Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][C:51]=1[S:57][CH2:58]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:58][S:57][C:51]2[CH:52]=[C:53]([CH3:56])[CH:54]=[CH:55][C:50]=2[CH3:49])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c(SCCO)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCSc4cc(C)ccc4C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 84.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (70 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (108 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-[(2,5-dimethylphenyl)sulfanyl]-1-ethanol (65 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (101 mg, yield 79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:16](=[O:17])[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH2:4][CH2:3]1.C1COCC1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1.CCOCC>[NH4+].[Cl-]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:16]2([OH:17])[C:6]3[CH:7]=[C:8]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)[S:9][C:5]=3[CH2:4][CH2:3][C:2]2([CH3:18])[CH3:1])=[CH:27][CH:26]=1
Reactant: CC1(C)CCc2sc(-c3ccncc3)cc2C1=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 100 mL round bottomed flask were placed 5,5-dimethyl-2-pyridin-4-yl-6,7-dihydro-1-benzothiophen-4(5H)-one (380 mg, 1.5 mmol) and THF (30 mL). To the mixture was added a solution of 4-chlorophenylmagnesium bromide in ether (1.0 M, 3.5 mL, 3.5 mmol) then the reaction was stirred for 3 hr at rt. LCMS indicated that starting material still remained, so additional 4-chlorophenylmagnesium bromide in ether (1.0M, 2.5 mL, 2.5 mmol) was added and the reaction was stirred for 16 hr at rt then for 10 hr at 70° C. The mixture was allowed to cool to rt then additional 4-chlorophenylmagnesium bromide in ether (1.0M, 5 mL, 5 mmol) was added and the mixture was stirred for 16 hr at rt. The mixture was then diluted with a saturated aqueous solution of NH4Cl (50 mL) and was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous MgSO4. The insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (24 g RediSep column, gradient 30% EA in hexane to 100% EA in hexane) to give the product (530 mg; 97%) as a colorless foam: 1H NMR (400 MHz, DMSO-d6) δ: 8.48 (dd, 2H), 7.45 (dd, 2H), 7.32-7.35 (m, 2H), 7.23-7.25 (m, 3H), 5.55 (s, 1H), 2.87-2.91 (m, 2H), 1.84-1.90 (m, 1H), 1.57-1.63 (m, 1H), 0.91 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[NH:12][C:11]([C:13]([C:43]4[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=4)=[C:14]4[N:42]=[C:17]([C:18]([C:36]5[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=5)=[C:19]5[NH:35][C:22](=[C:23]([C:29]6[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=6)[C:24]6[CH:25]=[CH:26][C:27]=2[N:28]=6)[CH:21]=[CH:20]5)[CH:16]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:3][CH:2]=1.[Br:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]([OH:57])=[O:56]>C(Cl)(Cl)Cl.CO>[Br-:49].[C:55]([CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][N+:46]1[CH:45]=[CH:44][C:43]([C:13]2[C:11]3[NH:12][C:8]([C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:27]4[N:28]=[C:24]([C:23]([C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)=[C:22]5[NH:35][C:19](=[C:18]([C:36]6[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=6)[C:17]6[CH:16]=[CH:15][C:14]=2[N:42]=6)[CH:20]=[CH:21]5)[CH:25]=[CH:26]4)=[CH:9][CH:10]=3)=[CH:48][CH:47]=1)([OH:57])=[O:56]
Reactant: O=C(O)CCCCCBr
Reactant: C1=Cc2nc1c(-c1ccncc1)c1ccc([nH]1)c(-c1ccncc1)c1nc(c(-c3ccncc3)c3ccc([nH]3)c2-c2ccncc2)C=C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)CCCCC[n+]1ccc(-c2c3nc(c(-c4ccncc4)c4ccc([nH]4)c(-c4ccncc4)c4nc(c(-c5ccncc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Product: [Br-]
Yield: 12.7 %

Procedure:
180 mg of 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine are dissolved in 70 ml of chloroform/methanol (9:1), treated with 585 mg of 6-bromo-caproic acid and subsequently heated at reflux for 20 hours. The solution is then concentrated in vacuo to 5 to 10 ml and the product is precipitated by the addition of 250 ml of ether. The product is added to a 15 cm long silica column, whereupon the elution is carried out with 500 ml of chloroform/methanol (9:1), the starting zone is removed from the column and extracted with 1 liter of methanol and then with 1 liter of chloroform/methanol/water (2:7:1). The material obtained from the extracts is purified further by preparative thick-layer chromatography; eluent: chloroform/methanol/dimethylformamide/water (1:2:1:1). After scratching off, the main zone is extracted twice with 250 ml of methanol each time and twice with 250 ml of chloroform/methanol/water (2:7:1) each time. The product is finally re-precipitated a further four times. For this purpose, it is firstly dissolved in the smallest amount of methanol possible and then precipitated by the slow dropwise addition of 250 ml of chloroform. There are obtained 30 mg of 1-(5-carboxypentyl)-4-(10,15,20-tri-4-pyridyl-21H,23H-porphin-5-yl)pyridinium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH:15][C:47](=[O:48])[CH2:46][O:45][CH3:44])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccc(C#N)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.1 %

Procedure:
To a solution of 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (1200 mg, 2.344 mmol) in THF (15 ml) was added Et3N (471 mg, 4.668 mmol) followed by 2-methoxyacetyl chloride (254 mg, 2.344 mmol). The reaction was stirred at room temperature for 20 min. After this time, the reaction was diluted with EtOAc (100 ml) and the resulting solution was wash with water (2×50 ml) and saturated NaCl (50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated chromatography system (120 g silica gel, 20-60% EtOAc/CH2Cl2) to the give product N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methoxyacetohydrazide as a light yellow solid 780 mg (57% yield). HPLC retention time 2.858 min (Method A); LCMS (M+H)=583.0.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C:23]3=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=[C:22]3[C:21]2=[O:31])=[C:16]([CH3:32])[CH:15]=1.[Cl:33][C:34]1[S:38][C:37]([CH2:39][NH2:40])=[CH:36][CH:35]=1>C(Cl)Cl.C(N(CC)C(C)C)C.CCN(C(C)C)C(C)C>[Cl:33][C:34]1[S:38][C:37]([CH2:39][NH:40][C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:24](=[O:25])[C:23]4[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:22]=4[C:21]3=[O:31])=[C:16]([CH3:32])[CH:15]=2)=[O:4])=[CH:36][CH:35]=1
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(Cl)s1
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)NCc2ccc(Cl)s2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Yield: 52.8 %

Procedure:
To a solution of triphosgene (22 mg, 0.074 mmol) in CH2Cl2 (1 mL) was added a suspension of N-(4-amino-2-methylphenyl)-4-chlorophthalimide (57 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) and diethylisopropylamine (70 μL) dropwise over 10 min. The reaction mixture was stirred for 10 nm, then a solution (5-chloro-2-thienyl)methylamine from step B (47 mg, 0.32 mmol) in CH2Cl2 (1 mL) and DIEA (35 μL) was added. The mixture was stirred at room temp for 17 hr, acidified and HPLC purified to give {[(5-chloro(2-thienyl))methyl]amino}-N-[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]carboxamide (18 mg, 20%). ES-MS (M+H)+=460, 462 (Cl). 1H-NMR (DMSO-d6): δ 2.02 (s, 3H), 4.34-4.36 (d, 2H), 6.77-6.80 (t, 1H), 6.82-6.93 (2d, 2H), 7.14-7.16 (d, 1H), 7.29-7.32 (dd, 1H), 7.41 (d, 1H), 7.93 (ABq, 2H), 8.02 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[C:6](F)=[N:7][CH:8]=[CH:9][C:10]=1I)=O.O.[NH2:16][NH2:17].[CH3:18]COC(C)=O.C([O-])(O)=O.[Na+].[Cl-].[Na+].O>O1CCOCC1>[CH3:18][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:16][N:17]=[C:3]([C:2]([F:14])([F:13])[F:1])[C:5]=12
Reactant: NN
Reactant: CCOC(C)=O
Reactant: O=C(c1c(I)ccnc1F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccnc2[nH]nc(C(F)(F)F)c12
Temperature: 90 °C
Yield: 73 %

Procedure:
2,2,2-trifluoro-1-(2-fluoro-4-iodo-3-pyridyl)ethanone (40 g, 125.4 mmol) was dissolved in 1,4-dioxane (300 mL). Hydrazine monohydrate (18.83 g, 18.30 mL, 376.2 mmol) was added dropwise and the mixture heated to 90° C. for 90 minutes. The mixture was cooled and poured into EtOAc (800 ml) and 3:1 sat NaHCO3/brine (500 ml). The organic layer was separated and the aqueous extracted with EtOAc (3×50 ml). The combined organics were washed with brine (100 ml), dried (MgSO4), filtered and concentrated. The residue was slurried in DCM (50 ml) and the resultant white solid was isolated by filtration, washed with DCM and dried (28.7 g, 73% Yield).
Reaction SMILES: [CH2:1](N(C(C)C)C(C)C)C.[SH:10][C:11]1C=[CH:15][CH:14]=[C:13](OC)[C:12]=1[OH:19].[CH3:20][OH:21]>>[SH:10][C:11]1[C:20]([O:21][CH3:1])=[CH:15][CH:14]=[CH:13][C:12]=1[OH:19]
Reactant: CO
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc(S)c1O
Product: COc1cccc(O)c1S

Procedure:
N-ethyldiisopropylamine (12.9 mL) and 2-mercapto-6-methoxyphenol (9.8 g) synthesized in Reference Example 8(4) were added in that order to a methanol (180 mL) solution of the compound obtained in the above (4), and stirred at room temperature for 14 hours. The reaction solvent was evaporated off under reduced pressure, the residue was dissolved in ethyl acetate, and extracted twice with distilled water. The organic layer was dried with magnesium sulfate, and the solvent was evaporated off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (chloroform 100%) to obtain the intended compound (28.7 g, 100%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:21]1[CH:25]=[CH:24][C:23]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)=[CH:22]1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1Cc2ccc(-c3ccsc3)cc2N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) dissolved in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and thiophene-3-boronic acid (4.3 g, 33.6 mmol). The mixture was stirred at 100° C. in an oil bath for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 mL), washed with IN hydrochloric acid (200 mL), water (200 mL), saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to give a black solid. The solid was triturated with methylene chloride to give 2.02 g (36%) of 6-thiophen-3-yl-1,3-dihydroindol-2-one as a purple-gray solid.
Reaction SMILES: ClC1C=CC(N)=CC=1.C([CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C.Cl.C([OH:23])C>>[O:23]=[C:11]([CH2:17][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: CCO
Agent: Cl
Agent: Nc1ccc(Cl)cc1
Product: CCOC(=O)C(=O)CC

Procedure:
The p-chlorophenylhydrazone of ethyl 2-oxobutanoate was prepared by adaptation of the Japp-Klingemann reaction as described by Lions and Hughes (J. Proc. Roy. Soc. N.S. Wales 1939, 71: 445) to p-chloroaniline and ethyl 2-ethylacetoacetate. This phenylhydrazone was treated with HCl-ethanol according to the procedure of Lions and Hughes (J. Proc. Roy. Soc. N.S. Wales 1939, 71: 445) as applied therein to the corresponding bromophenylhydrazone. The title substance was collected by filtration as an orange solid after suspending the concentrated residue in water.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:19]=CC3C(=CC=CC=3)N=2)=[O:9])=[CH:4][CH:3]=1.N1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:19]=[C:30]3[C:25](=[CH:24][CH:23]=2)[N:26]=[CH:27][CH:28]=[CH:29]3)=[O:9])=[CH:20][CH:21]=1
Reactant: c1cnc2cc[nH]c2c1
Reactant: ClCc1ccccn1
Reactant: O=C(NCc1ccc(O)cc1)c1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1ccc(OCc2ccccn2)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of quinoline carboxylic acid 4-hydroxybenzylamide described in Preparation Example E+-1 (20 mg, 0.0719 mmol) and 2-chloromethyl-pyridine hydrochloride (12 mg, 0.0719 mmol) in N,N-dimethyl formamide (1.0 mL) was added potassium carbonate (298 mg, 2.16 mmol), and the solution was stirred at room temperature for 12 hours. Ethyl acetate and water were added to the reaction solution, which was then partitioned, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound was obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([CH:10]3[CH2:14][CH2:13][CH2:12][O:11]3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)C1CCCO1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(C3CCCO3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 1.2 %

Procedure:
A mixture of 2-phenyl-1-(tetrahydrofuran-2-yl)ethanone (Intermediate 90) (522 mg, 2.75 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (695 mg, 3.3 mmol), and urea (495 mg, 8.25 mmol) in anhydrous EtOH (4 mL) was added concentrated HCl solution (0.2 mL), the reaction mixture was refluxed for 14 hours. The reaction mixture was concentrated, and purified by column chromatography and preparative HPLC to give product, contaminated with an impurity (21 mg). This was further purified by preparative TLC and preparative HPLC to give Compound 171 (14 mg). 1H NMR (DMSO-d6 400 MHz): δ 10.170 (s, 1H), 8.318 (s, 1H), 7.629 (d, J=2.4 Hz, 1H), 7.276-7.344 (m, 5H), 7.066-7.163 (m, 2H), 5.384 (s, 1H), 4.245 (d, J=4.0 Hz, 1H), 3.844-4.025 (m, 4H), 1.964-2.220 (m, 4H), 1.227-1.262 (t, J=3.0 Hz, 3H); MS (ESI): m/z 426.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[F:21][C:20]([F:23])([F:22])[CH2:19][N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:33]5[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=5)[C:26]([OH:28])=[O:27])[CH:25]=[CH:24][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: O=C(O)c1cccc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)c1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-carboxyphenylboronic acid to give 149. MS(ESI+) 473.0. 1H NMR (400 MHz, DMSO) δ 13.05 (br, 1H), 8.42 (d, J=8.3, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.00 (d, J=7.8, 1H), 7.96 (d, J=7.8, 1H), 7.65-7.54 (m, 2H), 7.42 (d, J=1.6, 1H), 5.88 (q, J=8.6, 2H), 4.45 (t, J=4.9, 2H), 3.51 (t, J=4.9, 2H)
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][N:7]1[C:33](=[O:50])[C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:37]([O:44][CH3:45])=[C:36]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:35]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([NH:11][C@@H:9]2[CH2:8][N:7]([C:33](=[O:50])[C:34]3[CH:39]=[C:38]([C:40]([CH3:41])([CH3:42])[CH3:43])[C:37]([O:44][CH3:45])=[C:36]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:35]=3)[C@H:6]([C:4]([OH:5])=[O:3])[CH2:10]2)=[O:32])=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1C(=O)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc(C(=O)N2C[C@@H](NC(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C[C@H]2C(=O)O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To the solution of (2S,4S)-4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidine-2-carboxylic acid ethyl ester (33) (0.32 g, 0.52 mmol) in THF (15 ml), MeOH (5 ml) and water (5 ml) was added LiOH (0.1 g, 2.45 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was neutralized with 2N HCl to pH˜2 and dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2: MeOH (10:1) to give 0.26 g of desired product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][P:12]([CH2:19][O:20]S(C1C=CC(Cl)=CC=1)(=O)=O)(=[O:18])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:34][CH:33]=1>>[C:43]([O:42][C:41]([NH:40][CH2:39][CH2:38][C:35]1[CH:34]=[CH:33][C:32]([O:20][CH2:19][P:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:18])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:37][CH:36]=1)=[O:47])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: CCCCOP(=O)(CCCOCc1ccccc1)COS(=O)(=O)c1ccc(Cl)cc1
Product: CCCCOP(=O)(CCCOCc1ccccc1)COc1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared from 3-benzyloxypropyl-(4-chlorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester and 2-(4-hydroxyphenyl)ethylcarbamic acid, t-butyl ester according to the procedure described in Procedure 24. The crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][C:11]1=[O:17].Br[CH2:19][C:20]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:21]=1[C:22](OC)=[O:23]>CN(C)C=O.C(#N)C>[O:23]=[C:22]1[C:21]2[C:20](=[C:29]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:27][CH:26]=2)[CH2:19][N:9]1[CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Temperature: 52.5 °C

Procedure:
Triethylamine (140.8 g, 2.29 mol) was added at 25-30° C. to a solution of 3-amino-piperidine-2,6-dione hydrochloride (100 g, 0.61 mol) in N,N-dimethylformamide (800 ml). A solution of methyl 2-bromomethyl-3-nitro-benzoate (186.0 g, 1.13 mol) in acetonitrile (200 ml) was then added under stirring and a nitrogen atmosphere and the reaction mixture was heated to 50-55° C. for 8-10 hours. After completion of the reaction approximately 60% solvent was removed by distillation at 50-60° C. under reduced pressure (100 mbar). Water (1000 ml) was added to the residual mixture at 50-55° C. and stirred for 1 hour at this temperature. The resultant solid product was cooled to 25-30° C. and filtered. The solid was washed with water (500 ml) at 50-55° C., cooled at ambient temperature and filtered again. Finally the solid was washed with methanol (500 ml) at 50-55° C., cooled at 25-30° C. and filtered. The filtered solid product was dried at 50-55° C. under low pressure (200 mmHg) for 4 hours to give 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a purple to ash coloured solid.