Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[N:10]=1.O[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:18][CH:17]=1>>[N:25]1([CH2:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:14][CH2:13][CH2:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[O:7][CH:8]=3)=[CH:17][CH:18]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: OCCCc1coc(-c2cccs2)n1
Product: c1csc(-c2nc(CCCOc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 72 %

Procedure:
In substantially the same manner as in Working Example 146, 3-[2-(2-thienyl)-4-oxazolyl]propanol was mesylated and then reacted with 1-[3-(4-hydroxyphenyl)propyl]imidazole to obtain 4-[3-[4-[3-(1-imidazolyl)propyl]phenoxy]propyl]-2-(2-thienyl)oxazole. The yield was 72%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 99-100° C.
Reaction SMILES: S(Cl)(Cl)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([F:17])[C:13]=1[N+:14]([O-:16])=[O:15])[C:9]#N.[CH3:18][OH:19]>>[CH3:18][O:19][C:9](=[O:2])[C:8]1[CH:7]=[C:6]([F:5])[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([F:17])[CH:11]=1
Reactant: N#Cc1cc(F)c([N+](=O)[O-])c(F)c1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)c1cc(F)c([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionylchloride (1.0 mol, 134 mL) was added to MeOH (400 mL) at −10° C. to −20° C. over a period of 0.5 h. To this solution was added 3,5-difluoro-4-nitro-benzonitrile (33.5 g, 180 mmol) and the reaction mixture was allowed to warm to 25° C. and stirred overnight at 25° C. Afterwards the temperature was slowly increased to 50° C. over 2 h and the evolving gas was trapped in a gas washer. Finally the reaction mixture was heated at reflux for 2 h. The cooled reaction mixture was filtered and concentrated. The crude product was dissolved in EtOAc and washed with cold aq. NaHCO3 solution and brine, dried over MsSO4, filtered and concentrated. The residue was crystallized from EtOAc-hexane to yield the title compound as an orange solid: TLC (hexane-EtOAc 3:1) Rf=0.38; HPLC RtA=1.74 min; 1H NMR (400 MHz, CDCl3): δ 7.76 (d, 2H), 3.98 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[O:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.O[Li:26].O>CO.O>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[O:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O-:16])=[O:15])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.[Li+:26]
Reactant: CCOC(=O)c1ccc(COc2ccccc2-c2c[nH]cn2)cc1
Reactant: [Li]O
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccc(COc2ccccc2-c2c[nH]cn2)cc1
Product: [Li+]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 4-((2-(1H-imidazol-4-yl)phenoxy)methyl)benzoate (0.33 mmol, 105 mg) was diluted with MeOH (3 mL) and water (1 mL) followed by the addition of LiOH.H2O (0.33 mmol, 14.35 mg). After stirring for 4 h at room temperature, the solvent was removed under vacuum to afford the product.
Reaction SMILES: C[O:2][CH2:3][C:4]([O:6][CH3:7])=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1COCC1>CCOCC>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:3](=[O:2])[CH2:4][O:6][CH3:7])[CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Reactant: COCC(=O)OC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of methyl methoxyacetate (available from Aldrich) (0.48 mL, 4.8 mmol) in ether (20.0 mL) was added a 1.0 M solution of (3-(benzyloxy)phenyl)magnesium bromide in THF (available from Aldrich) (5.0 mL, 5.0 mmol) dropwise at −78° C. The mixture was warmed to room temperature overnight, quenched with 1 N HCl, and diluted with EtOAc. The organics were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 1-(3-(benzyloxy)phenyl)-2-methoxyethanone (0.17 g, 14%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[CH3:13][C:14]([CH3:26])([CH3:25])[C:15]#[C:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18].C(=O)(O)[O-].[Na+].[Cl-]>C(O)(C)C.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:16]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:15]([C:14]([CH3:26])([CH3:25])[CH3:13])[O:11][N:10]=1
Reactant: CC(C)(C)C#CC(=O)c1cccnc1
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)(C)c1onc(-c2ccc(Cl)cc2Cl)c1C(=O)c1cccnc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 76.6 %

Procedure:
A mixture of 72 mg (0.32 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 60 mg (0.32 mmol) of 4,4-dimethyl-1-(3-pyridyl)-2-pentyn-1-one, and 32 mg (0.38 mmol, 1.2 equivalents) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. for 16 hrs on a rotary table shaker. A second addition of 25 mg of carboximidoyl chloride and 10 mg of sodium bicarbonate was followed by another 20 hrs at 55° C. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 92 mg of oily product, 3-(2,4-dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)carbonyl]isoxazole. 1H NMR (CDCl3): δ 1.47 (s, 9), 7.90 (m, 1), 7.60 (br s, 1) and 8.72 ppm (br s, 1). MS m/z: 375.0 (M+H).
Reaction SMILES: C(N(CC)C1C=CC=CC=1)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:27](=O)[NH:26][CH:25]=[N:24][C:23]=3[O:22][CH:21]=2)=[CH:16][CH:15]=1.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][C:27]1[C:28]2[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)=[CH:21][O:22][C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: COc1ccc(-c2coc3nc[nH]c(=O)c23)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc(-c2coc3ncnc(Cl)c23)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
Add 14.5 ml (13.6 g, 90.8 mmol) N,N-diethylaniline to a suspension of 10.0 g (41.3 mmol) 5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4(3H)-one in 250 ml toluene and heat to 100° C. At this temperature, add 4.2 ml (7.0 g, 45.4 mmol) phosphoryl chloride dropwise, and stir the reaction mixture for 15 h at 100° C. Then add a further 1.2 ml (2.0 g, 13 mmol) phosphoryl chloride and stir the reaction mixture again for 22 h at 100° C. After cooling to room temperature, quickly wash the reaction solution with, successively, 250 ml ice water, twice with 250 ml cold 20% sodium hydroxide solution each time, again with 250 ml ice water, 250 ml satd. sodium chloride solution, 1 N hydrochloric acid and 250 ml ice water. Dry the organic phase over sodium sulphate, filter and concentrate by vacuum evaporation. 6.3 g (59% of theor.) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]4=[N:17][CH:18]=[C:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:45][C:46]([CH3:48])=[CH2:47].CCOC(C)=O>CN(C=O)C.O>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:29]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]4=[N:17][CH:18]=[C:19]([N:21]([CH2:47][C:46]([CH3:48])=[CH2:45])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: C=C(C)CBr
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)CN(C(=O)OC(C)(C)C)c1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Temperature: 65 °C
Yield: 105.8 %

Procedure:
tert-Butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.50 g, 0.95 mmol) and Cs2CO3 (1.55 g, 4.75 mmol) were combined in DMF (19 mL). 3-Bromo-2-methylpropene (0.191 mL, 1.90 mmol) was added and the mixture was heated at about 65° C. for about 3 h. EtOAc (50 mL) and water (50 mL) were added and the layers separated. The organic layer was washed with 5% aqueous LiCl (3×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl(2-methylallyl)carbamate (0.584 g, 106%): LC/MS (Table 2, Method h) Rt=2.43 min.; MS m/z: 581 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[CH3:18][C:14]1[N:13]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccc(C)n2)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1cccc(O[C@H]2CC[C@H](C(=O)NN)CC2)n1
Temperature: 125 °C

Procedure:
A mixture of trans-4-(6-methyl-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.62 g, 2.5 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) in n-butanol (1 ml) was heated at 125° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.48 g, 86%) as white solid, which was used in the next step without further purification. MS m/e: 250 (M+H+)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])(=[O:13])=[O:12].[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)C=C)CCC>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[S:11]([N:6]1[C:7]2[C:3](=[C:2]([CH:23]=[CH2:24])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1)(=[O:13])=[O:12]
Reactant: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(Br)cccc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1cc(C)ccc1OC
Temperature: 110 °C
Reaction time: 17 h
Yield: 588.4 %

Procedure:
4-bromo-1-[(2-methoxy-5-methylphenyl)sulfonyl]-1H-indole (518 mg, 1.36 mmol; Intermediate 6), tributyl(vinyl)stannane (0.438 mL, 1.50 mmol) and Pd(PPh3)2OAc2 (51 mg, 0.068 mmol) were mixed in dry toluene (8 mL) and stirred 17 h at 110° C. using a STEM block. The mixture was filtered and additional tributyl(vinyl)stannane (0.200 mL, 0.68 mmol) and Pd(PPh3)2OAc2 (30 mg, 0.040 mmol) were added with continuous stirring for 23 h. Same procedure was repeated once more (additional reagents) with continuous stirring 24 h gave full conversion. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (DCM/hexane 2:3). This gave the desired product (2.62 g, 59%) as an off white solid. MS (ESI+) for C18H17NO3S m/z 328 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][CH:17]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([CH:39]2[CH2:41][CH2:40]2)=[O:38])=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].Cl.CO>O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([CH:39]2[CH2:40][CH2:41]2)=[O:38])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(Cc2ccc(C(=O)O)o2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of methyl 5-{[6-(4-cyanophenyl)-5-(cyclopropylcarbonyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]methyl}-2-furoate (Example 42) (50 mg, 0.09 mmol) in tetrahydrofuran (1.5 ml) is treated with a solution of lithium hydroxide (2.34 mg, 0.1 mmol) in water (1.5 ml). After three hours stirring at room temperature, additional lithium hydroxide (2.34 mg, 0.1 mmol) is added. The reaction solution is stirred overnight (16 h), then allowed to stand for 48 h. The solution is acidified with 1 N hydrochloric acid (500 μl). After 5 minutes stirring, a precipitate is obtained. Methanol (3 ml) is added, and the crude reaction solution is purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/water 30:70→90:10). The title compound is isolated as a brownish solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@H:14]([CH2:26][O:27][CH3:28])[CH2:15][CH2:16][N:17]2[CH2:24][CH2:23][C:20]3([CH2:22][CH2:21]3)[C@H:19]([OH:25])[CH2:18]2)[C:10](=[O:29])[C@@H:9]1[CH3:30])=[O:7])(C)(C)C.Cl.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]=C=O)[CH:36]=[CH:37][C:38]=1[F:39]>O1CCOCC1>[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C@H:14]([CH2:26][O:27][CH3:28])[CH2:15][CH2:16][N:17]3[CH2:24][CH2:23][C:20]4([CH2:22][CH2:21]4)[C@H:19]([OH:25])[CH2:18]3)[C:10](=[O:29])[C@@H:9]2[CH3:30])=[O:7])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1=O
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(F)c(Cl)c2)[C@@H](C)C1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (intermediate 23; 47 mg, 0.11 mmol) in 1,4-dioxane (0.5 mL) was cooled to 0° C. and treated with hydrogen chloride solution (4 M in 1,4-dioxane, 0.28 mL, 1.1 mmol) The ice bath was removed, the reaction mixture stirred for 4 h, then 4-methylmorpholine (112 mg, 1.1 l mmol) and N,N-dimethylformamide (1 mL) were added. To this reaction mixture was added 3-chloro-4-fluorophenyl isocyanate (19 mg 0.11 mmol), then after 16 h the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution gradient 98:2:0.25 to 90:10:0.25) furnished the title compound (52 mg, 95%). Light yellow gum, MS (ISP)=497.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][NH:7][CH:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:5])[N:7]([CH3:6])[CH:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:2]
Reactant: CNC1c2ccccc2Oc2ccccc21
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N(C)C1c2ccccc2Oc2ccccc21

Procedure:
Ethyl isocyanate (1 ml.) was added to a solution of 9-methylaminoxanthen (2.02 g.) in methylene chloride (10 ml.). There was an exothermic reaction and after 20 minutes at room temperature the solvent was evaporated. The residue was recrystallised from benzene to give N'-ethyl-N-methyl-N-9-xanthenylurea, m.p. 139°-141°C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36](=O)[O:37]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C.CCOC(C)=O>[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=3)[CH:8]=2)[CH2:3][CH2:2]1)=[O:37]
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)NCC3)n1
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1csc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CC3)n1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A mixture of ethyl 2-(indolin-6-yl)thiazole-4-carboxylate (28D) (56 mg, 0.14 mmol), K2CO3 (22 mg, 0.16 mmol), and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (48 mg, 0.15 mmol) was heated to reflux in acetonitrile (3 mL) for 5.5 hours. The reaction mixture was cooled to rt and diluted in EtOAc (5 mL), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE/EtOAc (1:1), to provide 22 mg (34%) of the desired product ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylate (28E): 1H NMR (300 MHz, CDCl3) δ 8.67 (1H, s), 8.12 (1H, s), 7.68 (2H, m), 7.52 (1H, m), 7.38 (1H, m), 7.25 (2H, m), 4.43 (2H, q), 4.22 (2H, m), 3.18 (2H, m) 1.45 (3H, t). LC/MS (APCI): m/z 451.1 (M+H).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2].[CH3:37][NH2:38]>CN(C=O)C.C(O)C>[C:1]([N:3]=[C:4]([NH:38][CH3:37])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2]
Reactant: CSC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: CN
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 16 h

Procedure:
A solution of 50 mg of the product of Example 50 in 10 ml of DMF was treated with 4 ml of a 33% solution of methylamine in ethanol. The mixture was stirred for 16 hours and the solvents were then removed under reduced pressure. The residue was chromatographed on silica gel with ethyl acetate to give 46 mg of 3-[1-[3-(2-cyano-3-methylguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 190°-193° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.C([O:27][CH2:28][CH3:29])(=O)C>O>[ClH:1].[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH:8][C@H:11]2[CH2:15][CH2:29][C@H:28]([OH:27])[CH2:13][CH2:12]2)=[N:3][C:4]=3[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(C)=O
Reactant: Clc1nc(NCc2ccccc2)c2ncn(C3CCCC3)c2n1
Solvent: O
Product: Cl
Product: O[C@H]1CC[C@H](Nc2nc(NCc3ccccc3)c3ncn(C4CCCC4)c3n2)CC1
Reaction time: 4 h

Procedure:
1 g of trans-1,4-aminocyclohexanol is mixed which is then taken to a temperature of 50 to 60° C. and 212 mg of the product obtained in Stage 1 above is added and taken to a temperature of 140 to 150° C. for approximately 4 hours. The reaction medium is then left to return to a temperature of 100° C., 10 ml of water is added, the reaction medium is left to settle, 10 ml of water, 20 ml of ethyl acetate are added and the medium is taken to a temperature of approximately 70° C. Then 10 ml of water is added and the reaction medium is left overnight at ambient temperature, then left to settle, followed by re-extracting with 2×20 ml of methylene chloride with 20% of methanol, combining the organic phases, washing with 10 ml of water and 10 ml of an aqueous solution of sodium chloride, drying and evaporating to dryness. The residue is then dissolved in the minimum amount of ethanol, 1.4N hydrochloric acid in ethanol is added and the reaction medium is left to crystallize, followed by diluting in 5 ml of ethanol then leaving for one hour at ambient temperature, separating, washing with 10 ml of ethanol and drying at a temperature of approximately 50° C. In this way 215 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13]([NH2:17])(=[O:16])[CH:14]=[CH2:15].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:15][CH2:14][C:13]([NH2:17])=[O:16])=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1S
Reactant: C=CC(N)=O
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: CO
Solvent: O
Product: NC(=O)CCSc1ccc(Br)cc1C(F)(F)F
Reaction time: 40 h
Yield: 98.2 %

Procedure:
4-Bromo-2-trifluoromethyl-benzenethiol (259.2 g, 1.01 mol) was dissolved in methanol (1.3 L) and water (2.6 L), then acrylamide (130 g, 1.82 mol), followed by sodium tetraborate (25.9 g, 129 mmol) were added at room temperature. The suspension was stirred for 40 h. After filtration, the solid was washed with water (2.6 L) and n-heptane (2.6 L) and dried in vacuo to yield the title compound as a white powder (325.6 g, 98%). MS (EI): m/z=330.0, 328.0 [M+H]+. 1H NMR (d6-DMSO, 400 MHz): δ 2.40 (t, J=7.2 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 6.92 (bs, 1H), 7.37 (bs, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.82-7.88 (m, 2H).
Reaction SMILES: O1C2(CCCCC2)[NH:2]1.[CH3:9][NH:10][C@@H:11]([CH3:20])[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].[ClH:21]>CCOCC.CO>[ClH:21].[CH3:9][N:10]([C@@H:11]([CH3:20])[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13])[NH2:2]
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Reactant: C1CCC2(CC1)NO2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H]([C@H](O)c1ccccc1)N(C)N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-oxa-2-azaspiro[2.5]octane (0.60 g, 5.3 mmol) in ether (20 ml) a solution of (1R*,2S*)-2-methylamino-1-phenyl-1-propanol (0.86 g, 5.3 mmol) in ether (5 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes then evaporated to dryness. 5% Hydrochloric acid (30 ml) was added to the residue and the mixture was stirred at ambient temperature for 1 h. The mixture was washed with Et2O (2×30 ml), made alkaline with Na2CO3 under ice-cooling and extracted with EtOAc (3×50 ml). The combined EtOAc extracts were dried and evaporated to give a solide residue which was dissolved in methanol (5 ml) and converted to the crystalline hydrochloride salt by using 22% ethanolic hydrogen chloride (2 ml) and diethyl ether. Crystals were filtered off and recrystallized from methanol/diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([O:16]N3C(=O)CCC3=O)=O)[C:10](=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([CH2:13][C:14]([N:28]3[CH2:29][CH2:30][NH:25][C:26](=[O:31])[CH2:27]3)=[O:16])[C:10](=[O:24])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CC(c2ccc(F)cc2)CC1=O)ON1C(=O)CCC1=O
Reactant: O=C1CNCCN1
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)CN2CC(c3ccc(F)cc3)CC2=O)CCN1

Procedure:
10 g (30 mmol) of N-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetoxy]-succinimide and 3.0 g (30 mmol) of piperazin-2-one (ketopiperazine) are stirred at room temperature in 100 ml of dimethylformamide for 16 hours. The whole is concentrated to dryness by evaporation at 70° under reduced pressure, extracted at boiling temperature with trichloromethane, allowed to cool, filtered with suction and allowed to dry in the air. 1-[4-(p-fluorophenyl)-2-oxopyrrolidin-1-ylacetyl]-3-oxopiperazine having a melting point of 200°-203° is obtained.