Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:21][CH:22]=1)(=[N:4][S:31]([CH3:30])(=[O:33])=[O:32])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=N)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N=S(C)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 2-(4-(S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 17b, 2.50 g, 7.95 mmol) and triethylamine (2.2 mL, 16 mmol) in dichloromethane (20 mL) is cooled at 0° C. and treated with methanesulfonyl chloride (620 μL, 8.0 mmol). The mixture is stirred at this temperature for 1.5 h and then washed with water. The organic layer is concentrated under reduced pressure, and the residue is suspended in a mixture of methanol and water. The precipitate is filtered, washed with water, and dried. Yield: 273 mg (8% of theory); ESI mass spectrum: [M+H]+=393, r.t. HPLC: 0.44 min (X012_S01).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12](=[O:17])[C:9]=2[NH:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O.O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:10]1[CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:18])[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12](=[O:17])[C:9]1=2)[CH3:31]
Reactant: CCOC(=O)c1c[nH]c2c(=O)ccccc2c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C(=O)OCC)c(=O)c2ccccc(=O)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid ethyl ester (1 g, described in example 2), potassium carbonate (1 g) and ethyl bromoacetate (1 g) in dimethylformamide (DMF, 50 ml) was stirred at 25° C. for 5 hr. The reaction mixture was diluted with water and extracted with chloroform. The chloroform extract was evaporated to dryness. The residue was purified by chromatography on silica gel using chloroform-methanol (99:1) as the eluant. The appropriate fractions were pooled and crystallized from acetone to give the title compound; mp 152°-154° C.; nmr (CDCl3) δ1.3 (t, 6H), 4.3 (m, 4H), 4.85 (s, 2H), 7.0 (m, 3H), 8.2 (m, 2H); ir (CHCl3) 1740, 1730, 1690, 1630 cm-1 ; uv λ max (MeOH) 349 nm (ε12,625), 235 (18,760), 212 (25,070); Anal Calcd for C17H17NO6 : C, 61.63% H, 5.17% N, 4.23% Found: C, 61.67% H, 5.23% N, 4.25%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[CH:13]([NH:15][NH2:16])=O.C1(O)CCCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:13]=[N:15][N:16]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2cc(Br)ccc2N1
Reactant: NNC=O
Solvent: OC1CCCCC1
Solvent: O
Product: Brc1ccc2c(c1)CCc1nncn1-2
Temperature: 120 °C

Procedure:
A flask containing the title compound from Example 22, Step A (0.200 g, 0.826 mmol), formic hydrazide (0.099 g, 1.65 mmol) and cyclohexanol (6.00 ml, 0.826 mmol) was heated to 120° C. for 16 hours. The reaction was then cooled to room temperature, poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0-15% methanol in ethyl acetate) provided the title compound: LCMS m/z 251.90 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 9.12 (s, 1H), 7.63-7.54 (m, 3H), 3.19-3.16 (m, 2H), 3.11-3.08 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29].O>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[C:21]([NH2:22])=[N:27][C:28]([NH2:30])=[N:29]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(N)N
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2C#N)CC1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3nc(N)nc(N)c23)CC1
Temperature: 145 °C
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
In a reaction vessel, 4-(2-cyano-3-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (613.7 mg; 2 mmol) and guanidine carbonate (360.6 mg; 2 mmol) were suspended in 2 mL DMA. The reaction mixture was heated to 145° C. for 22 hours. The mixture was cooled to room temperature and 4 mL of water was added and stirred for 15 minutes. The solid was collected by vacuum filtration and washed with water and ethyl acetate and dried under vacuum to yield 278.4 mg (40% yield) of the title compound.
Reaction SMILES: [Na].[C:2]([O:5][C:6](=[O:8])[CH3:7])(=O)[CH3:3].[C:9]([O-])(=O)C.[K+].[CH2:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2C(O)CC(OCC)=O)[CH2:16][CH2:15]1>C(OCC)(=O)C>[CH:17]1([CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH:9]=[CH:7][C:6]([O:5][CH2:2][CH3:3])=[O:8])=[CH:26][CH:27]=2)[CH2:16][CH2:15][CH2:14][CH2:19][CH2:18]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)CC(O)c1ccccc1NCC1CCCCC1
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(NCC2CCCCC2)cc1

Procedure:
The 4-(substituted-amino)phenylalkenoic acids may be prepared by condensation of the appropriate aldehydes or by dehydration of the corresponding substituted-phenylhydroxyalkanoic acids. For example, ethyl 5-[4-(cyclopentylmethylamino)phenyl]-2,4-pentadienoate is obtained by the Wittig reaction of 4-(cyclopentylmethylamino)benzaldehyde with the Wittig reagent, triethyl 4-phosphonocrotonate. Alternatively, these alkanoic acids are obtained by heating 4-[N-(10-cyclopentyldecyl-N-methylamino]benzaldehyde and the like with the sodium salt of the carbonion of ethyl acetate or with a mixture of ethyl acetate, acetic anhydride and potassium acetate. The second method is illustrated by dehydration of ethyl 3-[(4-cyclohexylmethylamino)phenyl]-3-hydroxypropionate to yield ethyl 4-cyclohexylmethylaminocinnamate.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12](=[O:34])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][C:14]=3[O:32][CH3:33])[C:4]=2[N:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12](=[O:34])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][C:14]=3[O:32][CH3:33])[C:4]=2[N:3]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(N)nc12
Product: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(NC(C)=O)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-(2-amino-1H-benzimidazol-4-yl)-2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (90 mg) and acetic anhydride (1.0 ml) was stirred for 1 hour at room temperature and allowed to stand overnight at the same temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The resulting solution was washed with saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-ethyl acetate=10-1) to give N-(2-acetamido-1H-benzimidazol-4-yl)-2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (42 mg).
Reaction SMILES: [CH2:1]1COC2(C3C=CC(CC#N)=CC=3C=CC3C=CC=CC2=3)O1.Cl.[CH:24]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29](=[O:39])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH2:40][C:41]([OH:43])=[O:42].C1COC2(C3C=CC(C(C)C#N)=CC=3C=CC3C=CC=CC2=3)O1>O.C(OCC)(=O)C.C(O)(=O)C>[CH:24]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29](=[O:39])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:40]([CH3:1])[C:41]([OH:43])=[O:42]
Reactant: N#CCc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Reactant: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Agent: CC(C#N)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 75 %

Procedure:
23.4 Gm. of 5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl acetonitrile is refluxed for 7 hours in 160 ml. of acetic acid and 240 ml. of concentrated hydrochloric acid. The solution is cooled and added to ethyl acetate and water. The organic layer is washed with water then extracted with aqueous sodium carbonate. The extract is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated to afford the product which is recrystallized from acetone/hexane to give 9.5 gm., 50%, of 5H-dibenzo[a,d]cyclohepten-5-on-2-yl acetic acid, m.p. 148°-149.5° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionitrile gives a 75% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16].C([BH3-])#N.[Na+]>O>[C:10]([CH:9]([NH:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:12])=[O:11]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A mixture of 4-phenyl-2-oxobutyric acid (1.49 g) and L-alanyl-L-proline (0.31 g) in water are adjusted to pH 7.5 with caustic and treated with sodium cyanoborohydride (0.32 g) overnight. The product is absorbed on strong acid ion exchange resin and eluted with 2% pyridine in water to give 0.36 g of crude diastereomeric product, N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline. A portion is purified by gel filtration (LH-20) for spectrographic analysis. The nmr spectrum in DMSO shows aromatic hydrogen at 7.20, a broad singlet at 4.30, broad multiplets at 3.0 to 3.9, 2.67 and 1.94, and a doublet at 1.23 and 1.15. The mass spectrum shows a molecular ion at 492 m/e for the ditrimethylsilylated species.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[NH3:8].[CH3:9][Si:10]([CH3:19])([CH3:18])[C:11]1[O:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1>CO>[C:1]([O:7][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[NH2:8]/[C:3](/[CH3:5])=[CH:2]\[C:1]([OH:7])=[O:6].[CH3:9][Si:10]([CH3:19])([CH3:18])[C:11]1[O:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)O
Reactant: N
Agent: C[Si](C)(C)c1ccc(CO)o1
Solvent: CO
Product: C/C(N)=C/C(=O)O
Product: COC(=O)CC(C)=O

Procedure:
This compound is prepared by the method comprising condensation of methyl ester of acetoacetic acid, ammonia and 5-trimethylsilylfurfurol in solution of methanol. Furthermore, this compound can be obtained by condensation of methyl ester of acetoacetic acid, methyl ester of β-aminocrotonic acid and 5-trimethylsilylfurfurol in a medium of an organic solvent. The reaction is carried out under normal pressure under heating. The product is obtained in a good yield.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23])=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 95.5 %

Procedure:
To a solution of tert-butyl (2S)-2-[(2-{[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate 271 (0.37 g, 0.74 mml) in methanol (25 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate 272 (0.29 g, 96%) as a white foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][Li])=[CH:3][CH:2]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[ClH:13].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:3][CH:2]=1
Reactant: [Li]Cc1ccncc1
Reactant: ClCCCBr
Product: Cl
Product: ClCCCCc1ccncc1

Procedure:
The reaction of 4-picolyllithium and 3-bromo-1-chloropropane was exothermic. It was extremely critical to keep internal temperature less than -65° C. to avoid the reaction of the desired product with 4-picolyllithium to give 1,5-bis-(4-pyridinyl)-pentane. The addition took about 2 h.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][NH:16][C:15](=[O:18])[CH:14]([N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:13][S:12]1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][N:16]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:15](=[O:18])[CH:14]([N:19]2[C:20](=[O:29])[C:21]3=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]3[C:23]2=[O:24])[CH2:13][S:12]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCC(c2ccc3ccccc3c2)SCC1N1C(=O)c2ccccc2C1=O
Product: CC(C)(C)OC(=O)CN1CC(c2ccc3ccccc3c2)SCC(N2C(=O)c3ccccc3C2=O)C1=O

Procedure:
4.15 g of 2-(2-naphthyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepine [prepared as described in step (e) above] were treated with t-butyl bromoacetate in same manner as described in Example 36(f), to give 3.35 g of the title compound as a crystalline solid, melting at 208°-209.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[O-:38][C:39]#[N:40].[K+]>CO.O>[NH:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:29][CH:30]=1)[C:39]([NH2:40])=[O:38]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN)cc1)c1ccccc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CNC(N)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
300 mg of 3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone are dissolved in 15 ml of methanol and 200 ml of triethylamine are added. Then 400 mg of potassium cyanate in 5 ml of water are added. After 2 days of stirring at room temperature the reaction solution is concentrated by rotary evaporation, the residue taken up in methylene chloride and washed once with water and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation. The residue is dried in vacuo at 100° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:13][CH:14]([F:17])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>O>[F:13][CH:14]([F:17])[CH2:15][O:16][C:2]1[N:3]=[C:4]([CH3:12])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(Cl)nc1C
Reactant: OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ncc(OCC(F)F)nc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.1 %

Procedure:
To a mixture of methyl 5-chloro-3-methylpyrazine-2-carboxylate (255 mg, 1.367 mmol) in 2,2-difluoroethanol (0.52 mL, 8.20 mmol) was added potassium carbonate (227 mg, 1.640 mmol). The reaction was stirred at ambient temperature for 1.5 hrs. The reaction was treated with water and extracted with ethyl acetate. The organic portion was dried over Na2SO4, filtered, concentrated and purified by column chromatography, eluting with 0-2% MeOH/DCM to give the title compound (63.8 mg, 0.275 mmol, 20.1%). MS m/z=233.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)CC(=O)C>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: CC(=O)CC(C)C
Solvent: Cc1ccccc1C
Product: OC(CCNC1=NCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α-(2-aminoethyl)benzylalcohol, 6.5 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred and refluxed for 3 hours with waterseparator. The reaction mixture is cooled and the separated oily product is dissolved in 4-methyl-2-pentanone. The solvent is evaporated in vacuo, yielding α-{2-[N-(2-imidazolin-2-yl)amino]ethyl} benzylalcohol as a residue.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1(C=O)[CH2:9][CH2:8][CH:7]=[CH:6][CH2:5]1)[CH3:3].[CH:12](=[O:16])[CH:13]([CH3:15])[CH3:14].B(F)(F)F.C[CH2:22][O:23]CC>ClCCCl>[CH:22]([O:16][CH:12]([CH2:3][C:2](=[C:4]1[CH2:9][CH2:8][CH:7]=[CH:6][CH2:5]1)[CH3:1])[CH:13]([CH3:15])[CH3:14])=[O:23]
Reactant: C=C(C)C1(C=O)CC=CCC1
Reactant: CCOCC
Reactant: CC(C)C=O
Agent: FB(F)F
Solvent: ClCCCl
Product: CC(CC(OC=O)C(C)C)=C1CC=CCC1
Yield: 697.2 %

Procedure:
Following the general procedure as described in Example 1, 1-(prop-1-en-2-yl)cyclohex-3-enecarbaldehyde (1.50 g, 10 mmol), isobutyraldehyde (0.86 g, 12 mmol) and boron trifluoride etherate (0.14 g, 1.0 mmol) in 1,2-dichloroethane (10 mL) were reacted to give the title product as a colorless liquid (1.55 g, 70% yield). Mixture of E/Z isomers in a ratio 2:1.
Reaction SMILES: [C:1]([S:4][CH:5]([CH3:9])C(O)=O)(=[O:3])[CH3:2].[OH:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1.[C:33](OCC)(=[O:35])C>>[CH3:2][C:1]([S:4][CH2:5][CH2:9][C:33]([O:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])=[O:35])=[O:3]
Reactant: CCOC(C)=O
Reactant: O=C1CCC(=O)N1O
Reactant: CC(=O)SC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(=O)SCCC(=O)ON1C(=O)CCC1=O
Yield: 50 %

Procedure:
16.2 g (0.1 mol) S-acetyl-mercaptopropionic acid, 12.7 g (0.11 mol) N-hydroxysuccinimide and 22.7 g (0.11 mol) dicyclohexylcarbodiimide are stirred in 0.4 l absolute ethyl acetate for 16 hours at 20° C. The precipitate which forms is filtered off and the filtrate is evaporated in a vacuum. The oily residue is taken up in a small amount of ethyl acetate and cooled. In this process further precipitate is formed which is discarded. This process is repeated twice. 13 g (50%) SATP is obtained from the last filtrate after evaporation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19]([Cl:24])=[N:20][CH:21]=[CH:22][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:24][C:19]1[C:18]([NH:17][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C=C(Nc2cccnc2Cl)c2ccncc2)cc1
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(pyridin-4-yl)ethanone (5.20 g, 24 mmol) and 3-amino-2-chloropyridine (4.04 g, 31.4 mmol) in toluene (150 ml) was added p-toluenesulfonic acid monohydrate (457 mg. 2.4 mmol) and the reaction mixture was brought to reflux with Dean-Stark removal of the toluene/water azeotrope. After 24 h, toluene was removed in vacuo and the residue was resuspended in ethyl acetate. The precipitate was collected by vacuum filtration to give (2-chloropyridin-3-yl)-[2-(4-fluorophenyl)-1-(pyridin-4-yl)-vinyl]amine (5.0 g) as a tan solid. The filtrate was concentrated in vacuo and purified by flash column chromatography (50%-80% ethyl acetate:hexanes gradient) to give additional 1.50 g of product.
Reaction SMILES: [CH2:1]([C:3]([CH2:11][CH3:12])([CH2:7][C:8]([OH:10])=O)[C:4]([OH:6])=[O:5])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[F:24])[N:20]=[C:19]([CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])[CH:18]=[CH:17]2>>[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[F:24])[N:20]=[C:19]([CH2:25][O:26][C:27]1[CH:28]=[C:29]([NH:30][C:8](=[O:10])[CH2:7][C:3]([CH2:1][CH3:2])([CH2:11][CH3:12])[C:4]([OH:6])=[O:5])[CH:31]=[CH:32][CH:33]=1)[CH:18]=[CH:17]2
Reactant: Nc1cccc(OCc2ccc3cc(F)c(F)cc3n2)c1
Reactant: CCC(CC)(CC(=O)O)C(=O)O
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3cc(F)c(F)cc3n2)c1)C(=O)O

Procedure:
Analogously to Example 3, the title compound is prepared from 2,2-diethylsuccinic acid and 3-(6,7-difluoro-2-quinolinylmethoxy)aniline. It is obtained in the form of a white solid; 1H-NMR, 200 MHz, DMSO, delta (ppm)=9.90 (s, 1H), 8.42 (d, 1H), 8.10 (m, 2H), 7.70 (d, 1H), 7.45 (m, 1H), 7.07 (m, 2H), 6.73 (d, 1H), 5.35 (s, 2H), 2.58 (s, 2H), 1.80 (m, 4H), 0.80 (t, 6H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CC(C)(O)CCN
Product: CC(C)(O)CCNc1ccc2ncc(Br)n2n1
Yield: 82 %

Procedure:
The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was reacted with 4-amino-2-methylbutan-2-ol using the same reaction conditions as described in example 5.6.42, Part A to obtain 82% product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=2[C:21]2[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:23]3[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=3[C:21]3[CH:41]=[CH:42][CH:43]=[CH:44][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared. The reaction was monitored by tlc (Rf=0.35, 3% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).