Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C:6]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=1)[C:7]([F:10])([F:9])[F:8])(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[F:28][C:27]([F:29])([F:30])[C:25]1[CH:26]=[C:21]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=2)[C:7]([F:8])([F:9])[F:10])[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=1
Reactant: Cc1cc(C(OS(C)(=O)=O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
A solution of 1-(3,5-bis-trifluoromethylphenyl)-2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethyl methanesulfonate (0.5 g) in tetrahydrofuran (5 ml) was slowly added dropwise to a solution of lithium aluminium hydride (0.04 g) in tetrahydrofuran (10 ml) in an ice bath. After stirring for 30 minutes, the reaction solution was diluted with ethyl ether, and then stirred for 30 minutes by slowly adding a saturated salt solution (1 ml). After the insoluble matter was separated by filtration, the solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1-(3,5-bis-trifluoromethylphenyl)-2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethane (0.11 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]([CH:19]=[CH2:20])[CH2:17][N:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:29])[NH2:28])[CH:22]=3)[C:15]2=[O:30])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]([CH:19]=[CH2:20])[CH2:17][N:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:28])[NH2:29])[CH:22]=3)[C:15]2=[O:30])[CH2:10][CH2:9]1
Reactant: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCNCC1
Yield: 130.5 %

Procedure:
1-(1-t-Butoxycarbonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone (1.32 g, 3.3 mmol) was stirred in 1:1 dichloromethane:trifluoroacetic acid (30 ml) for 4 h. This solvent was removed in vacuo, and 1.35 g of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone was obtained as the trifluoroacetic acid salt LRMS (M+H)+ m/z 297.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1>C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:9][C:4]1[N:3]=[C:2]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1cc(Cl)nc(C)n1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccccc3C2)nc(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
A mixture of 4-chloro-2,6-dimethylpyrimidine (Chem. Ber. 1902, 35, 1575; 1.24 g, 8.70 mmol) and 1,2,3,4-tetrahydroisoquinoline (3.47 g, 26.1 mmol) was stirred at room temperature for 3 h. The solid formed was then dissolved in toluene (15 ml) and 1 M aqueous potassium phosphate buffer (pH 6.85, 15 ml). The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Recrystallization in hexane (150 ml) yielded 2-(2,6-dimethyl-pyrimidin-4-yl)-1,2,3,4-tetrahydro-isoquinoline (1.71 g, 82%) as a crystalline light yellow solid. EI mass spectrum, m/e: 239.1 (M calculated for C15H17N3: 239).
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([O:16]CC)=[O:15].O1CCCC1.CO.[OH-].[Na+]>O>[OH:1][CH:2]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1sc(-c2ccncc2)cc1C(O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccncc2)cc1C(O)c1ccc2ccccc2c1
Yield: 13.8 %

Procedure:
Ethyl 3-[hydroxy(2-naphthyl)methyl]-5-pyridin-4-ylthiophene-2-carboxylate (70.0 mg, 0.180 mmol) was placed in a round bottomed flask equipped with a stirbar. Tetrahydrofuran (2.00 mL), methanol (1.00 mL), and water (1.50 mL) were added with stirring—all solids dissolved. Sodium hydroxide (1.0 M, 1.50 mL, 1.50 mmol) was added in a single portion and the resulting solution was stirred under an atmosphere of nitrogen overnight, resulting in a clear light yellow solution. The reaction was quenched into water and the pH of the mixture was adjusted the pH to ˜6-6.5 with sodium bicarbonate solution. The mixture was extracted with ethyl acetate, the extracts were combined and then rotovapped to leave crude product as a light yellow solid. The crude product was purified by HPLC to yield 9 mg (14% yield) product as a pale yellow powder. LC/MS (FA) ES+ 362. 1H NMR (400 MHz, DMSO) δ 8.60-8.51 (d, J=6.1 Hz, 2H), 7.98-7.94 (s, 2H), 7.91-7.75 (m, 4H), 7.68-7.58 (m, 3H), 7.53-7.37 (m, 2H), 6.64-6.36 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:15][CH:16]=2)=[C:9]([C:19]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in methanol and powdered 3 Å sieves were added. Morpholine (2 eq) was added, followed by acetic acid (5 eq). After stirring for 30 minutes, sodium cyanoborohydride (2 eq) was added portionwise and the suspension was stirred under nitrogen at ambient temperature for 16 hours. The reaction mixture was filtered through celite and concentrated to dryness. Column chromatography, eluting with 5% MeOH in DCM gave 5-(2,4-bis-benzyloxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5](Br)=[CH:4][N:3]=1.C[O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)=O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:6]1[CH:5]=[CH:4][N:3]=[C:2]2[C:7]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12](=[O:11])[NH:1]2
Reactant: COC(=O)c1ccccc1B(O)O
Reactant: Nc1ncc(Br)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2ncccc2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 3.1 %

Procedure:
2-Amino-3-iodo-5-bromopyridine (299 mg, 1.00 mmol), 2-methoxycarbonylphenylboronic acid (189 mg, 1.05 mmol), palladium(II) acetate (9 mg, 0.04 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (33 mg, 0.08 mmol), and potassium carbonate (414 mg, 3.00 mmol) were dissolved in dioxane/H2O (2.0 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture was concentrated, suspended in EtOAc/H2O, and filtered. The precipitate was washed with EtOAc/H2O, and dried under vacuum to provide 1 (6 mg, 7% yield) as a solid. LC-MS (M+H=275, obsd.=275). 1H NMR (400 MHz, d6-DMSO): δ 12.22 (s, 1H), 9.11 (d, 1H), 8.64 (d, 1H), 8.61 (d, 1H), 8.33 (d, 1H), 7.91 (t, 1H), 7.73 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:21][C:17]1[O:16][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccco1
Product: Clc1c(CCCNCc2ccco2)ccc2ccccc12
Yield: 45 %

Procedure:
The reductive ammination of 3-(1-chloronaphthalen-2-yl)propan-1-amine and furan-2-carbaldehyde was performed as described for compound I to obtain the compound as a pale yellow oil (45% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]([NH:20][NH2:21])=O)=[CH:4][CH:3]=1.[N:22]([CH3:25])=[C:23]=[S:24]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[S:24][C:23]([NH:22][CH3:25])=[N:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CN=C=S
Solvent: CCO
Product: CNc1nnc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(2-(4-chlorophenyl)imidazo[1,2-α]pyridin-3-yl)acetohydrazide (0.1 g, 0.33 mmol) in EtOH (1 mL) was treated with isothiocyanatomethane (0.023 mL, 0.33 mmol) and refluxed for 3 h. The precipitated thiosemicarbazide was filtered and dissolved in concentrated sulfuric acid. The reaction mixture was stirred for 30 min at rt. The mixture was poured into cold water and the precipitated product was filtered in vacuo and washed with ditilled water. The crude product was recrystallized in EtOH to provide the title product as a yellow solid. M/e+ 356 for C17H15ClN5S (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.15 (d, J=6.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.22 (m, 2H), 6.84 (t, J=6.6 Hz, 1H), 4.65 (s, 2H), 2.98 (s, 3H) ppm.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:17])[CH2:15]Br)[CH2:5]1)=[N+:2]=[N-:3].[N-:27]=[N+:28]=[N-:29].[Na+].O.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[N:1]([C@@H:4]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:17])[CH2:15][N:27]=[N+:28]=[N-:29])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CC[C@@H](N=[N+]=[N-])C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@]12CC[C@@H](N=[N+]=[N-])C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CN=[N+]=[N-])CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3α-azido-21-bromo-5α-pregnan-20-one (35 mg, 0.083 mmol) in DMSO (3 mL) was treated with sodium azide (33 mg, 0.5 mmol) and the resulting mixture was stirred at RT for 24 h. Addition of water and ethyl acetate and extraction of the organic layer with water, brine, drying (Na2SO4) and evaporation of the solvent in vacuo afforded after purification of the residue using flash colunm chromatography with dichloromethane/ethyl acetate 90/10 as elution solvent the compound named above.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:10]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:18]([CH:17]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])[CH2:16][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCC(Br)C(=O)OCC
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC(Oc1ccccc1C)C(=O)OCC
Temperature: 70 °C

Procedure:
A mixture of o-cresol (0.1 mol) and diethyl 2-bromoglutarate (0.1 mol) and K2CO3 (0.11 mol) in 50 mL of DMF are heated at 70° C. overnight. The reaction is poured into water and extracted with ethyl acetate. The organic solution is washed with water, 0.1N NaOH solution, dried and evaporated to give ethyl 4-carbethoxy-4-(2-methylphenoxy)butyrate which is used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH2:12]([N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[C:16]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[N:15]1)[CH3:13]>>[Cl:8][C:6]1[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]2=[C:2]([C:17]2[C:16]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[N:15][N:14]([CH2:12][CH3:13])[CH:18]=2)[CH:7]=1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: Clc1cc(Br)c2cc[nH]c2n1
Product: CCn1cc(-c2cc(Cl)nc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 6 with 4-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine and 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole afforded the title compound. ESMS [M+H]+: 368.2
Reaction SMILES: C([O:8][C:9]([CH:11]1[C:18](=[O:19])[N:17]2[CH:13]([CH2:14][CH2:15][C:16]2=[O:20])[CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[O:19]=[C:18]1[N:17]2[CH:13]([CH2:14][CH2:15][C:16]2=[O:20])[CH2:12][CH:11]1[C:9]([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)C1CC2CCC(=O)N2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C(O)C1CC2CCC(=O)N2C1=O

Procedure:
A solution of hexahydro-3,5-dioxo-1H-pyrrolizine-2-carboxylic acid benzyl ester 25.90.1 g, yy mole) in dioxane (200 ml) is treated with hydrogen gas in the presence of 20% Pd/C catalyst for eight hours. The mixture is filtered and concentrated at reduced pressure (below 25° C.) to yield pure hexahydro-3,5-dioxo-1H-pyrrolizine-2-carboxylic acid.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>C(Cl)(Cl)Cl>[CH2:16]([O:10][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]=1)[CH3:17]
Reactant: CC[O+](CC)CC
Reactant: O=C1NCc2ccccc21
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC1=NCc2ccccc21

Procedure:
Scheme VIII shows the synthesis of a benzyl-protected isoindolin-1-one oxime intermediate 27. Isoindolinone 25 is alkylated with triethyloxonium tetrafluoroborate in chloroform to afford the 3-ethoxy-1H-isoindole 26, which is reacted with O-benzylhydroxylamine hydrochloride and sodium carbonate in ethanol, providing intermediate 27. Intermediate 27 can be coupled by Suzuki reaction with intermediates 3 or 6 as in Schemes I and II. Alternatively, intermediate 27 can be converted to the boronate ester intermediate 28 by reaction with bis(pinacolato)diboron in dioxane, using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride dichloromethane complex. The boronate ester intermediate 28 can be coupled by Suzuki reaction with intermediates 1 or 5 as in Schemes I and II.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([N:20]=[C:21]([S-])[S-](C)C)[CH:17]=[CH:18][CH:19]=1.CC#N>CS(C)=O.C(O)(C(F)(F)F)=O>[N:3]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:7][C:21]=1[NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=1
Reactant: C[S-](C)C([S-])=Nc1cccc(C(F)(F)F)c1
Reactant: NCc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CC#N
Product: FC(F)(F)c1cccc(NC2=Nc3ccccc3CN2)c1
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
Under an atmosphere of nitrogen, sodium hydroxide (0.1 ml, solution in water, 20 mol/l, 2 mmol) was added to a solution of 2-aminobenzylamine (92 mg, 0.75 mmol) in DMSO (1 ml). After 30 min, a solution of (3-trifluoromethyl-phenyl)-dimethyl-dithiocarbonimidate (200 mg, 0.75 mmol) in DMSO (1 ml) was added, and the mixture was heated to 190° C. for 3 h. The title compound (50 mg, 23%, MS: m/e=292.1 [M+H+]) was isolated from the reaction mixture by preparative, reverse phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([C:8]1[O:12][C:11]([C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](=[NH:30])[NH:25]OC(=O)C)=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[CH:10][CH:9]=1)=[NH:7])(=[O:3])[CH3:2].C(O)C>C(O)(=O)C.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[O:14][C:13]([C:11]3[O:12][C:8]([C:6]([NH2:7])=[NH:5])=[CH:9][CH:10]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=1)(=[NH:25])[NH2:30]
Reactant: CC(=O)ONC(=N)c1ccc(-c2ccc(-c3ccc(C(=N)NOC(C)=O)o3)o2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: N=C(N)c1ccc(-c2ccc(-c3ccc(C(=N)N)o3)o2)cc1
Reaction time: 4 h
Yield: 67 %

Procedure:
To a solution of 7 (246 mg, 0.6 mmol) in glacial acetic acid (8 mL), and ethanol (20 mL) was added 10% palladium on carbon (60 mg). The mixture was placed in a Parr hydrogenation apparatus at 50 psi for 4 h at room temperature. The mixture was filtered through hyflo and the filter pad washed with water. The filtrate was evaporated under reduced pressure and the precipitate was collected and washed with ether to give 8a in 67% yield, mp 240-242° C. 1H NMR (D2O/DMSO-d6); δ 1.80 (s, 2×CH3), 7.06 (d, J=3.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 7.36 (d, J=3.6 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H). Calcd for C16H14N4O2-2.0AcOH-2.4H2O: C, 52.48; H, 5.87; N, 12.23. Found. C, 52.28; H, 5.49; N, 11.91.
Reaction SMILES: CS[C:3]([N:6]1[N:10]=[CH:9][C:8]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:7]1)=[N:4][CH3:5].[Cl:16][C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[S:25]([NH2:28])(=[O:27])=[O:26])[CH:22]=[CH:21][S:20]2>C(#N)C>[CH3:5][NH:4][C:3]([N:6]1[N:10]=[CH:9][C:8]2([CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH2:7]1)=[N:28][S:25]([C:24]1[N:23]2[C:19]([S:20][CH:21]=[CH:22]2)=[N:18][C:17]=1[Cl:16])(=[O:27])=[O:26]
Reactant: CN=C(SC)N1CC2(C=N1)CCOCC2
Reactant: NS(=O)(=O)c1c(Cl)nc2sccn12
Solvent: CC#N
Product: CNC(=NS(=O)(=O)c1c(Cl)nc2sccn12)N1CC2(C=N1)CCOCC2
Yield: 0.1 %

Procedure:
0.42 g (1 mol equiv.) N-Methyl-8-oxa-2,3-diaza-spiro[4.5]dec-3-ene-2-carboximidothioic acid methyl ester and 0.46 g (1.05 mol equiv.) 6-chloro-imidazo[2,1-b]thiazole-5-sulfonic acid amide were added to 7 mL acetonitrile and the reaction mixture was refluxed overnight. Volatiles were removed under reduced pressure, and the residue was taken up in ethylacetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (EtOAc) afforded 0.56 g (69%) 6-chloro-imidazo[2,1-b]thiazole-5-sulfonic acid methylamino-(8-oxa-2,3-diaza-spiro[4.5]dec-3-en-2-yl)-methylene-amide. 1H NMR (400 MHz, CDCl3) δ 1.51-1.57 (m, 2H), 1.80-1.89 (m, 2H), 3.10 (d, J=5.0 Hz, 3H), 3.51-3.59 (m, 2H), 3.83-3.90 (m, 4H), 3.89 (s, 2H), 6.89 (s, 1H), 6.99 (d, J=4.6 Hz, 1H), 7.12 (br.s., 1H), 8.01 (d, J=4.6 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[C:6]([C:9]1[C:10]([I:33])=[C:11]([NH:17][C:18](=[O:32])[CH2:19][N:20]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]([I:16])=[CH:13][C:14]=1[I:15])([OH:8])=[O:7].Cl>O.[OH-].[Na+]>[C:6]([C:9]1[C:10]([I:33])=[C:11]([NH:17][C:18](=[O:32])[CH2:19][N:20]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]([OH:5])=[O:4])[CH2:28][CH2:27][N:26]([CH2:2][C:3]([OH:5])=[O:4])[CH2:25][CH2:24][N:23]([CH2:2][C:3]([OH:5])=[O:4])[CH2:22][CH2:21]2)[C:12]([I:16])=[CH:13][C:14]=1[I:15])([OH:8])=[O:7]
Reactant: O=C(CN1CCNCCNCCNCC1)Nc1c(I)cc(I)c(C(=O)O)c1I
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)Nc2c(I)cc(I)c(C(=O)O)c2I)CCN(CC(=O)O)CC1
Yield: 70.7 %

Procedure:
18.9 g of bromoacetic acid (product available on the market) (0.136 mol) are dissolved in 20 ml of H2O, and by keeping the temperature below 10° C., the solution pH is adjusted to 5 with 68 ml of 2N NaOH (0.136 mol). After adding a solution of 30 g of compound. (B) N-(3-carboxy-2,4,6-triiodophenyl)-1,4,7,10-tetraazacyclododecane-1-acetamide (0.041 mol) in 20.5 ml of 2N NaOH, the reaction mixture is heated at 50° C. for 15 h keeping the pH at 10 with 6.15 ml of 2N NaOH (0.123 mol). A solid precipitates which is then filtered and dissolved in 200 ml of H2O. After acidification of the solution with 82 ml of HCl 2N (0.164 mol) the precipitate is filtered. 28.2 g of 10-[2-[(3-carboxy-2,4,6-triiodophenyl)amino]-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (0.029 mol) are obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.CCCCCC.[C:23]([C:25](=[C:30]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH:26]=[CH:27][CH:28]=[O:29])#[N:24]>O1CCCC1.Cl>[C:23]([C:25](=[C:30]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])#[N:24]
Reactant: N#CC(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(C#N)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a chilled suspension (0° C., ice-water bath) of sodium hydride (120 mg, 60% suspension in mineral oil, 3 mmol) in dry tetrahydrofuran (2 mL) under an inert atmosphere was added ethyl acetoacetate (330 μL, 2.6 mmol) in 4 equal portions over a period of 10 minutes. The homogeneous clear solution was stirred at 0° C. for 30 minutes followed by the dropwise addition of 2.5 M n-BuLi hexane solution (1.15 mL, 2.9 mmol) over 15 minutes. The orange dianion solution was stirred at 0° C. for an additional hour. The ice-water bath was replaced by an acetone-dry ice bath at -78° C. and the dianion solution was transferred via a cannula into a tetrahydrofuran (10 mL) solution containing 4-cyano-5,5-bis(4-fluorophenyl)-2,4-pentadienal (0.5 g, 1.7 mmol). The reaction mixture was allowed to stir at -78° C. for 5 minutes then was diluted with 40 mL of 1 M HCl aqueous solution. The organic material was extracted twice with ethyl acetate (50 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. The desired product was partitioned over a silica gel column and eluted with 1.5 liters of 30% (v/v) ethyl acetate in hexanes to give 0.57 g (79%) of the title compound as a gummy solid.