Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]#[N:15].C(=O)([O-])[O-:17].[K+].[K+].OO>CS(C)=O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:15])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(Nc2cccnc2)n[nH]c1N
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolved 5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile (100 mg) in DMSO (5 mL), added potassium carbonate (0.50 eq., 50 mg), then added hydrogen peroxide solution (40 uL of 50% solution in H2O) dropwise over ice bath over the course of 10 minutes. After the final addition, kept on ice bath for 2 hrs, then heated to room temperature and stirred until complete by TLC. After 24 hrs, reaction was incomplete so additional (120 uL) hydrogen peroxide was added and reaction was heated to 50 degrees C. Reaction was complete by TLC after 3 days of stirring at 50 degrees C. and was poured into 20 mL of ice water but no precipitate was observed. Extracted with EtOAc three times, washed with brine and dried with MgSO4. Volatiles were removed via vacuo. 5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide was obtained as a brown oil (100 mg, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:25]([CH3:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:24]3[CH:23]=[CH:22][C:21](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[C:20]([CH3:19])[C:25]=3[CH3:26])=[C:11]([C:15]([F:16])([F:18])[F:17])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Reactant: CCOC(=O)/C=C/c1ccc(O)c(C)c1C
Product: Cc1c(/C=C/C(=O)O)ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 5 and 6 by coupling of (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and (E)-ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)acrylate then hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=7.5 Hz, 2H), 7.55 (d, J=11.5 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 6.96 (d, J=5.5 Hz, 1H), 6.62 (d, J=12.0 Hz, 1H), 5.08 (s, 2H), 2.21 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH2:22].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:22]/[C:15]1[C:14]([Cl:13])=[CH:19][C:18]([F:20])=[CH:17][C:16]=1[Cl:21])=[N+:2]=[N-:3]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.44 g, 14.7 mmol), 2,6-dichloro-4-fluorophenylamine (2.65 g, 14.7 mmol) and triethylamine (6.1 mL, 44 mmol) in DCM (50 mL) was added titanium tetrachloride (1M in DCM, 8.8 mL, 8.8 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature, and stirred for a further 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in toluene and filtered through Celite®. The filtrate was concentrated under to dryness under reduced pressure to afford the title compound that was used without further purification.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[CH:14][S:15][C:8]=12.IC>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([CH3:1])[S:15][C:8]=12
Reactant: Clc1ccnc2ccsc12
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2nccc(Cl)c2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium (0.71 ml, 1.77 mmol) in THF (20.0 mL) was cooled to −78° C. and 7-chlorothieno[3,2-b]pyridine (200 mg, 1.18 mmol) was added dropwise. The mixture stirred at −78° C. for 1 h to afford a yellow suspension. A solution of iodomethane (0.22 ml, 3.54 mmol) in THF (1.0 mL) was added dropwise via syringe, and the mixture stirred at −78° C. for 3 h.; LCMS showed completion of the reaction. The reaction was quenched with water and warmed to RT. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a tan solid. This material was purified via column chromatography (RediSep 40 g column, gradient elution with 10-50% ethyl acetate-hexane) to afford 7-chloro-2-methylthieno[3,2-b]pyridine as white solid. MS [M+H]=184.1; Calc'd for C8H6ClNS: 183.7.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[N:24]=[C:23]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:22]=[CH:21][N:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nccc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nccc(N4CCN(C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(4-chloropyrimidin-2-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30 mg, 0.06 mmol) in dioxane (1 mL) was added 1-methylpiperazine (56.7 mg, 0.063 mL, 0.566 mmol). The RM was stirred at room temperature for 20 minutes, concentrated, and used without further purification. LCMS-ESI+ calc'd for C31H37ClN5O3S (M+H+): 594.2; Found: 593.7 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[CH3:11])=[O:5])[CH3:2].S(Cl)([Cl:15])(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([Cl:15])[O:8][C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccoc1C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)oc1C
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-3-furancarboxylic acid ethyl ester (10.5 g) was dissolved in acetonitrile (50 ml), and sulfuryl chloride (5.6 ml) was added under ice-cooling. The mixture was stirred at 10° C. for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) as oil. 5-Chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) was dissolved in ethanol (100 ml), and 1N aqueous sodium hydroxide (60 ml) was added. The mixture was stirred under reflux for 30 minutes and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were recrystallized from acetone-hexane to give 5-chloro-2-methyl-3-furancarboxylic acid (5.5 g) as crystals.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:15]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[O:16])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Product: O=C(O)COc1ccc(-c2ccc(Cl)cc2)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and 4-chlorophenylboronic acid according to GP4: LC/MS (an10n8): Rt 3.08 min, m/z 432.5 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:15][C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:4][CH2:3]1.[N:20]#[C:21][NH2:22]>Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:21]([NH2:22])=[NH:20])=[C:10]([O:15][C:16]([F:19])([F:17])[F:18])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)c(OC(F)(F)F)c2)CC1
Reactant: N#CN
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(NC(=N)N)c(OC(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 4-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (275 mg, 1 mmol) in HCl 6N (1 mL), cyanamide (336 mg, 8.0 mmol) was added and the reaction was stirred at 60° C. for 1 hours. The mixture was cooled down to room temperature, diluted with H2O (3 mL), extracted with DCM (10 mL). NaOH 2N was added to pH>11. The aqueous phase was extracted with Et2O (3×10 mL), dried over Na2SO4 and concentrated. The residue was crystallized from Et2O to give the title compound (240 mg, 76% yield) as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][C:4]1[CH:3]=[N:2][N:1]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:5]=1
Reactant: O=C(O)Cc1ccc(-n2cccn2)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1ccc(-n2cc(Br)cn2)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
20.2 g (100 mmoles) of 4-(pyrazol-1-yl)phenylacetic acid are dissolved in 400 ml of carbon tetrachloride. 16 g of bromine (200 mmoles) in 400 ml of carbon tetrachloride are added dropwise, with ice cooling, to the resulting solution. After subsequent stirring for half an hour at room temperature, washing with sodium dithionite solution is effected; this is followed by drying with sodium sulfate and, finally, by evaporation to dryness to obtain 27.5 g (98% of theory) of 4-(4-bromo-pyrazol-1-yl)phenylacetic acid, m.p. 187° C. (from acetonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.C(N(CC)CC)C.Cl.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:36]([C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)[N:37]=1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
1.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 0.5 ml of triethylamine and 0.7 g of 4-nitrophenylhydrazine hydrochloride are boiled under reflux for 1 h in 10 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-nitrophenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 180-183° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](I)=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Br:1][C:2]1[C:3]2[N:4]([C:9]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnc3c(Br)cc(Cl)nn23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
A pressure bottle charged with a mixture of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (1.4 g, 3.91 mmol), 4-fluorophenylboronic acid (0.558 g, 3.98 mmol), dioxane (20 mL), and tetrakis(triphenylphosphine)palladium(0) (0.452 g, 0.39 mmol), and K3PO4 (2.49 g, 11.72 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 85° C. for 8 h. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (0-20% EtOAc/CH2Cl2, 1.2 L) to give the product (0.56 g, 44%). LC/MS: Rt=3.22 min. LC/MS (Condition A): 325.83/327.83/329.83.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)c1ccc(Cl)cc1
Product: CN(C)C=CC(=O)c1ccc(Cl)cc1

Procedure:
Stage 3.05 g (3.23 mmol) of 4-chloroacetophenone are stirred in 3.6 ml of dimethylformamide diethylacetal for 17.5 h at 110°. After cooling, precipitation is effected with hexane and the precipitate is isolated by filtration and dried. 3-dimethylamino-1(4-chloro-phenyl)-2-propen-1-one is obtained; 1H-NMR (DMSO): 2.9 (3H,s), 3.1 (3H,s), 5.8 (1H,d), 7.5 (2H,m), 7.75 (1H,d), 7.95 (2H,m).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].S([O-])([O-])(=O)=[O:37].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][C:21](=[O:37])[C:20]=3[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3)CC1
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
4-[4-(2-Methyl-benzoylamino)-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester (1.12 g, 2.24 mmol) was dissolved in acetone (25 mL) and a 15% aqueous solution of magnesium sulfate (2.5 mL). The solution was cooled in an ice bath and potassium permanganate (1.9 g, 12.3 mmol) was added and the solution was stirred for 15 min at which time the solution was allowed to warm to room temperature and stirred for 3 hr. The solution was concentrated and diluted with 150 mL water. The product was exhaustively extracted from the aqueous layer with methylene chloride. The organic was then washed with brine, dried over anhydrous magnesium sulfate, concentrated and purified on silica (Isco flash column, 0 to 40% ethyl acetate in hexane). The title compound was isolated in 17% yield (200 mg).
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[S:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][N:18]=2)[C:11](=[O:13])[O-])=CC=1)([O-])=O.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(#N)C>[CH:19]([C:16]1[S:15][C:14]([NH:10][C:11]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([I:22])[CH:24]=2)=[O:13])=[N:18][CH:17]=1)([CH3:20])[CH3:21]
Reactant: Nc1cccc(I)c1
Reactant: CC(C)c1cnc(N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)s1
Solvent: CC#N
Product: CC(C)c1cnc(NC(=O)Nc2cccc(I)c2)s1
Temperature: 70 °C
Yield: 73.3 %

Procedure:
1 g (3.25 mmol) of 4-nitrophenyl-5-isopropyl-1,3-thiazol-2-ylcarbamate and 0.39 ml (3.25 mmol) of 3-iodoaniline were suspended under argon in 25 ml of acetonitrile. After 2 hours at 70° C. the resulting solution was cooled, giving rise 0.923 g of the title compound, recrystallized from a mixture of diethylether/pentane 1/1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]=12.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>C(O)CCC>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:28]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCCCC2
Reactant: COc1ccc(NN)cc1
Solvent: CCCCO
Product: COc1ccc(-n2nc3c4c([nH]cc-3c2=O)CCCCCC4)cc1

Procedure:
A mixture of 2.24 g of ethyl 4-chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-carboxylate and 1.16 g of 4-methoxyphenylhydrazine is stirred and heated at reflux under a nitrogen atmosphere for 20 hours in 20 ml of n-butanol. The solvent is then evaporated under reduced pressure and the residual material stirred with 20 ml of 1N sodium hydroxide, ether, and water. The layers are separated, the aqueous phase is extracted with ether and then treated with an aqueous solution of 1.07 g of ammonium chloride. The precipitate is filtered off and washed with water to give 2-(4-methoxyphenyl)-2,3,6,7,8,9,10,11-octahydrocycloocta[b]pyrazolo[3,4-d]pyridin-3(5H)-one, m.p. 275°-277°, the compound of formula II wherein n represents the integer 6, R4 and R5 represent hydrogen, and R1 represents p-methoxyphenyl. Further purification gives m.p. 283°-285°.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:16][CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(CBr)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
5 g of 4-(bromomethyl)benzenesulfonyl chloride (18.6 mmol, 1 eq.) were dissolved under argon atmosphere in 82.5 ml of dichloromethane and cooled down at −10° C. internal temperature. A solution of 1.29 ml cyclopropanamine (18.6 mmol, 1 eq.) and 2.59 ml of triethylamine (18.6 mmol, 1 eq.) in 82.5 ml of dichloromethane were added dropwise at −10° C. internal temperature and stirred at this temperature for one hour. The reaction mixture was washed once with 1 M aqueous hydrogen solution and twice with distilled water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product contained a mixture of bromomethyl- and chloromethyl-substituents.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][C:12](=[O:14])[OH:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41](ON1C(=O)CCC1=O)=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1.C(N(CC)CC)C>CN(C=O)C>[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C(N)=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C(N)=O)c1ccccc1
Yield: 65.3 %

Procedure:
2.2 g (5.3 mmoles) of H-Leu-Asp-L-Phg-NH2.HCl, prepared as described in Example 6, Step 3, are reacted with 2.32 g (5.8 mmoles) of BOC-Trp-OSu in 50 ml of DMF in the presence of 1.48 ml (10.6 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo and the residue is triturated with water. The obtained crude product, weighing 3.30 g, is crystallized from 70 ml of 80% ethanol under decolourizing. 2.30 g (65%) of BOC-Trp-Leu-Asp-L-Phg-NH2 are obtained; m.p.: 205°-207° C. (decomposition), Rf5 : 0.40, [α]D : -7.3° (c: 1.0, in dimethyl formamide).
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([N:38]([CH2:51][CH2:52][CH2:53][CH3:54])[C:39]1[CH:46]=[C:45]([O:47][CH3:48])[C:42]([CH:43]=O)=[C:41]([O:49][CH3:50])[CH:40]=1)[CH2:35][CH2:36][CH3:37].C(Cl)(Cl)Cl>O1CCCC1>[CH2:34]([N:38]([CH2:51][CH2:52][CH2:53][CH3:54])[C:39]1[CH:46]=[C:45]([O:47][CH3:48])[C:42]([CH:43]=[CH:14][C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)=[C:41]([O:49][CH3:50])[CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCN(CCCC)c1cc(OC)c(C=O)c(OC)c1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1cc(OC)c(C=Cc2cccs2)c(OC)c1
Temperature: 0 °C
Yield: 62.6 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 3.76 g of a 19% phenyllithium solution (8.5 mmol), and 0.78 g (1.98 mmol) of thiophene-2-ylmethyltriphenylphosphonium bromide was added thereto under cooling. After the mixture was well-stirred, 0.58 g (1.98 mmol) of 4-dibutylamino-2,6-dimethoxybenzaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 1.5 hours. After the mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 463 mg (yield: 62%) of 2-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene as a dark purple crystal (mp: 90° C.)
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[C:15](=O)[CH2:14][CH2:13][S:12][CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1>>[CH2:7]([C:8]1[C:10]2[CH2:11][S:12][CH2:13][CH2:14][C:15]=2[N:32]=[C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH3:17])=[CH:24][CH:25]=2)[N:31]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: O=C1CCSCC1C(=O)Cc1ccccc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CSCC3)cc1
Yield: 28 %

Procedure:
4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (74 mg, 28%) was synthesised from 3-(2-phenylacetyl)dihydro-2H-thiopyran-4(3H)-one and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 414.2 (M+H)+