Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([C:6]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:9]([NH2:10])=[CH:8][C:7]=1[N:16]1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1)(=[O:5])=[O:4].O.Cl>[Fe].C(O)C>[CH3:1][N:2]([CH3:23])[S:3]([C:6]1[C:7]([N:16]2[CH:17]=[CH:18][C:19](=[O:22])[CH:20]=[CH:21]2)=[CH:8][C:9]([NH2:10])=[C:11]([NH2:13])[CH:12]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N)cc1-n1ccc(=O)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(N)c(N)cc1-n1ccc(=O)cc1
Yield: 95.1 %

Procedure:
First, a mixture containing 1.50 g of 4-dimethylsulfamoyl-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline, 1.49 g of iron powder, 9 ml of water, 36 ml of ethanol, and 0.45 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 45 minutes. The subsequent processes were conducted in the same way as in Reference Example 3 to give crude crystals. The crude crystals were recrystallized with methanol/isopropanol to give 1.30 g of crystals of 4-dimethylsulfamoyl-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11].C(N(CC)C(C)C)(C)C.[C:37]([CH2:40][CH:41]([C@@H:43]1[CH2:47][C@H:46]([S:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[CH2:45][N:44]1[C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=1)=[O:59])[OH:42])(O)=[O:38].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[OH:42][CH:41]([C@@H:43]1[CH2:47][C@H:46]([S:48][CH2:49][C:50]2[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)[CH2:45][N:44]1[C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]([N+:68]([O-:70])=[O:69])=[CH:66][CH:67]=1)=[O:59])[CH2:40][C:37]([N:25]1[CH2:26][CH2:27][C@H:23]([N:9]([CH3:8])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:24]1)=[O:38]
Reactant: CN(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(O)CC(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CS[C@H]2C[C@@H](C(O)CC(=O)N3CC[C@H](N(C)C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
In dimethylformamide (5 ml), (3S)-3-[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]pyrrolidine trifluoroacetate (400.9 mg) was dissolved. To the solution, N,N-diisopropylethylamine (0.444 ml) and a solution of (2S,4S)-2-(2-carboxy-1-hydroxyethyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.5 g) in dimethylformamide (5 ml), were added at room temperature. To the resulting mixture, 1-hydroxybenzotriazole (151.5 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (273.5 mg) and water (1 ml) were added successively and the mixture was stirred overnight at the same temperature. The reaction mixture was concentrated by evaporation under reduced pressure. Ethyl acetate was then added to the residue. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate methanol=50:1), whereby (2S,4S)-2-[1-hydroxy-2-[(3S)-3-[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]pyrrolidin-1-ylcarbonyl]ethyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (523.5 mg) was obtained
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([Cl:20])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([Cl:20])[S:17][C:15]=2[N:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Product: Fc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine yields 2,6-dichloro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([OH:34])[CH:9]=2)[CH:3]=1.IC.[C:37](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([O:34][CH3:37])[CH:9]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2O)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(-n2cc(F)c(F)c2)ccc1-n1cc(OC)c(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A suspension of 1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (231 mg), iodomethane (0.0375 mL) and potassium carbonate (138 mg) in DMF (2.5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF), and recrystallized from methanol/water to give the title compound (232 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@@H:7]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[C@@H:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:12][C:13]#[N:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][N:33](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@@H:7]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[C@@H:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:32]#[N:33])[CH:16]=2)[CH2:12][C:13]#[N:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(CC#N)c1cccc(Br)c1)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@H](NC(CC#N)c1cccc(C#N)c1)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 180 °C

Procedure:
A solution of 164 mg (0.33 mmol) of 3-(1(S)-(4-chlorobenzyl)-2(S)-((1-(3-bromophenyl)-2-cyanoethyl)amino)propyl)benzonitrile (mixture of two diastereomers) in 2 mL of DMF and 0.02 mL of water was treated with 35 mg of Zinc cyanide, 7 mg (0.008 mmol) of tris(dibenzylidineacetone) dipalladium and 11 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocene. The solution was degassed by bubbling N2 for 30 min, while the color changed from brown to yellow-orange. The vial was sealed and heated in a microwave reactor at 180° C. for 1 hr. After the reaction cooled, it was filtered through a pad of CELITE, diatomaceous earth, and the solids were washed with ether. The filtrate was diluted with ether, washed with water, and brine, then dried and concentrated. The residue was purified by prep TLC to obtain the less polar isomer, 3-(1(S)-(4-chlorobenzyl)-2(S)-((1-(3-cyanophenyl)-2-cyanoethyl)amino)propyl)benzonitrile (Diastereomer A); LC-MS: m/e=439 (M+1), 441 (M+3) (3.62 min) and more polar isomer 3-(1(S)-(4-Chlorobenzyl)-2(S)-((1-(3-cyanophenyl)-2-cyanoethyl)amino)propyl)benzonitrile (Diastereomer B); LC-MS: m/e=439 (M+1), 441 (M+3) (3.41 min).
Reaction SMILES: [Li+].[AlH4-].S(=O)(=O)(O)O.[C:8]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([Br:22])=[CH:14][C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)(=O)[CH3:9].[OH-].[Na+]>O1CCCC1.O>[Br:22][C:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([CH2:8][CH3:9])[C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[CH:14]=1
Reactant: CC(=O)N1c2ccccc2C=C(Br)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [AlH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1c2ccccc2C=C(Br)c2ccccc21
Reaction time: 0.5 h

Procedure:
To 275 parts of a vigorously-stirred 31/2% solution of lithium tetrahydroaluminate(1-) in tetrahydrofuran at 0°-5° is slowly added 8 parts of concentrated sulfuric acid. The resultant mixture is stirred at 0°-5° for 1 hour, whereupon a solution of approximately 63 parts of 5-acetyl-10-bromo-5H-dibenz[b,f]azepine in 135 parts of tetrahydrofuran is stirred in during 30 minutes, producing a yellow color. The mixture thus obtained is stirred at 0°-5° for 30 minutes, whereupon a mixture of 20 parts of water and 35 parts of tetrahydrofuran, followed first by 40 parts of aqueous 25% sodium hydroxide and finally by 30 parts of water, are consecutively introduced. Insoluble solids are thereupon filtered out and washed with hot tetrahydrofuran, and the washings are combined with the filtrate. The resultant solution is dried over magnesium sulfate and stripped of solvent by vacuum distillation. The residual yellow solid, recrystallized from 2-propanol, affords 10-bromo-5-ethyl-5H-dibenz[b,f]azepine melting at approximately 147.5°-148.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:9]I)=[CH:4][C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[CH2:24]([NH:31][CH2:32][CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:24]([N:31]([CH2:32][CH2:33][OH:34])[CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:4]=1)[O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(Cl)c(NS(C)(=O)=O)c1
Reactant: OCCNCc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)O[C@@H](CN(CCO)Cc1ccccc1)c1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(R)—N-(2-Chloro-5-(2-iodo-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (3 g) and 2-(benzylamino)ethanol (6 mL; Tokyo Chemical Industry, Co., Ltd.) were admixed with each other and stirred overnight at 100° C. The reaction solution was cooled to room temperature, added with toluene and Et2O, and then washed with water three times. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=84:16→64:36) to obtain the title compound (2.1894 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26]C(C)(C)[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]([C:27]([OH:28])=[O:26])=[C:23]([OH:24])[CH:31]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)OC(C)(C)OC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(C(=O)O)c(O)c1
Yield: 76.3 %

Procedure:
To a solution of 7-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (613 mg, 1.2 mmol) in THF (18 mL) was added a suspension of lithium hydroxide monohydrate (1.47 g, 35.1 mmol) in water (5.0 mL). The resulting mixture was refluxed for 48 hrs. The reaction mixture was diluted with Et2O (60 mL) and washed with an aqueous solution of HCl (3×15 mL, 1N) and brine. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure to give 443 mg (78%) of the title compound as a yellow powder. HPLC, Rt: 6.2 min (purity: 97.7%). LC/MS, M−(ESI): 482.2. 1H NMR (CDCl3) δ: 10.59 (s, 1H), 7.66 (d, J=9 Hz, 1H), 7.45 (m, 4H), 7.13 (m, 4H), 6.21 (m, 1H), 6.14 (m, 1H), 4.58 (s, 2H), 3.40 (m, 2H), 2.60 (t, J=7.5 Hz, 2H), 1.72-1.51 (m, 2H), 1.42-1.20 (m, 10H), 0.95-0.82 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:23]1[N:19]([CH3:18])[N:20]=[CH:21][CH:22]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(C)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of methyl 4-bromo-5-methyl-2-furancarboxylate (2.1 g, 9.59 mmol), potassium carbonate (6.63 g, 47.9 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.24 g, 0.48 mmol) in 1,4-dioxane (40 ml) and water (8 ml) was stirred at 80° C. in a sealed tube for 1 h. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.245 g, 0.48 mmol) were added and the reaction stirred an additional 1 h and was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (1.7 g, 7.72 mmol, 81% yield) as a yellow oil: LCMS (ES) m/e 221 (M+H)+.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-:5])=[O:4].Cl[CH2:14][CH:15]=[CH2:16].CS(C)=O>O>[CH2:16]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])[CH:15]=[CH2:14]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A solution of 64 g of sodium hydroxide in 75 ml of water was added drop-to-drop (over 15 minutes) to a stirred mixture of 209.6 g of 2-nitrophenol, 115.5 g of 3-chloropropene and 500 ml of dimethyl sulfoxide (DMSO), at room temperature. The mixture was stirred at 85°-90° C. for 18 hours and then mixed with 3 liters of water. The resulting mixture was extracted with methylene chloride, the extract was washed with ice water, dried (MgSO4) and the solvent was evaporated, to give 1-(2-propen-1-yloxy)-2-nitrobenzene (1A), as an amber syrup.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=C2C3C(=CC=CC=3)CC2C2C=CC=CC=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([CH:35]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=O)[CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[C:12]([CH:13]=[C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:44][CH:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36]2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccccc2)Cc2ccccc21
Reactant: C(=C1c2ccccc2CC1c1ccccc1)c1cncn1Cc1ccccc1
Product: C(=C1CC(c2ccccc2)Cc2ccccc21)c1cncn1Cc1ccccc1

Procedure:
1-Benzyl-5-(3-phenyl-3,4-dihydro-2H-naphthalen-1-ylidenemethyl)-1H-imidazole was prepared as 1-benzyl-5-(2-phenylindan-1-ylidenemethyl)-1H-imidazole above except that 3-phenyl-3,4-dihydro-2H-naphthalen-1-one (prepared according to J. Vebrel and R. Carrie Bull. Soc. Chem. Fr. (1982) 116) was used as a starting material. The crude product as its hydrochloride salt was used in the next step without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N1C2C(=C(NC3C([N+]([O-])=O)=CC=CC=3C(O)=O)C=CC=2)C=N1.[BH4-].[Na+].Cl>[OH-].[Na+].CC(O)=O>[CH:3]1[C:4]2=[C:5]3[C:6](=[CH:7][CH:8]=[C:9]2[NH:1][N:2]=1)[N:21]=[C:20]1[C:11]([C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=[CH:19]1)=[N:10]3
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Nc1cccc2[nH]ncc12
Agent: Cl
Agent: O=C(O)c1cccc([N+](=O)[O-])c1Nc1cccc2[nH]ncc12
Agent: [BH4-]
Solvent: CC(=O)O
Product: O=C(O)c1cccc2nc3ccc4[nH]ncc4c3nc12
Yield: 43.2 %

Procedure:
A solution of methyl 2-(1H-indazol-4-ylamino)-3-nitrobenzoate (254 mg, 0.85 mmol) in 2 M NaOH (20 mL) was stirred at room temperature for 1 h to complete hydrolysis to 2-(1H-indazol-4-ylamino)-3-nitrobenzoic acid then NaBH4 (194 mg, 5.11 mmol) was added and the mixture heated under reflux for 30 min. The mixture was then acidified with conc. HCl, then glacial AcOH, until the pH reached 5. This aqueous solution was then extracted with EtOAc (3×50 mL), the extracts combined and dried (Na2SO4), and the solvent removed under reduced pressure. Crystallization from acetone gave 3H-pyrazolo[4,3-a]phenazine-10-carboxylic acid (97 mg, 43%); mp 305-310° C.; 1H NMR [(CD3)2SO] δ 7.98 (br s, 1 H, H-4), 8.07 (dd, J=8.6, 7.2 Hz, 1 H, H-8), 8.20 (d, J=9.2 Hz, 1 H, H-5), 8.53 (dd, J=8.5, 1.3 Hz, 1 H, H-7 or H-9), 8.60 (dd, J=7.1, 1.3 Hz, 1 H, H-9 or H-7), 8.90 (v br s, 1 H, H-1), 14.26 (v br s, 1 H, NH or COOH), 14.76 (v br s, 1 H, NH or COOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=2)=[N:6][CH:7]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:33][C:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:21][N:20]=1)=[O:24])([CH3:39])[CH3:35]
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of 5-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridine-2-carboxylic acid (82 mg, 0.25 mmol) and TBTU (88 mg, 0.27 mmol) in DMF (1.2 mL) was added DIPEA (213 μL, 1.25 mmol). Then isopropylamine (23 μL, 0.27 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (57 mg, 62%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([C:7]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13](Cl)[CH:12]=2)[CH2:10][CH2:9][CH2:8]1)(=O)[CH3:5].Cl>C(O)=O.O>[ClH:17].[CH2:1]([NH:3][CH:4]([C:7]1([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH2:10]1)[CH3:5])[CH3:2]
Reactant: CCN
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: CCNC(C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 140 °C

Procedure:
A mixture of 70% aqueous ethylamine (50 ml) and water (100 ml) was gradually mixed with a mixture of 98% formic acid (50 ml) and water (100 ml) to give a neutral solution which was evaporated at 100° C./100 mg Hg until 180 ml of water had been collected. The residue was heated to 140° C. and 1-acetyl-1-(4-chlorophenyl)cyclobutane (10.4 g) prepared in a similar manner to that described in Example 1 for 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid (10 ml) were added. The mixture was heated on an oil bath at a temperature of 180°-200° C. for sixteen hours. The mixture was distilled until an internal temperature of 170° C. was obtained and this temperature was maintained for two hours. Any volatile material was removed by distillation at 160° C./20 mm and the residue heated under reflux with concentrated hydrochloric acid (15 ml) and industrial methylated spirit (IMS) (15 ml) for three hours. The IMS was evaporated on a rotary evaporator and the residue washed with ether. The aqueous phase was brought to pH 12 with sodium hydroxide and extracted with ether. The ether extract was dried and on evaporation yielded a residue which was treated with aqueous hydrochloric acid to give N-ethyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 203°-205° C.) (Formula I R1 =Me; R2 =H; R3 =Et; R4 =H; R5 =4-Cl; R6 =H).
Reaction SMILES: [NH3:1].Cl[CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1>C(Cl)Cl>[NH2:1][CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1
Reactant: O=C1Nc2ccccc2SC1Cl
Reactant: N
Solvent: ClCCl
Product: NC1Sc2ccccc2NC1=O
Yield: 41 %

Procedure:
Anhydrous ammonia gas was bubbled for one hour through a suspension of 500 mg (2.5 mmol) of 2-chloro-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (prepared by the method of Worley, et al; J. Org. Chem., 40, 1731-1734 (1975)) in 5 mL of methylene chloride. The mixture was filtered through Celite and the filtrate evaporated under vacuum. The residue was triturated with 20 mL of chloroform, filtered and the filtrate evaporated under vacuum. Purification by flash chromatography on silica, eluting with ethyl acetate, afforded 185 mg (1.0 mmol, 41%) of the product. 1H NMR (200 MHz, CDCl3): 2.00 (br s,2H), 4.68 (br s,1H), 6.9-7.4 (m,4H), 9.05 (br s,1H). FAB-MS: calculated for C8H8N2OS 180; found 181 (M+H,54%).
Reaction SMILES: [N+]([O-])(O)=O.CC1C=C(C)N(C(N)=N)N=1.[CH2:15]([CH2:28][CH2:29][N:30]=[C:31]([NH2:33])[NH2:32])[CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=O)=[O:19].CC(CCCCN)[C:36]([OH:38])=[O:37].C(OC(NCCCCCC(O)=O)=O)CCC.CC(CCCN)C(O)=O.C(OC(NCCCCC(O)=O)=O)CCC.NC(N)=[NH2+]>>[CH2:23]([CH2:22][CH2:21][NH:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:28][CH2:29][N:30]=[C:31]([NH2:33])[NH2:32])=[O:19])[CH2:24][CH2:25][C:36]([OH:38])=[O:37]
Reactant: CC(CCCCN)C(=O)O
Reactant: NC(N)=NCCCCCC(=O)NCCCCC(=O)O
Agent: CC(CCCN)C(=O)O
Agent: CCCCOC(=O)NCCCCC(=O)O
Agent: CCCCOC(=O)NCCCCCC(=O)O
Solvent: O=[N+]([O-])O
Product: NC(N)=NCCCCCC(=O)NCCCCCC(=O)O

Procedure:
In Greenspoon et al., the design and preparation of nonpeptide analogues of RGD are described as follows. Compounds SF-6,5 and SFN-70 were prepared by coupling of methyl-5-aminovaleric acid with N-(butyloxycarbonyl)-6-aminohexanoic acid. The reaction was carried out using the 1,3-dicyclohexylcarbodiimide and 1 hydroxybenzotriazole in tetrahydroduran procedure. The butyloxycarbonyl protecting group was then removed by 50% trifluoroacetic acid in dichloromethane. Removal of the methyl ester protecting group was carried out with sodium hydroxide at pH 9.5, yielding SFN-70. The amine was converted to guanidium using 3,5-dimethylpyrazole-1-carboxamidine nitrate at pH 9.5 t produce the compound designated SF-6,5. Compound SF-6,6 was prepared from methyl-6-aminohexanoic acid and N-(butyloxycarbonyl)-6-aminohexanoic acid under the same conditions as used for SF-6,5. GK-5,5 was prepared from methyl-5-aminovaleric acid and N-(butyloxycarbonyl)-5-aminovaleric acid. Compounds AC-4 and AC-14 were prepared by stepwise synthesis either in solution or on a Merrifield resin, followed by deprotection and conversion of the amine to the guanidinium by the above-described methods. The final compounds were purified on preparative RP-18 columns and were judged pure by thin-layer chromatography (single spot) and 1H NMR spectroscopy. Compounds were characterized by 1H NMR and FAB-MS spectroscopy. The structures deduced from spectroscopy were consistent with the assigned structure. (Table 1). Table 1 shows a schematic presentation of the RGD-NH2 peptide and the corresponding non-peptide surrogates. Note that the distance between positions a and b is 11 atoms.