Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]3[C:21]4[C:26]([CH2:27][CH2:28][C:17]=23)=[CH:25][C:24]([CH:29]=C)=[CH:23][CH:22]=4)[O:9][N:8]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+].O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]3[C:21]4[C:26]([CH2:27][CH2:28][C:17]=23)=[CH:25][C:24]([CH:29]=[O:35])=[CH:23][CH:22]=4)[O:9][N:8]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccn2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a mixture of 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 63F, 0.098 g, 0.239 mmol) and a 50% aqueous solution of NMO (0.050 mL, 0.239 mmol) at room temperature was added a 4% aqueous solution of osmium tetroxide (0.075 mL, 9.58 μmol). The reaction mixture was stirred at room temperature over the weekend. The intermediate diol had an HPLC ret. time=2.66 min and an LCMS M+1=443.8. Sodium periodate (0.077 g, 0.359 mmol) was added to the homogeneous mixture followed by water (0.15 mL), and the reaction was stirred for 60 min. at room temperature. Concentration under reduced pressure afforded a tan solid residue that was then diluted with ethyl acetate (40 mL), washed with the water (10 mL), and washed with brine (10 mL). The organic layer was collected, and the aqueous layer was washed with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.096 g, 0.233 mmol, 97% yield) as a pale yellow solid. The product had an HPLC ret. time=3.00 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=411.9.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>C(OCC)(=O)C.CN(C=O)C>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1[C:1]([NH:5][C:4](=[O:6])[CH:3]=1)=[O:7]
Reactant: BrCCCCCBr
Reactant: O=C1C=CC(=O)N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C=C(CCCCCBr)C(=O)N1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
12 g (0.124 mole) maleimide were dissolved in 60 ml ethyl acetate and 22.4 g (0.33 mole) distilled furane were added over 10 minutes, whereupon the mixture became slightly warm, and the batch was stirred for 25 hours at room temperature. The precipitate was subsequently filtered off under suction and was dried under vacuum at room temperature. Yield: 10.5 g=51.3% theoretical. The substance was pure as determined by GC and its IR, NMR and mass spectra corresponded to the desired 7-oxabicycloheptene-1,2-dicarboxylic acid imide. 10 g (0.06 mole) of this imide were is dissolved in 300 ml distilled DMF, an amount of KI which covered the tip of a spatula was added, and 8.1 g (0.072 mole) K-tert-butylate were added under N2. After 2 hours 69.6 g (0.303 g) 1,5-dibromopentane in 100 ml DMF were added drop-wise over 7 hours with stirring and at room temperature. The batch was subsequently stirred for 50 hours at room temperature. The DMF solution was filtered from the precipitated KBr and the DMF was substantially removed by distillation in a rotary evaporator under vacuum. The liquid residue was distilled in a microdistillation apparatus under a vacuum of 1×10−3 mbar, whereupon at a boiling temperature of 50-55° C. it was solely the excess 1,5-dibromopentane which distilled over. The temperature of the oil bath was then slowly raised to 140° C. After a preliminary flow of 2.3 g, 5.5 g product distilled over at a boiling temperature of 113° C./3×103 mbar. This product was pure as determined by G C, and its IR, NMR and mass spectra corresponded to the desired 5-bromopentylmaleimide. Yield: 5.5 g=37.4%.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][C@H:10]2[C:9]2=[C:14]([C:17]([O:19]CC)=O)[N:15]=[CH:16][N:8]2[C:7]2[CH:22]=[CH:23][S:24][C:6]1=2>C(O)C>[O:4]=[C:5]1[N:11]2[CH2:12][CH2:13][CH:10]2[C:9]2=[C:14]([C:17]([NH:2][NH2:3])=[O:19])[N:15]=[CH:16][N:8]2[C:7]2[CH:22]=[CH:23][S:24][C:6]1=2
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ncn2c1C1CCN1C(=O)c1sccc1-2

Procedure:
10 ml of hydrazine hydrate were added to a suspension of 6.0 g (19.8 mmol) of ethyl (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylate in 50 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 5.6 g (98%) of S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno-[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide as colourless needles of m.p. 260°-263°.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[C:19]([OH:21])[CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[C:19]([O:21][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=2[Cl:13])[CH:20]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 3 step (i) and the product of example 18 step (iv).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[N:14]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[C:13]=2[S:12][C:11]=1[C:25]([O:27]CC)=O)#[N:2].C(OCCO)C.[NH3:36]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[N:14]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[C:13]=2[S:12][C:11]=1[C:25]([NH2:36])=[O:27])#[N:2]
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccsc2)c1Nc1ccccc1C#N
Reactant: N
Solvent: CCOCCO
Product: N#Cc1ccccc1Nc1c(C(N)=O)sc2c1ccc(=O)n2-c1ccsc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of Example 66 (100 mg), 2-ethoxyethanol and liquid ammonia was placed in a sealed pressure vessel and heated at 80° C. and 400 psi for 48 h. The volatiles were removed in vacuo and the residue purified by column chromatography (silica, EtOAc) to give the title compound (30 mg). δH (CDCl3) 7.59-7.46 (4H, m), 7.28-7.21 (3H, m), 7.20 (1H, t, J 2.0 Hz), 7.01 (1H, d, J 8.3 Hz), 6.49 (1H, d, J 9.7 Hz), 5.55 (2H, br s). LCMS (ES+) RT 2.845 minutes, 392.9 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.O>C1COCC1.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1cc(Br)ccc1OCC1CC1
Temperature: 70 °C
Reaction time: 40 h
Yield: 82.8 %

Procedure:
To 5-bromo-2-hydroxybenzaldehyde (1.00 g, 4.97 mmol, 1.00 equiv) and K2CO3 (3.44 g, 24.9 mmol, 5.00 equiv) in THF (10 mL) in an oven-dried round-bottom flask fitted with a reflux condenser under a N2 atmosphere at 23 ° C. was added (bromomethyl)cyclopropane (1.01 g, 0.724 mL, 7.46 mmol, 1.50 equiv). The reaction mixture was warmed in an oil heating bath at a temperature of 70 ° C. and heated at reflux with vigorous stirring for 40 hours. The reaction mixture was cooled to 23 ° C. and poured into H2O (30 mL) in a separatory funnel. CHCl3 (30 mL) was added, the funnel was shaken and the organic phase collected. The aqueous phase was then extracted with CHCl3 (2×30 mL). The combined organic phases were washed with brine (30 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 2-7% EtOAc in hexanes (v/v) to afford 1.05 g of the title compound as a colorless solid (83% yield). Rf=0.30 (hexanes/EtOAc 19:1 (v/v)). NMR Spectroscopy: 1H NMR (600 MHz, CDCl3, 23 ° C., δ): 10.45 (s, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.9, 2.6 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 3.91 (d, J=7.2 Hz, 2H), 1.32-1.26 (m, 1H), 0.71-0.63 (m, 2H), 0.41-0.34 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 188.7, 160.5, 138.3, 130.9, 126.5, 115.0, 113.5, 73.9, 10.1, 3.4. HRMS-FIA (m/z): calcd for C11H11BrNaO2[M+Na]+, 276.9840; found, 276.9820.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.C(O)C.Cl[CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1>C(OCC)C>[C:1]([CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1)#[N:2]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: C=Cc1ccc(CC#N)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
As shown in the following Reaction 1a, 49.01 g of sodium cyanide (NaCN), 70.07 g of water and 50.96 g of ethanol were added into a 500 ml 4-neck flask equipped with a mechanical stir, and the temperature of the solution was elevated to 60° C. to completely dissolve NaCN. To the solution, 87.50 g of 4-chloromethylstyrene was slowly added and the reaction was carried out for 3 hours at the temperature of 60-70° C. After completion of the reaction, the solution was cooled to 40° C., 100 g of diethylether was added to the solution, and the diethylether layer was separated. The separated organic layer was extracted with 300 g of water three times. The water layer was extracted with 50 g of diethylether and the diethylether extract was added to the organic layer. The separated organic layer was dried with magnesium sulfate for one day, and then the organic solvent was removed using an evaporator to obtain 4-cyanomethylstyrene of deep purple color. The yield of the product was 80%.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:12]=1.B(Br)(Br)Br.C1CCCCC=1>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:12]=[C:11]2[C:4]1[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(-c2nn(CC(C)C)c3c(F)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)Cn1nc(-c2ccc(O)cc2O)c2cccc(F)c21
Yield: 56.6 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-7-fluoro-1-isobutyl-1H-indazole (0.177 g, 0.5 mmol), boron tribromide (0.275 mL, 2.90 mmol) and 1.0 mL of cyclohexene to give the product (0.085 g) as a white solid.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:23]1[C:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1.C(N(C(C)C)C(C)C)C.C(OC([N:53]1[CH2:58][CH2:57][CH:56]([NH:59][CH:60]2[CH2:62][CH2:61]2)[CH2:55][CH2:54]1)=O)(C)(C)C.C>CN(C)C=O>[CH:60]1([N:59]([CH:56]2[CH2:57][CH2:58][NH:53][CH2:54][CH2:55]2)[C:32](=[O:34])[C:31]2[CH:30]=[CH:29][C:28]([C:27]3[O:23][CH:24]=[N:25][CH:26]=3)=[CH:36][CH:35]=2)[CH2:62][CH2:61]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (6.10 g) is added to a solution of 4-oxazol-5-yl-benzoic acid (3.00 g) and ethyldiisopropylamine (5.56 mL) in N,N-dimethylformamide (50 mL) at room temperature. The solution is stirred for 10 min prior to the addition of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (4.57 g). The resulting mixture is kept at room temperature over night. The mixture is treated with activated charcoal and filtered through a pad of basic aluminum oxide. The pad is washed with N,N-dimethylformamide/methanol (9:1) and the combined filtrates are concentrated in vacuo. The residue is dissolved in 1,4-dioxane (35 mL), a 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL) is added and the resulting mixture is stirred at room temperature for 2 h. The solvent is evaporated and the residue is taken up in water. The resulting mixture is washed with dichloromethane, basified with NaOH solution and extracted with dichloromethane. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to afford the title compound. LC (method 1): tR=0.70 min; Mass spectrum (ESI+): m/z=312 [M+H]+.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:40]=[CH:39][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:35]=[CH:36][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:11]5[CH:39]=[CH:40][C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:48]([NH:47][C:41]6[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=6)=[O:49])=[CH:9][CH:10]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:24][CH:25]=2)[S:32]1
Reactant: CCCCCCNc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)Nc1ccccc1)c1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reaction time: 48 h

Procedure:
A mixture of 5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g), phenyl isocyanate (95 mg) and anhydrous tetrahydrofuran (20 ml) was allowed to stand at room temperature for 2 days. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2 as the eluant and the product was reprecipitated from a mixture of n-hexane and diethyl ether to afford the title compound (0.30 g, Rf=0.56: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=2:1 as the eluant).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:18][CH2:19]Cl)[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=[O:6].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:22]1([N:21]2[CH2:19][CH2:18][N:4]([C:5]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)=[O:6])[CH2:3][CH2:2]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCc2cc(C(=O)N(CCCl)CCCl)ccc2N1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(=O)N3CCN(c4ccccc4)CC3)ccc2N1
Yield: 37.2 %

Procedure:
A mixture consisting of 15.9 g of 6-[bis-(2-chloroethyl)aminocarbonyl]-3,4-dihydrocarbostyril, 5.5 g of aniline and 70 ml of methanol was refluxed for 15 hours. After cooled the reaction mixture, 3.06 g of sodium carbonate was added to the reaction mixture and the reaction mixture was further refluxed for 8 hours. The reaction mixture was cooled and crystals precipitated in the reaction mixture were collected by filtration, and recrystallized from isopropanol to obtain 6.3 g of 6-(4-phenyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 200°-201° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([NH:28][C:29]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:36]=2)=[O:30])[CH:16]=1>>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:28][C:29]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:36]=2)=[O:30])[CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2F)cc1NC(=O)c1cncc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2F)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (3.0 mL) was added to the obtained tert-butyl 4-(2-fluorophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration. Dioxane (3.0 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.041 mL) were added to the obtained solid substance, followed by stirring at room temperature for 1 hour. A 10% aqueous solution of citric acid was added to the reaction mixture, and the solid substance was collected by filtration to obtain 36 mg of 4-(2-fluorophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25]O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][O:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a mixture of 1.0 g (6.37 mmole) of 3-fluoro-4-nitrophenol, 1.78 g (8.27 mmole) of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester, 2.81 g (10.71 mmole) of triphenylphosphine and 50 mL of tetrahydrofuran was added 1.67 mL (10.71 mmole) of diethylazodicarboxylate. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 0:100-40:60) to give 2.16 g of 4-(3-fluoro-4-nitro-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (IV.23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32].[O-]S([O-])(=O)=O.[Mg+2].[Al]>CC(C)=O>[CH2:34]([O:33][C:31]([C:30]1[N:26]=[C:24]([NH:23][C:12]2[C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[N:10][CH:11]=2)[S:25][CH:29]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1cc2c(NC(N)=S)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)n1
Reaction time: 3 h

Procedure:
A solution of (6,7-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (50 mg, 0.127 mmol) and ethyl bromopyruvate (30.4 mg, 0.140 mmol) in acetone (1.4 mL) in a conical vial was added MgSO4 (7.7 mg, 0.0637 mmol). The resulting suspension was placed in an aluminum block preheated to 60° C. and was allowed to stir for 3.0 h. The reaction was cooled and concentrated. The residue was purified using a 5 g silica cartridge (MeOH/CH2Cl2, 1:99) to give 2-[1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-ylamino]thiazole-4-carboxylic acid ethyl ester as a pale yellow solid (42.2 mg; 68%). 1H-NMR (CDCl3): δ, 8.51 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 6.13 (s, 1H), 4.91 (d, 2H, J=4.7 Hz), 4.39 (q, 2H, J=7.0 Hz), 4.05 (s, 3H), 3.99 (s, 3H), 1.50 (s, 9H), 1.40 (t, 3H, J=7.3 Hz); MS: calculated for C23H28N4O6S+H 489.0; found: 489.0.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:5]3[CH2:4][CH2:3][CH2:2][S:1](=[O:11])(=[O:10])[CH2:8][CH2:7][C:6]=3[C:15]=2[CH:14]=1
Reactant: O=C1CCCS(=O)(=O)CCC1
Reactant: NNc1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=S1(=O)CCCc2[nH]c3ccc(Br)cc3c2CC1

Procedure:
A mixture of 14.1g (0.08 mole) of 1-thiacyclooctane-5-one 1,1-dioxide and 16.1g (0.086 mole) of p-bromophenylhydrazine in 125 ml of glacial acetic acid is treated according to the procedure in Example 2. There is obtained 14.2g (54%) of a buff solid, m.p. 280° C., dec. Recrystallization from dimethylformamide-methanol gives 11.5g (44%) of an analytical sample, m.p. 283° C., dec.
Reaction SMILES: [C:1](=[O:14])([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:2][CH:3](Cl)[CH3:4].[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O-:28])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16].[K+].[I-].[Na+]>CN(C=O)C>[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O:28][CH:3]([O:2][C:1]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH3:4])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(Cl)OC(=O)OCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)OCc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 168 h

Procedure:
1-Chloroethyl benzyl carbonate (prepared according to Synthesis 1986, 627), (2.36 g, 11.0 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 20 mmol) and sodium iodide (0.15 g, 1 mmol) in dry DMF (50 ml). After stirring at 50° C. for 7 hours and at room temperature for 7 days the solvent was removed at reduced pressure. The residue was dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After treatment with magnesium sulfate the solution was evaporated to dryness. Yield: 6.8 g. Purity by HPLC: 97% 1H-NMR(DMSO-d6): delta=1.64 (CHCH3); 1.66(N(CH3)COCH3); 2.05 (NCOCH3); 5.23 (CH2); 7.00 (CH); 7.30-7.45(arom.); 10.12 ppm (NH).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O.[CH3:21][N:22](C=O)C>>[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH2:16][CH2:17][C:18]([NH:22][CH3:21])=[O:20]
Reactant: CN(C)C=O
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1F
Solvent: O=S(Cl)Cl
Product: CNC(=O)CCCc1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Thionyl chloride (0.01 mL, 0.11 mmol) was added slowly to a solution of 4-(2-Fluoro-4-nitrophenyl)butanoic acid (82) (20 mg, 0.09 mmol) in DMF (3 mL) cooled at −5° C. The mixture was stirred for an additional 1 h at −5° C. Excess methylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 h. Ethyl acetate (30 mL) was added to the mixture, which was washed with brine (2×30 mL). The organic layer was dried over MgSO4, and concentrated to yield 4-(2-Fluoro-4-nitrophenyl)-N-methylbutanamide (81) (18 mg, 85%): 1H NMR δ 7.97 (dd, 1H, J=8.4, 2.2 Hz), 7.89 (dd, 1H, J=9.5, 2.2 Hz), 7.40 (dd, 1H, J=8.4, 7.3 Hz), 5.44 (br s, 1H), 2.81 (d, 3H, J=4.9 Hz) 2.79 (t, 2H, J=7.6 Hz) 2.22 (t, 2H, J=7.3 Hz) 1.96-2.04 (m, 2H).