Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1)(=O)=O.[CH3:30][O-:31].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:31][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nnc(-c2ccc3ncn(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Reaction time: 2 h
Yield: 26.9 %

Procedure:
To a solution of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole (150 mg, 0.35 mmol) in N,N-dimethylformamide (3 mL) was added sodium methoxide (23 mg, 0.42 mmol) at room temperature, and the resulting mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (35.4 mg, yield 27%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=1)[CH3:2].Cl.[Cl:18][C:19]1[C:20]([CH3:27])=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:22]3[C:21](=[C:20]([CH3:27])[C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:13]=2[CH3:14])[CH:6]=1)[CH3:2]
Reactant: Cc1c(Cl)cccc1NN
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(C)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, step 1, using the following starting materials: 3-(2-Oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-Chloro-2-methyl-phenyl)-hydrazine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[C:8]2=[O:23])=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:27][CH3:26])=[N:10][N:9]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[C:8]2=[O:23])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(-c2cccc(C#N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
According to Scheme 2 Step 4: To a stirred solution of 3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile (0.300 g, 0.72 mmol) in DMF (5 ml) was added, dropwise, at 0° C., 2M solution of sodium methoxide (0.72 mmol, 0.359 ml). The mixture was stirred 1 hour at 0° C. then quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water then with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 10 g prepacked column, DCM 100%. 150 mg (Yield=57%) of 3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile were recovered and used for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:14]1[CH2:15][CH2:16][C@@H:12]([O:11][C:10]2[CH:17]=[CH:18][C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH2:13]1
Reactant: Clc1ccc(Oc2ccc(O[C@@H]3CCNC3)cc2)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccc(Cl)cc3)cc2)C1
Temperature: 60 °C
Yield: 21.2 %

Procedure:
(R)-3-[4-(4-Chloro-phenoxy)-phenoxy]-pyrrolidine (344 mg, 1.05 mmol) was taken into anhydrous dimethylformamide (5 mL), and methyl-4-bromobutyrate (209 mg, 1.16 mmol), potassium carbonate (290 mg, 2.1 mmol) was added. The reaction was sealed and heated to 60° C. and left to react for 24 h. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate 3×. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash column chromatography (50:1 packing ration, eluted with 5% methanol in dichloromethane) to obtain the title product (86.8 mg, 21%); LCMS; m/z 390 (M) 71% pure; 1H NMR (400 MHz, DMSO); δ 1.66-1.80 (m, 3H), 2.22-2.26 (m, 1H), 2.31-2.35 (m, 2H), 2.37-2.41 (m, 3H), 2.58-2.67 (m, 2H), 2.81-2.84 (m, 1H), 3.58 (s, 3H), 4.80-4.83 (m, 1H), 6.91-6.95 (m, 4H), 6.98-7.00 (m, 2H), 7.37-7.39 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C:16]([F:19])([F:18])[CH2:15][N:14]3C(OC(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][C:16]([F:18])([F:19])[CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CN[C@H](c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Reaction time: 2 h

Procedure:
In a 10 ml, pear-shaped flask, (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4,4-difluoropyrrolidine-1-carboxylate (1.0 g, 2.33 mmol) was combined with CH2Cl2 (6 ml) to give a light yellow solution. TFA (2.96 g, 2 mL, 26.0 mmol) was added and stirred for 2 hr. It was concentrated in vacuo to afford (S)-5-(4-bromophenyl)-2-(4,4-difluoropyrrolidin-2-yl)-1H-imidazole as a viscous oil and used for the next step without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[O-]S([O-])(=O)=O.[Mg+2].[CH:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1.[C:18](O)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([O:16][C:15]([CH:12]1[CH2:14][CH2:13]1)=[O:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)O
Reactant: O=C(O)C1CC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC1
Reaction time: 0.33 h
Yield: 48.7 %

Procedure:
The esterification was performed following conditions described in Wright, Stephen W.; Hageman, David L.; Wright, Ann S.; Mc Clure, Lester D., Tetrahedron Letters 1997, 38(42), 7345-7348. 8.04 ml (150 mmol) concentrated sulfuric acid was added to a vigorously stirred suspension of 72.22 g (600 mmol) MgSO4 in 450 ml CH2Cl2. The mixture was stirred for 20 min, after which 11.90 ml (150 mmol) of cyclopropanecarboxylic acid was added. 55.59 ml (750 mmol) of tert-butanol was added last. The mixture was sealed tightly and stirred for 18 h at room temperature. The reaction was quenched with aqueous saturated NaHCO3 and stirred until all MgSO4 had dissolved. The aqueous phase was extracted with ether (two times). The organic phases were washed with water (5×), aqueous saturated NaCl solution and dried (Na2SO4) to give 10.38 g of the title compound as volatile, light yellow liquid.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[Cl:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:15]12>O1CCOCC1>[Cl:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]1[C:22]([N:1]=[O:2])=[C:21]([CH3:23])[N:20]=[C:15]12
Reactant: Cc1cn2ccc3c(Cl)cccc3c2n1
Reactant: CC(C)CCON=O
Solvent: C1COCCO1
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N=O
Yield: 39.7 %

Procedure:
Isoamyl nitrite (140 g) was added to a suspension of 7-chloro-2-methylimidazo[2,1-a]isoquinoline (17.1 g) in dioxane (170 ml) at 50° C. and the mixture was refluxed for 15 minutes. After being cooled, the resulting precipitate was collected by filtration, washed successively with dioxane and diethyl ether and dried in a desiccator to give 7-chloro-2-methyl-3-nitrosoimidazo[2,1-a]isoquinoline (7.7 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)=[C:5]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:4]=1>C(OCC)(=O)C.C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)=[C:5]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:4]=1
Reactant: COC(=O)Cc1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(Cl)ccc1C1=CCNCC1
Reaction time: 1 h
Yield: 175.6 %

Procedure:
A saturated solution of hydrogen chloride in ethyl acetate (6 mL) was added to a solution of tert-butyl 4-[4-chloro-2-(2-methoxy-2-oxoethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (1-5) (0.950 g, 2.60 mmol) in methylene chloride (6 mL) at 0° C. After 1 h, the volatiles were evaporated in vacuo, and the crude residue triturated twice with dry diethyl ether to give 1-6 (0.690 g) as a flocculent pale yellow solid (m/z (ES) 266 (MH+).
Reaction SMILES: [OH-].[Na+].O.[C:4]1([C:10]2([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:17](=S)=[S:18]>>[C:4]1([C:10]2([CH2:15][N:16]=[C:17]=[S:18])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: S=C=S
Reactant: NCC1(c2ccccc2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: S=C=NCC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 parts of sodium hydroxide and 300 parts of water is cooled to ±10° C. and there are added successively 41.8 parts of carbon disulfide and then dropwise 95 parts of 1-phenyl-cyclopentylmethylamine (exothermic reaction). Upon completion, the cooling-bath is removed and the whole is stirred at 30 minutes at room temperature. Then there are added dropwise at 30° C., 54.25 parts of ethyl chloroformate (exothermic reaction: cooling is necessary). The whole is stirred for 3 hours at 50° C. The reaction mixture is cooled and the product is extracted with benzene. The extract is dried, filtered and evaporated. The oily residue is distilled, yielding 86 parts of (1-phenylcyclopentylmethyl)isothiocyanate; bp. 125° C. at 0.2 mm pressure; nD20 :1.5848; d2020 :1.0910.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[K+].O.[CH2:17]([SH:20])[CH2:18][CH3:19]>CO>[CH2:17]([S:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:18][CH3:19]
Reactant: CCCS
Reactant: O=C(O)CCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCSCCCCCCCCCC(=O)O
Temperature: 69 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
10-bromodecanoic acid (1.0 g, 3.98 mmol) was added to a solution of potassium hydroxide (0.893 g, 15.9 mmol) in 1-propanethiol (30 mL) and methanol (30 mL) and stirred at 69° C. for 18 hrs. The reaction was allowed to cool to room temperature after the addition of 20 mL water. After acidification to pH=1 and extraction into ethyl acetate, the organic phase was dried over sodium sulfate and solvent removed at reduced pressure to yield a white crystalline powder. The product was purified by silica column chromatography in 8% ethyl acetate/hexane/0.3% formic acid and recrystallization from hexane to yield 10-(propylthio)decanoic acid (210 mg, 21%), mp 42°-43.5° C.; 1H NMR (300 MHz, CDCl3) δ0.96 (t, 3H, J=7.3, CH3) 1.15-1.40 (bm, 10H, methylene envelope), 1.49-1.64 (bm, 6H, CH3CH2CH2SCH2CH2, CH2CH2COOH), 2.32 (t, 2H, J=7.6, CH2COOH), 2.40-2.55 (bm, 4H, CH3CH2CH2SCH2), 10.93 (Br, 1H, COOH); 13C NMR (75.4 MHz, CDCL3) δ 13.64, 23.09, 24.71, 28.96, 29.07, 29.13, 29.24, 29.36, 29.77, 32.16, 34.10, 34.28, 179.98; m/z 247 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:17][C:18]([F:21])([F:20])[F:19].B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:31])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:17][C:18]([F:20])([F:19])[F:21]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To the solution of 1-chloro-2-(trifluoromethoxy)-4-(4-vinylphenoxyl)benzene (1.2 g, 3.81 mmol) in dry THF (10 mL), was added 9-BBN (15.25 mL, 7.63 mmol) at 0° C. The mixture was stirred at room temperature overnight. aq. NaOH (6.5 mL, 19.50 mmol), and 30% H2O2 (2.0 mL, 19.58 mmol) were added. The reaction mixture was heated at 55° C. for 4 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (450 mg, 1.353 mmol, 35.5% yield) as a white oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2)=[O:12])#[N:2].Cl.[H][H]>C(O)(C)C.C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2)=[O:12]
Reactant: [H][H]
Reactant: Cc1ccc(C#N)c(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1ccc(CN)c(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1

Procedure:
A mixture of 1-(2-cyano-5-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g), and 5-6M HCl in isopropanol (2 mL) in acetic acid (15 mL) is hydrogenated under 50 psi hydrogen for 48 hrs. The mixture is filtered through Celite, the filtrate is evaporated under vacuum, and the residue is purified by preparative HPLC to provide the product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:6]=[N:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[N:3][CH:2]=1)#[N:9]
Reactant: CCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCOc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
5.0 G. of 4-chloro-5-cyano-2-(4-ethoxyphenyl)-pyrimidine are reacted in 250 ml. of 50% dioxane with 22.2 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-ethoxyphenyl)-pyrimidine as colorless crystals having a melting point of 152.6°-153.0° C. which on cooling are nematic (monotropic) at 149.7° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([F:25])[CH:18]=2)[CH:10]=1)[CH3:2].[NH2:26][NH2:27].CCN(C(C)C)C(C)C>CC#N>[CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[C:23]3[C:20]([C:21]([NH2:22])=[N:26][NH:27]3)=[C:19]([F:25])[CH:18]=2)[CH:10]=1)[CH3:2]
Reactant: NN
Reactant: CC[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(NC)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@@H]1COCCN1c1cc(-c2cc(F)c3c(N)n[nH]c3c2)nc(NC)n1
Yield: 29.3 %

Procedure:
4-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (0.453 g, 1.261 mmol) was taken up in CH3CN (5 mL) followed by the addition of hydrazine (0.158 mL, 5.04 mmol) and Hunig's base (1.76 mL, 10.1 mmol) in a 20 mL microwave vial. The reaction was irradiated at 150° C. for 1 hour. The reaction mixture was concentrated and purified by reverse phase HPLC (8-28% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution (2×) that was back extracted with EtOAc. The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (137 mg) as a white fluffy powder. LC-MS (ES) m/z=372 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 1.60-1.81 (m, 2H), 2.82 (d, J=4.0 Hz, 3H), 3.05-3.16 (m, 1H), 3.43 (d, J=2.53 Hz, 1H), 3.51 (dd, J=11.5, 2.9 Hz, 1H), 3.83 (d, J=11.4 Hz, 1H), 3.89 (dd, J=11.1, 3.0 Hz, 1H), 4.03 (d, J=7.1 Hz, 1H), 4.16-4.28 (m, 1H), 4.30-4.43 (m, 1H), 5.26 (s, 2H), 6.58 (bs, 2H), 7.36 (d, J=12.4 Hz, 1H), 7.84 (bs, 1H), 11.89 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][C:7]2([CH3:15])[CH3:14].FC(F)(F)[C:20](O)=[O:21].C1N2CN3CN(C2)CN1C3>>[F:1][C:2]1[C:3]([CH:20]=[O:21])=[C:4]([O:16][CH3:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][C:7]2([CH3:14])[CH3:15]
Reactant: COc1cc(F)c2c(c1)C(C)(C)CC(=O)N2C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(c(F)c1C=O)N(C)C(=O)CC2(C)C
Temperature: 25 °C
Yield: 52 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 74 mg (0.312 mmol) 8-fluoro-6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one, 3 ml of trifluoroacetic acid and 53 mg (0.38 mmol) of hexamethylene tetraamine. The mixture was stirred under reflux for 16 hours and then cooled to ambient temperature. The reaction mixture was quenched first with water and then 30 ml of saturated aqueous bicarbonate solution and extracted with ethyl acetate (3×30 ml). The combined organics were then washed with brine followed by drying over sodium sulfate and evaporation in vacuo. The crude product was purified on silica gel eluting with ethyl acetate to afford 43 mg (52%) of the desired product. Mass spectrum APCI m/e 266 (p+1).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>>[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([S:2]([N:1]=[C:23]=[O:24])(=[O:3])=[O:4])[CH:14]=1)[CH3:17]
Reactant: CCOc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Reactant: CCCCN=C=O
Agent: O=C(Cl)Cl
Product: CCOc1ccc(C(=O)OC)c(S(=O)(=O)N=C=O)c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of methyl 2-(aminosulfonyl)-4-ethoxybenzoate (7.56 g, 29.2 mmol), n-butyl isocyanate (3.29 mL, 29.2 mmol), and 1,4-diaza[2.2.2]bicyclooctane (0.13 g, 1.2 mmol) in mixed xylenes was heated at reflux for 10 minutes. Phosgene was then added at such a rate that the internal temperature stayed at 133° C. or above. When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporation gave methyl 4-ethoxy-2-(isocyanatosulfonyl)benzoate as a cloudy yellow oil (8.2 g). This was used immediately without further purification or characterization.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[CH:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[F:35][C:36]([F:53])([F:52])[CH2:37]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:19][C:20]1[CH:32]=[C:31](/[CH:33]=[CH:37]/[C:36]([F:53])([F:52])[F:35])[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1F
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(/C=C/C(F)(F)F)cc1F
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Molecular sieves 4 Å (powder, 24 g) was added to a 1 M solution of TBAF in THF (30 mL, 30 mmol), and the mixture was stirred at room-temperature overnight under an argon atmosphere. To the mixture were added a solution of tert-butyl 2-fluoro-4-formylbenzoate (750 mg, 0.0033 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (1.9 g, 0.0067 mol) in THF (30 mL). After the mixture was stirred for 2 h it was filtered. The filtrate was concentrated under vacuum and water (120 mL) was added. The mixture was extracted with AcOEt and the organic extract was washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel using AcOEt-hexane (0-15%) as eluent to give (E)-tert-butyl 2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoate as a colorless oil (620 mg, 64%), followed by (Z)-tert-butyl 2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoate as a colorless oil (80 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18]([NH:8][C:5]2[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COc1nc(Cl)cnc1N
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1C

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.15 g). Yield 0.085 g.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([CH:19]([CH3:20])[CH3:21])=[CH:23][CH:24]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)C)cc3)CC2)ccc1Cl
Yield: 17 %

Procedure:
The title compound (7 mg, 17%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-isopropylbenzoic acid. MS: 415.5 (MH+)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1)C1C=CC=CC=1>C(O)(C)C.[Pd].Cl>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5-(4-benzylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (1.00 g) in isopropanol was added to 10 % palladium on charcoal (265 mg) pretreated under hydrogen in hydrochloric acid, and the resulting mixture was stirred under hydrogen at room temperature for 12 hours. After elimination of the catalyst by filtration, the filtrate was evaporated. The residue was neutralized with 10 % aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was washed with water, dried and evaporated to afford 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene as oily material. M.P., 221° - 224° C (oxalate).