Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([CH2:17][OH:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Cl:19]N1C(=O)CCC1=O.S(=O)(=O)(O)O.[C:32]([OH:35])(=O)[CH3:33]>O>[C:32]([O:18][CH2:17][C:14]1[C:13]([Cl:19])=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)[O:16][N:15]=1)(=[O:35])[CH3:33]
Reactant: OCc1cc(-c2ccc(C(F)(F)F)c(F)c2)on1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OCc1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a solution of (5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazol-3-yl)methanol (1.4 g, 5.36 mmol) in acetic acid (12 mL), N-chlorosuccinimide (1.07 g, 8.04 mmol) and sulphuric acid (0.6 mL) were added. The reaction mixture was stirred for 5 hours at 120° C. before being allowed to cool and then diluted with water (100 mL). The aqueous reaction mixture was extracted with diethyl ether (3×100 mL), the organics combined, washed with brine, dried with Na2SO4. The volatiles were removed in vacuo and the resulting residue was purified by silica gel chromatography, eluting with heptane to 20% ethylacetate in heptane, to afford (4-chloro-5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazol-3-yl)methyl acetate (1 g, 2.96 mmol).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>CN(C=O)C>[O:1]([C:2]1[CH:7]=[CH:6][C:5]([O:19][CH2:16][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCBr
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(Oc2ccc(OCCCCCCC)cc2)cc1

Procedure:
4,4′-oxydiphenol (4,4′-dihydroxydiphenyl ether) (1 eq, 10 g, 49.5 mmol), potassium carbonate (2.5 eq, 17.1029 g, 123.75 mmol, 138.205 g/mol), and 1-bromoheptane (2.5 eq, 22.1636 g, 19.5 mL, 123.75 mmol, 179.10 g/mol, d=1.14 g/mL) were dissolved in DMF (100 mL) at 80° C. The reaction was stirred until complete as determined by TLC. The reaction was poured into water and filtered. The crude product was taken up in methanol and heated while stirring, followed by sonication. The suspension was then filtered warm and the product washed with room temperature methanol to yield a white powder (compound characterized by Structure A: 4,4′-oxybis((heptyloxy)benzene)). The yield was 16.3 g (83.6%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.C(N(CC)CC)C.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([Cl:24])=[O:23]>C(OCC)(=O)C.N1C=CC=CC=1>[ClH:24].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][CH2:2][CH2:3][NH:4][CH3:5])=[O:23]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CNCCOC(=O)C(C)(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (15 mL) was added triethylamine (1.67 mL) and a mixture of trimethylacetyl chloride (1.35 mL), and ethyl acetate (5 mL) was dropwise added. After stirring at room temperature for 2 hrs., pyridine (1.62 mL) was added, and the mixture was stirred overnight at room temperature. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride—ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hrs., diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure to give the title compound (1.65 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Yield: 23613.2 %

Procedure:
A solution of 4-bromobenzaldehyde (5 g, 0.027 mol), ethylene glycol (7.0 g, 0.11 mmol), and p-toluenesulfonic acid (0.1 g, 0.5 mmol) in benzene was heated at reflux for 24 h using a Dean-Stark setup to remove water. The reaction was taken up in diethyl ether (100 mL) and washed with water (5×30 mL) and brine (30 mL). The organic phase was dried over magnesium sulfate and concentrated under vacuum to afford 2-(4′-bromophenyl)-1,3-dioxolane (5.95 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=2[CH:17]=1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=1[CH3:26]>>[CH3:15][C:7]1([CH3:16])[C:6]2[CH:17]=[C:2]([C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=3[CH3:26])[CH:3]=[CH:4][C:5]=2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8]1
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(C(F)(F)F)N2

Procedure:
Prepared according to the coupling procedure for Example 13 from 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and 5-bromo-4-methyl-2-thiophene-carbonitrile. A yellowish solid: mp 97-98° C.; 1H-NMR (DMSO-d6) δ 7.82 (s, 1H), 7.26 (d, 1H, J=1.7 Hz), 7.21 (dd, 1H, J=8.1, 2.1 Hz), 7.16 (s, 1H), 6.88 (d, 1H, J=8.1 Hz), 5.40 (m, 1H), 2.27 (s, 3H), 1.56 (s, 3H), 1.55 (s, 3H); MS (ESI) m/z 351 [M−H]−.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][OH:19])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].[OH-].[Na+]>C(Cl)Cl.O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][O:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CO)CC[C@H]2C1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](COS(C)(=O)=O)CC[C@H]2C1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A solution of 6.0 g (22 mmol) of (7R,9aS)-2-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (WO 93/25552) and 3.41 mL (24.4 mmol) of triethylamine in 225 mL of dry methylene chloride was chilled to 0° C., and treated with 1.80 mL (23.3 mmol) of methansulfonyl chloride in 75 mL of methylene chloride. After stirring 1 h, water was added and the pH adjusted to 12 with 15% sodium hydroxide. The layers were separated and the aqueous phase extracted with methylene chloride. The combined organic phase was dried (magnesium sulfate), filtered and evaporated to give 7.73 g (100%) of (7R,9aS)-2-BOC-7-(methanesulfonyloxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])C.[CH3:16]I.[H-].[Na+]>C1COCC1.C(OCC)C>[C:12]([O:11][C:9]([N:1]([CH3:16])[C@H:2]([CH2:3][CH3:5])[C:6]([OH:8])=[O:7])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
To a solution of N-Boc-D-Val-OH (0.678 g, 3.34 mmol) in THF (11.1 mL) at 0° C. was added MeI (2.09 mL, 33.4 mmol, 10.0 equiv). NaH (60%, 1.33 g, 33.4 mmol, 10.0 equiv) was added as a solid to the suspension over a period of 2 hours. After stirring for 12 hours at room temperature, the reaction mixture was diluted with diethyl ether and quenched with water slowly. Aqueous layer was extracted with diethyl ether followed by acidified to pH 3 with 10% citric acid and extraction with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.1a (0.73 g) which was used for the next step without further purification. MS m/z (M+Na) 240.2. 1H NMR (400 MHz, CDCl3) 4.56 and 4.37 (br-s, 1H), 2.83 (br-s, 3H), 2.08-1.92 (m, 1H), 1.85-1.68 (m, 1H), 1.48 (br-s, 9H), 0.96 (t, J=7.38 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CN(C)C=O.[H-].[Na+].Br[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Reactant: Brc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccsc2)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
3.4 G. of 2-amino-4-mercapto-1-nitrobenzene is dissolved in 40 ml. of dimethylformamide under nitrogen and treated at 20°-25° C with 0.5 g. of 100% sodium hydride. After 1 hour, 2.8 g. of cuprous oxide and 4.0 g. of 3-bromothiophene are added. The mixture is heated in an oil bath for 5 hours at 140°-150° C, cooled, diluted with water, and extracted with chloroform. The chloroform solution is passed through a silica gel column and the eluate evaporated to yield 2-amino-4-(3-thienylthio)-1-nitrobenzene.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Cl:28])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:31]([O-:34])([O-])=O.[K+].[K+].[Na+].[I-]>CS(C)=O>[Cl-:28].[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N+:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:34][CH2:31][C:24]3[CH:23]=[CH:30][CH:29]=[CH:26][CH:25]=3)=[CH:20][CH:21]=2)([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:24][CH:25]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: N[C@H]1CCC[N+](Cc2ccc(OCc3ccccc3)cc2)(Cc2ccc(OCc3ccccc3)cc2)C1
Product: [Cl-]

Procedure:
(S)-Piperidin-3-yl-carbamic acid tert-butyl ester (150 mg), 4-benzyloxybenzyl chloride (383 mg), K2CO3 (227 mg) and NaI (34 mg) are stirred in dimethylsulfoxide (5 mL) for 16 h. Volatiles are evaporated in vacuo, the residue partitioned between water and ethyl acetate, the organic phase collected, dried (Na2SO4) and volatiles evaporated in vacuo to give 540 mg of crude product that is used without further purification. To the material thus obtained dichloromethane (15 mL) and trifluoroacetic acid (0.56 mL) are added. After 16 h at room temperature volatiles are evaporated in vacuo, methanolic NH3 is added until a slightly basic pH is reached, volatiles are again evaporated and the residue is purified by chromatography (silica gel, dichloromethane:MeOH containing NH3OH gradient of increasing polarity) to give the title compound. Yield 110 mg.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=1)[CH3:2].C([Li])(CC)C.[C:22](=[O:24])=[O:23].S(=O)(=O)(O)O>O1CCCC1.O>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]1[C:6](=[C:7]2[O:8][CH2:9][O:10][C:11]2=[CH:12][CH:13]=1)[C:22]([OH:24])=[O:23])[CH3:16]
Reactant: O=C=O
Reactant: CCN(CC)C(=O)c1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1ccc2c(c1C(=O)O)OCO2
Temperature: 0 °C

Procedure:
A solution of N,N-diethylpiperonylamide 10.0 g, 45.0 mmol) in tetrahydrofuran is added dropwise at -65° C. to -55° C. to a mixture of sec-Butyllithium (500 mL, 50.0 mmol, 1M in cyclohexane) in tetrahydrofuran under a nitrogen atmosphere. The reaction mixture is poured over tetrahydrofuran saturated with dry ice, allowed to warm to 0° C., treated slowly with water and acidified to pH 3 with concentrated sulfuric acid. The tetrahydrofuran is removed in vacuo and the aqueous residue is extracted with ethyl acetate. The organic extract is dried (MgSO4) and concentrated in vacuo to a yellow-orange gum, NMR and mass spectrographic analysis show it to be a mixture of starting material and the title product. The above aqueous layer is acidified further to pH 2, extracted with ethyl acetate, and the organic extract is dried (MgSO4) and concentrated in vacuo to yield the title product as a yellow foam, 4.00 g (33.6%) identified by NMR spectral analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:29][CH2:28]2)=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)=[CH:19]1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
Batch size: 6.3 g (42.5 mmol) 3-(3-pyridyl)-acrylic acid, 11 ml (127 mmol) oxalyl chloride and 10.5 g (38.7 mmol) 4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C[Al](C)C.[NH:24](/[C:28](/[CH3:34])=[CH:29]\[C:30](OC)=[O:31])[C:25]([CH3:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:30](=[O:31])[CH:29]=[C:28]([CH3:34])[N:24]=[C:25]2[CH3:27])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(NCCCCN2CCOCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCCCN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a solution of 2-fluoro-N1-(4-morpholinobutyl)benzene-1,4-diamine (1.07 g, 4.00 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (14 mL, 28 mmol, 2 M in toluene) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.30 g, 8.27 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt overnight, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellowish solid (0.26 g, 17%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Na].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]#[N:23])=[CH:16][CH:15]=1.C(OCC)(=O)C>C(O)C.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:20]([C:17]3[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=3)[CH2:21][C:22]([NH2:23])=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: CSc1ccc(C=CC#N)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ccc(C2CC(N)=NN2c2ccc(F)cc2)cc1
Yield: 67.6 %

Procedure:
4-Fluorophenylhydrazine hydrochloride 4 g) was added to a solution of sodium (1.13 g) in ethanol (50 ml), and the mixture was refluxed for 1 hour. To the cooled mixture was added 3-[4-(methylthio)phenyl]acrylonitrile (4.3 g), and the resulting mixture was refluxed overnight. Ethyl acetate and water were added, and the organic layer was separated, dried and concentrated. The oily residue (7.6 g) was purified by column chromatography on silica gel (76 g) eluting with a mixture of toluene and ethyl acetate (2:1) to give brown crystals of 4,5-dihydro-1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazol-3-amine (5 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[O:11][CH2:12][CH2:13][CH2:14][CH:15]=NNC(N)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.C(=O)([O-])[O-:27].[Na+].[Na+]>Cl.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[O:11][CH2:12][CH2:13][CH2:14][CH:15]=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)NN=CCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=CCCCOc1cccc(CN2CCCCC2)c1

Procedure:
4-[3-(1-piperidinylmethyl)phenoxy]butanal semicarbazone (9.43 g) and 37% formaldehyde (80 ml) in 2N hydrochloric acid (80 ml) were stirred at room temperature for 2.5 h and then diluted with water. The solution was basified with sodium carbonate and extracted with ether. The organic extract was washed with brine, and distilled to give the title compound as a colourless oil (5.59 g) b.p. 200°, 0.06 mm; tlc methanol Rf 0.7.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[CH2:26][CH2:27][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH2:23][CH2:24]2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Product: CC(=O)NC(C)(C)c1ccc(CN2CCN(c3ccccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=129-130° C.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:15]=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1>>[CH2:1]([C:8]1[S:9][C:10]([C:15]2[C:14]([Br:13])=[CH:19][N:18]=[C:17]([Cl:20])[N:16]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: c1ccc(Cc2cccs2)cc1
Product: Clc1ncc(Br)c(-c2ccc(Cc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 2-benzylthiophene and 5-bromo-2-chloropyrimidine in a manner analogous to Example 255, Step 1. MS (M+H)+ 365.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10](O)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[ClH:1].[Cl:20][CH:10]([CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=S(Cl)Cl
Reactant: OC(CSc1ccc(Cl)cc1)Cn1ccnc1
Product: Cl
Product: Clc1ccc(SCC(Cl)Cn2ccnc2)cc1

Procedure:
1-[3'-(4"-chlorophenylthio)-2'-hydroxypropyl]imidazole (2.0 g.) and 10 ml. thionyl chloride are warmed gently for 2 hours. Thereafter, the reaction mixture is evaporated to dryness to yield 1-[2'-chloro-3'-(4"-chlorophenylthio)propyl]imidazole hydrochloride as a gum. The gum is dissolved in dichloromethane (100 ml.), basified with aqueous potassium carbonate solution and the organic phase dried over magnesium sulfate and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Cl.[N:11]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:20]([CH2:22][C:23]([NH2:25])=[O:24])#[N:21]>O.CCO>[NH2:25][C:23](=[O:24])/[C:22](/[C:20]#[N:21])=[N:11]/[NH:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[Br:1]
Reactant: N#CCC(N)=O
Reactant: O=N[O-]
Reactant: Nc1cc(F)ccc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#C/C(=N\Nc1cc(F)ccc1Br)C(N)=O
Yield: 68.1 %

Procedure:
To a stirred vessel containing 2-bromo-5-fluoroaniline (20.0 g, 105 mmol) was added concentrated hydrochloric acid (26 mL, 3.0 eq) dropwise while maintaining the mixture temperature <5° C. To the cooled suspension was added dropwise a solution of sodium nitrite (7.1 g, 103 mmol) in water (25 mL). The mixture was stirred and cooled for 15 minutes. A solution of sodium acetate (26.0 g, 317 mmol) in water (120 mL) was added dropwise to the reaction mixture. The resulting diazonium salt solution (cloudy yellow suspension) was set aside. While the diazonium salt solution was stirred and cooled, a solution of sodium acetate (8.6 g, 105 mmol) in water (30 mL) was added to a solution of 2-cyanoacetamide (8.8 g, 105 mmol) in water (150 mL) and EtOH (120 mL). The mixture was cooled to a temperature <10° C. at which point the diazonium salt solution was added portion-wise and with vigorous stirring over a span of 25 minutes while maintaining the reaction temperature <10° C. Upon addition of the diazonium salt solution, a thick reddish yellow precipitate formed, and the mixture was stirred overnight at room temperature. The solid product was collected by vacuum filtration, washed with water (300 mL) and EtOH (800 mL), and dried in a vacuum to afford the title compound as a red solid (20.0 g, 66.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 14.52 (1H, s), 8.31 (1H, s), 8.12 (1H, s), 7.73-7.70 (1H, m), 7.36-7.33 (1H, m), 7.00-6.95 (1H, m).
Reaction SMILES: C(O[C:4](=[O:25])[C:5](=[N:9][N:10]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:11](=[O:18])[CH2:12][C:13]([O:15]CC)=O)[CH:6]([CH3:8])[CH3:7])C.C1CCN2C(=[N:30]CCC2)CC1.C(C(C(Cl)=O)C(Cl)=O)C.Cl.CC[O:49][C:50]([CH3:52])=[O:51]>O1CCCC1.O>[CH:19]1([N:10]2[C:11](=[O:18])[C:12]([C:13]([NH:30][CH2:52][C:50]([OH:49])=[O:51])=[O:15])=[C:4]([OH:25])[C:5]([CH:6]([CH3:7])[CH3:8])=[N:9]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCOC(C)=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)CC(=O)N(N=C(C(=O)OCC)C(C)C)C1CCCCC1
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nn(C2CCCCC2)c(=O)c(C(=O)NCC(=O)O)c1O
Reaction time: 0.17 h

Procedure:
Ethyl-2-{cyclohexyl[3-(ethyloxy)-3-oxopropanoyl]hydrazono}-3-methylbutanoate. DBU (0.35 ml, 2.322 mmol) was added to a solution of the compound from example 98a) (0.51 g, 2.122 mmol) in Tetrahydrofuran (THF) (1 ml) at 0° C. The reaction was brought to room temperature and stirred for 10 minutes. The temperature was then reduced to 0° C. and ethyl malonyl chloride (0.32 ml, 2.374 mmol) was added. The reaction was brought to room temperature and stirred for 2.5 h. 1N HCl was added and the solution diluted with H2O and EtOAc. The layers were separated and aqueous phase backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, 10-25% EtOAc/Hexanes) to give a mixture of the title compound and the cyclized product 55c) (126 mg, 13%). LCMS (ES+) m/z 355.2, 309.2 (MH+).
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([SH:15])=[N:12][N:11]=2)=[C:6]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]([NH:16][CH:17]([CH3:19])[CH3:18])[C:7]([C:10]2[O:14][C:13]([S:15][CH3:1])=[N:12][N:11]=2)=[CH:8][N:9]=1
Reactant: CI
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(S)o1
Solvent: CO
Product: CSc1nnc(-c2cnc(Cl)cc2NC(C)C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (22 mmol, 2 equiv.) was added to a solution of 5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-thiol (42) (1.5 g, 5.5 mmol) in MeOH (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mass was concentrated under reduced pressure. The crude material obtained was purified by column chromatography through silica gel and MeOH:DCM as eluent to furnish the desired compound, 2-chloro-N-isopropyl-5-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyridin-4-amine (43). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.994 min; LCMS (ES-API), m/z 285.1 (M+H).