: CC(C)(C)O
Reactant: C=CCCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 5-hexenoic acid (15.2 mL, 0.131 mol) in DCM (375 mL), cooled to 0° C., tert-butanol (176 mL, 1.84 mol) and then 4-dimethylaminopyridine (3.21 g, 26.3 mmol) were added. The mixture was stirred at room temperature for 22 hrs, filtered and concentrated. The residue was redissolved in DCM/n-hexane and concentrated under reduced pressure. The crude oil was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 5 to 10%), affording the title product.
Reaction SMILES: [NH2:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)C1C=CC=CC=1)C.[C:46]([CH2:48][CH2:49][C:50](Cl)=[S:51])#[N:47]>O1CCCC1>[C:46]([CH2:48][CH2:49][C:50]([NH:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[S:51])#[N:47]
Reactant: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: N#CCCC(=S)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Product: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1

Procedure:
To 244 mg of benzhydryl 7-amino-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate in 20 ml of anhydrous tetrahydrofuran were added dropwise at -7° C. with stirring 115 mg of N,N-diethylaniline and, subsequently, 115 mg of cyanomethylthioacetyl chloride in 5 ml of anhydrous tetrahydrofuran. After completion of the reaction, the reaction mixture was then treated in the same manner as in Example 1--(a) to give a crude product. The crude product was purified by developing it with ethyl acetate by the use of silica gel thin layer chromatography (20×20×0.2 cm) to yield 50 mg of benzhydryl 7-cyanomethylthioacetamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:25]([NH:32][C:33](=[S:36])[NH:34][NH2:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CCO>[CH2:25]([NH:32][C:33]([NH:34][N:35]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNC(=S)NCc1ccccc1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: O
Solvent: CCO
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C=NNC(=S)NCc4ccccc4)cc3)n2)cc1
Temperature: 80 °C

Procedure:
To a 50 mL round-bottomed flask containing 4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]benzaldehyde (500 mg, 1.5 mmol) in EtOH (3 mL) was added 4-benzylthiosemicarbazide (650 mg, 3.6 mmol). The reaction mixture was heated at 80° C. overnight. H2O was added upon completion of the reaction, and the crude product material was isolated by vacuum filtration. The title compound was isolated via RP-HPLC as a white solid (390 mg, 52%): mp 220-224° C.; 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.59 (s, 1H), 8.21 (d, J=8.4 Hz, 2H), 7.85-7.79 (m, 3H), 7.71 (d, J=8.4 Hz, 2H), 7.46-7.30 (m, 8H), 5.01 (d, J=5.8 Hz, 2H); ESIMS m/z 497.2 (M+H).
Reaction SMILES: O[C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[CH:10]=1.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)cn2ccccc12
Solvent: CC#N
Product: CCOC(=O)c1c(Cl)cn2ccccc12
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of 3.0 g of ethyl 2-hydroxypyrrolo [1,2-a]pyridine-1-carboxylate in 50 ml of acetonitrile, 2.7 g of phosphorus oxychloride is added at room temperature and stirred for 2 hours. The reaction mixture is concentrated under reduced pressure, added with water and then extracted with dichloromethane. The extract is dried on anhydrous sodium sulfate and distilled to remove dichloromethane. The residue is purified by silica gel chromatography (eluent: n-hexane-ethyl acetate) to give 2.0 g of the title compound as crystals.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]=[C:19]2[S:23][C:22](=[S:24])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]2=[O:29])[N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:9][C:10](=[S:11])[NH:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]=[C:19]2[S:23][C:22](=[S:24])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]2=[O:29])[N:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC(=S)NC(=O)c3ccccc3)n2)SC1=S
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.6 g of benzoyl isothiocyanate were added dropwise, at room temperature, to a solution of 4 g of 5-(2-aminothiazol-4-ylmethylene)rhodanine-3-acetic acid in 70 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 6 hours. then ethyl acetate was added and precipitated solids were filtered off. The ethyl acetate solution was washed with water and concentrated under reduced pressure, and the crystalline solid thus obtained was separated by filtration and recrystallized from acetic acid, giving the title compound as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.Cl.[CH:19]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][O:21][CH2:20]2.C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([N:26]2[CH:19]3[CH2:25][CH2:24][CH:23]2[CH2:22][O:21][CH2:20]3)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4CCC3COC4)n2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
In a 250 mL round-bottomed flask was placed 4,6-dichloro-2-(4-nitrophenyl)pyrimidine (59, 192 mg, 0.711 mmol) in dichloromethane (8 mL) to give a colorless solution. 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (33, 106 mg, 0.711 mmol) was added and the solution was cooled to 0° C. Triethylamine (0.297 mL, 2.133 mmol) was added slowly and the mixture was allowed to slowly warm to room temperature, and stirred for 16 hours at room temperature. The mixture was heated under reflux for 2 hours, diluted with dichloromethane and washed with saturated NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated. the crude product was applied to a silica gel column and eluted with 5-40% EtOAc in hexanes to give the title compound (212 mg, 86%). The sample was identical to the same compound prepared according to Scheme 16. HRMS: For [M+H]+ mass error=0.1 mDa or 0.39 ppm.
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]1([CH3:24])[O:12][CH:11]([CH2:13][O:14][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][O:9]1.[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>CC(O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:16]([C:15](=[CH:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:26]=1[Cl:25])[O:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]([CH3:7])([CH3:24])[O:12]1)=[O:23])[CH3:22]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)COCC1COC(C)(C)O1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CCOC(=O)CC(=O)C(=Cc1cccc(Cl)c1Cl)OCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
Piperidine (1.0 g) was added dropwise over 5 minutes to a stirred, ice-cooled solution of ethyl 4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy }acetoacetate (26.0 g) (see Preparation 5) and 2,3-dichlorobenzaldehyde (17.5 g) in 2-propanol (200 ml) and the mixture was stirred with ice-cooling for 2 hours and at room temperature for 14 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on silica (150 g) using toluene plus 0-40% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give essentially pure ethyl -(2,3-dichlorobenzylidene)-4-{(2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}acetoacetate (17.3 g) as an oil. A solution of this oil in 2-propanol (150 ml) was treated with methyl 3-amino-crotonate (5.0 g) and the mixture stirred at room temperature for 24 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on SiO2 (110 g) using toluene plus 0-10% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound (2.75 g), m.p. 135°-137° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([S:20][C:21](Cl)=[O:22])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([S:20][C:21](=[O:22])[NH:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[CH3:19]
Reactant: CCSC(=O)Cl
Reactant: NCCOc1ccc(Sc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSC(=O)NCCOc1ccc(Sc2ccccc2)cc1
Yield: 66.2 %

Procedure:
7 g of 2-[p-(phenylthio)phenoxy]ethylamine and 18.6 g of chlorothioformic acid S-ethyl ester are dissolved in 250 ml of acetone. 24 g of potassium carbonate are added to the solution and the mixture is heated under reflux for 6 hours. The mixture is then filtered, the residue is washed with acetone and the filtrate is evaporated in vacuo. The 13 g of residue are filtered through a 10-fold amount of silica gel with ether/cyclohexane (7:3). The first fractions yielded 10.2 g which, after recrystallization from ether/low boiling petroleum ether yields 6.3 g (76%) of 2-[p-(phenylthio)phenoxy]ethylthiocarbamic acid S-ethyl ester, m.p.--77°-79° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1(O)[CH:21]2[CH2:22][N:18]([CH2:19][CH2:20]2)[CH2:17]1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:7][C:16]1([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][N:10]=2)[CH:21]2[CH2:22][N:18]([CH2:19][CH2:20]2)[CH2:17]1
Reactant: OC1(c2cnccn2)CN2CCC1C2
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: FC1(c2cnccn2)CN2CCC1C2
Reaction time: 24 h
Yield: 14.8 %

Procedure:
Diethylaminosulphur trifluoride (0.42 g, 2.62 mmol) was added to a stirred solution of 3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (0.5 g, 2.62 mmol) in dichloromethane (30 ml), at -65° C. After 24 h, water (20 ml) was added, basified with potassium carbonate, and extracted into dichloromethane (3×50 ml). The combined extracts were dried (Na2SO4), evaporated, and the residue chromatographed through silica-gel, eluting with dichloromethane-methanol (90:10) to give 3-fluoro-3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptane (75 mg). The compound was further purified as the hydrogen chloride salt, m.p. 245° C. (dec.) (isopropylalcohol); (Found: C, 52.33; H, 5.79; N, 17.97. C10H12F.HCl requires C, 52.29; H, 5.66; N, 18.30%) m/e 193 (M+ for free base); δ(360 MHz, CDCl3) 1.06-1.13 (1H, m, CH of CH2 --N); 1.44-1.55 (1H, m, CH of CH2 --N); 2.58 (1H, dd, J=3.1 and 9.7 Hz, CH of CH2 --N); 2.65-2.72 (1H, m, CH of CH2 --N); 2.83-2.91 (2H, m, CH-bridgehead and CH of CH2 --N); 3.09-3.24 (2H, m, 2 of CH of CH2 --N); 3.59 (1H, ddd, J=3.1, 13.6 and 20.8 Hz, CH of CH2 --N); 8.50-8.53 (2H, m, 2 of pyrazine-H); 8.91 (1H, d, J=1.2 Hz, pyrazine-H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1.[CH2:21]([CH:29]1[CH2:31][O:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@H:29]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Reactant: c1ccc(CCC2CO2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCN(C[C@H](O)CCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=344.4 (M+H+) was prepared from (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoro-acetic acid and (RS)-2-phenethyl-oxirane.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:18]2[C@@H:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH:13](SC2C=CC=CC=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:18]2[C@@H:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@@H]2[C@@H](COC(=O)c3ccccc3)OC(Sc3ccccc3)[C@@H]2O1
Agent: [Ni]
Solvent: CCO
Product: O=C1C[C@H]2[C@H](CO[C@@H]2COC(=O)c2ccccc2)O1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A 3-neck, 1000 mL round-bottom flask, equipped for overhead mechanical stirring, was charged with 29.6 g of 8 (80 mmol), 500 mL of ethanol and approximately 30 g of Raney-Ni (Aldrich, which had been washed to neutrality with distilled water). The resulting slurry was heated at reflux for 5 h while stirring vigorously. The reaction mixture was then cooled to room temperature, and the solids were carefully filtered off through a pad of celite. The residue was washed thoroughly with ethanol, and the combined filtrates were concentrated to afford a yellow solid which was purified by chromatography on silica gel to afford 7.63 g (36% yield) of 9 as a white solid. A small sample was recrystallized from acetone/hexane to afford colorless needles: mp 89.5-90.0° C.; [α]D22 +3.18 (c=0.8 in CHCl3); Rf 0.36 (60% EtOAc/hexane); 1H-NMR (CDCl3) δ 8.01 (m, 2H), 7.40-7.65 (m, 3H), 5.15 (m, 1H), 4.41 (m, 2H), 4.05-4.32 (m, 3H), 2.80-3.05 (m, 2H), 2.56 (d, 1H, J=15.7 Hz); MS m/z at 263 for (M+H)+.