Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:23]=[C:19]([C:20]([OH:22])=[O:21])[C:18]([OH:24])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:1])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(OCc2ccccc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(OCc2ccccc2)cc1C(=O)O
Yield: 58.2 %

Procedure:
Anhydrous potassium carbonate (60 g.) was added slowly with stirring to a refluxing mixture of 5-benzyloxysalicylic acid (13 g.; prepared as described by H. Bogeny and R. Krattner, Arch.Pharm; 1960, 293, 393) and anhydrous ethanol (250 ml.). Dimethyl sulphate (36 ml.) was then added, and the mixture stirred under reflux for 24 hours. The solid was filtered off, and the filtrate evaporated in vacuo to give more solid. The combined solids were suspended in water (250 ml.), and sodium hydroxide (20 g.) was added. The mixture was stirred under reflux for 2 hours, and then concentrated hydrochloric acid was added through the condenser, at such a rate that the contents of the flask continued to reflux gently, until pH 1 was attained. After being cooled, the solid which separated was filtered off, and recrystallised from 50% aqueous ethanol, and then from ethanol, to give 5-benzyloxy-2-methoxybenzoic acid (8 g.), m.p. 114°-116° C.
Reaction SMILES: [C:1]([N:5]([CH2:14][C:15]([O:17]CC)=O)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>O1CCCC1>[C:1]([N:5]1[CH2:6][CH2:7][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:15](=[O:17])[CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCN(CC(=O)OCC)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(C)(C)C)CC1=O
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To a solution of the product of step B (14.0 g; 50.9 mmol) in tetrahydrofuran (200 mL) was added 1.05 eq of potassium tert-butoxide (6.0 g; 53.5 mmol). The reaction was maintained at ambient temperature for 2 h and then quenched with a sufficient amount of saturated aqueous ammonium chloride to make the solution pH 8. The tetrahydrofuran was removed in vacuo and the aqueous layer was extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (7.15 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([C:20]1[C:25]([O:26][CH2:27][C:28]([OH:30])=O)=[C:24]([Cl:31])[CH:23]=[C:22]([Cl:32])[CH:21]=1)([CH2:18][CH3:19])[CH3:17].[SH:33][C:34]1[S:35][CH2:36][CH2:37][N:38]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:16]([C:20]1[C:25]([O:26][CH2:27][C:28]([N:38]2[CH2:37][CH2:36][S:35][C:34]2=[S:33])=[O:30])=[C:24]([Cl:31])[CH:23]=[C:22]([Cl:32])[CH:21]=1)([CH2:18][CH3:19])[CH3:17]
Reactant: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)O
Reactant: SC1=NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)c1cc(Cl)cc(Cl)c1OCC(=O)N1CCSC1=S
Temperature: 0 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
A solution of 8.09 g of dicyclohexylcarbodiimide and 340 mg of 4-dimethylamino-pyridine in 60 ml of methylene chloride was added at -5°/0° C. to a solution of 9.78 g of (6-sec-butyl-2,4-dichloro phenoxy) acetic acid and 4.63 g of 2-mercaptothiazoline in 80 ml of methylene chloride and the mixture was stirred for 10 minutes at 0° C. and for four hours at ambient temperature. After filtering off the insolubles, the filtrate was evaporated to dryness, and the residue was chromatographed on silica (eluant: hexane-ethyl (7-3)) to obtain 10.3 g of expected product melting at 96° C.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:24][C@@:23]3([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]4[C@@H:22]3[CH2:21][CH2:20][C@@:18]3([CH3:19])[C@H:14]4[CH2:15][C@H:16]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[C@@H:17]3[OH:26])[CH2:9][C@@H:8]2[OH:32])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(#N)C>[C:40]([O:26][C@H:17]1[C@@H:16]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:15][C@H:14]2[C@H:13]3[C@H:22]([CH2:21][CH2:20][C@:18]12[CH3:19])[C@:23]1([CH3:25])[C@H:10]([CH2:9][C@H:8]([OH:32])[C@@H:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:24]1)[CH2:11][CH2:12]3)(=[O:42])[CH3:41]
Reactant: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@@H](N2CCCC2)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 2.5 °C
Yield: 66.8 %

Procedure:
To a suspension of 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol (2.067 Kg, 4.628 mol) in dichloromethane (103.35 L) at 20-22° C., was added triethylamine (1.935 L, 13.883 mol) under N2 atmosphere. The mixture was stirred until complete dissolution. Acetic anhydride (0.873 L, 9.255 mol) was charged slowly under continuous stirring and then the resulting reaction mixture was stirred for 22 h at a temperature of 20-22° C. A 5% Na2CO3 solution (41.34 L) was then added and the mixture was stirred for 5-10 min. The phases were separated and the organic phase was washed with water (2×41 L) at 15° C., dried with anhydrous Na2SO4 (10 Kg), and filtered under vacuum to remove salts, which were rinsed with dichloromethane (10 L). The solvent was removed under vacuum at a temperature lower than 20° C. until a final volume of 12 L was obtained. To the concentrated stirred solution at a maximum temperature of 20° C. was added wet acetonitrile (40 L), followed by concentrating under vacuum at a temperature lower than 15° C., to a total volume of 40 L of a suspension. The resulting suspension was cooled to 0-5° C., stirred for 1 h, filtered off under vacuum and washed with acetonitrile (3 L). The desired wet product was dissolved in dichloromethane (9.5 L) at 20-22° C., followed by addition of acetonitrile (38 L). The volume was reduced under vacuum at a temperature lower than 15° C. to a total volume of 39 L to give a suspension. The resulting suspension was cooled to 0-5° C. and stirred for 1 h. The obtained solid was filtered off under vacuum and the product was washed with acetonitrile (3 L). The pure product was dried in a vacuum oven at 40° C. for at least 15 h to give 1.51 Kg of a white solid. (68.8% molar yield and a purity of 99.9% by HPLC); M.P. 160° C.; [α]D20+55.5 (c=1.0 in CHCl3).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:11]([CH:2]1[O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1)=[O:13])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)C1COc2ccccc2O1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])C1COc2ccccc2O1
Yield: 33.4 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.91 g of 1,4-benzodioxane-2-carboxylic acid and 0.85 g of nitroxyethylamine nitrate, 0.45 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Mg+2].[Cl-].[Cl-].[F:14][C:15]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:16]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:20]1[CH:16]=[C:15]([F:14])[C:23]([F:24])=[C:22]([F:25])[C:21]=1[F:26])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium ethyl malonate (3.66 g, 21.5 mmol), MgCl2 (2.44 g, 25.7 mmol) and TEA (2.05 g, 20.3 mmol) were mixed in acetonitrile (70 ml) at 10-15° C. for 2.5 hr. 2,3,4,5-tetrafluorobenzoyl chloride (2.00 g, 10.3 mmol) in acetonitrile (10 ml) was added at 0° C. over 15 min followed by a second addition of TEA (0.23 g, 2.3 mmol). After allowing to warm to RT, the mixture was stirred for 16 hr. After removal of volatiles in vacuo Toluene (30 ml) was added and removed in vacuo. Following the addition of toluene (60 ml), HCl 1.5 M (40 ml) was added cautiously, ensuring the temperature did not exceed 25° C. The organic fraction was washed with HCl 1.5 M (2×25 ml) and water (2×25 ml), dried over MgSO4 and reduced to a light orange oil in vacuo ([M+1]+ 265, 98%).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C[N:14]1CCOCC1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[C:2]([Cl:1])(=[O:4])[NH2:14].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: NC(=O)Cl
Temperature: 25 °C

Procedure:
A stirring solution of triphosgene (27.78 g, 0.103 mol) in 40 mL toluene was cooled to -20 ° C. in an ice/salt bath under a blanket of nitrogen and treated with a solution of N-methylmorpholine (27.3 g, 0.27 mol) in 20 mL of toluene dropwise over 1 h. This solution was then treated with a solution of pyrrolidine (19.8 g, 0.27 mol) in 30 mL of toluene over a period of 30 m. The solution was allowed to warm to room temperature, filtered and the filtrate concentrated in vacuo to give an oil that was purified by vacuum distillation through a 12" Vigeraux column to give 20.7 g, 56%, bp 58° C. @0.6 mm, of pure product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH2:19]>C1COCC1.O.[Ni]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH2:19]
Reactant: COC(=O)c1cc(-c2ccoc2)c(C(F)(F)F)cc1N
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C2CCOC2)c(C(F)(F)F)cc1N
Temperature: 60 °C
Reaction time: 624 h
Yield: 46.7 %

Procedure:
2-Amino-5-furan-3-yl-4-trifluoromethyl-benzoic acid methyl ester (110 mg, 0.38 mmol) was dissolved in THF (15 mL) and, after addition of B113 W (Degussa) Ra/Ni (˜200 mg) in H2O the mixture was stirred for 26 d (TLC control) at 60° C. The mixture was filtered over Celite and evaporated under reduced pressure. The crude product was purified by flash chromatography with hexanes to hexanes/EtOAc 80:20 as eluent to furnish the title compound (51.3 mg, 46% yield) (290 [M+H]+, rt 5.52 min.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[N:13]1.S([O-])(O)(=O)=O.[K+]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[CH:4][C:3]=1[N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[N:13]1
Reactant: CC(C)(O)c1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=C(C)c1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
The 2[2-hydroxy-5-(2-hydroxy-2-propyl)phenyl]2H-benzotriazole (2H5PR) of Example 3 was dehydrated using potassium hydrogen sulfate to produce 2(2-hydroxy-5-isopropenylphenyl)-2H-benzotriazole (2H5P).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:10][C:9]=2[C:8]([O:21]C)=[CH:7][CH:6]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:21])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
2-(4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (3 g, 10.00 mmol) obtained in step 2 was dissolved in toluene, aluminum chloride (6.67 g, 30.00 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (1.96 g, 7.20 mmol) in a yield of 72%.
Reaction SMILES: [CH:1]([Si:9]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([Cl:11])[Cl:10])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:20][SiH:21]([Cl:23])[Cl:22]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:20][Si:21]([Cl:23])([Cl:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][Si:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Si:21]([Cl:23])([Cl:22])[Cl:20])([Cl:11])[Cl:10]
Reactant: CCCCCCC=C[Si](Cl)(Cl)C=CCCCCCC
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: Cl[Si](Cl)(Cl)CCCCCCCC[Si](Cl)(Cl)CCCCCCCC[Si](Cl)(Cl)Cl
Temperature: 110 °C
Yield: 94.9 %

Procedure:
To a 100 ml glass ampoule equipped with a magnetic stirring bar was added hexachoroplatinic acid (0.05 ml, 0.090M solution in isopropanol). After the solvent was removed under reduced pressure, bis(octenyl)dichlorosilane (6.02 g, 18.74 mmoles) was introduced into the ampoule in an inert atmosphere enclosure. Subsequently trichlorosilane (29.9 g, 198.6 mmoles) was condensed into the ampoule on the vacuum line. The in vacuo sealed ampoule was placed in an oil bath and heated up slowly to 110° C. at which temperature it was kept for twenty four hours. After opening the ampoule into the vacuum line, a small quantity of noncondensibles was observed. The excess trichlorosilane was distilled off to yield 10.53 g (94.9% yield) of bis (8-trichlorosilyloctyl)dichlorosilane.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[C:4]([CH3:6])=[O:5].[C:16]([O:22][CH2:23]Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[C:16]([O:22][CH2:23][O:12][C:11]([C:10]1[CH:14]=[CH:15][C:7]([CH2:3][C:4](=[O:5])[CH3:6])=[CH:8][CH:9]=1)=[O:13])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(=O)Cc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Cc1ccc(C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
Sodium hydride (0.48 g) was added to 4-acetonylbenzoic acid (3.56 g) in acetonitrile and the solution refluxed for 1/2 hour. Chloromethyl pivalate (3.02 g) was then added and the mixture refluxed for 22 hours. Acetonitrile was removed, the residue partitioned between ether and water and the organic layer separated and washed with sodium bicarbonate solution (×2). The ether layer was dried (MgSO4) and evaporated to give the title compound which was crystallised and recrystallised from hexane. τ(CDCl3) 8.77 (9H, s), 7.82 (3H, s), 6.25 (2H, s), 4.02 (2H, s), 2.73 (2H, d, J=9 Hz), 1.96 (2H, d, J=9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[O:5][C:6]1[N:7]=[C:8]([CH2:32][CH2:33][CH3:34])[C:9]2[N:14]=[C:13]([C:15]3[CH:29]=[C:28]([CH3:30])[C:18]([O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[C:17]([CH3:31])[CH:16]=3)[O:12][C:10]=2[N:11]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[O:5][C:6]1[N:7]=[C:8]([CH2:32][CH2:33][CH3:34])[C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[C:17]([CH3:31])[C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:28]([CH3:30])[CH:29]=3)[O:12][C:10]=2[N:11]=1
Reactant: CCCc1nc(Oc2cccc(Cl)c2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc(Oc2cccc(Cl)c2)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Yield: 42.8 %

Procedure:
Analogously to example 1 (j), the reaction of 115 mg of tert-butyl {4-[5-(3-chlorophenoxy)-7-propyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate with trifluoroacetic acid gave 44 mg (43%) of the title compound.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-:5])=[O:4].I[CH3:16]>CN(C)C=O>[CH3:16][N:10]1[C:11]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c([N+](=O)[O-])cccc21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred suspension of sodium hydride (0.14 g; 3.41 mM) in dimethylformamide (10 ml) at 0° C. under nitrogen was added 4-nitroindole (0.5 g; 3.1 mM) in dimethylformamide. After stirring for 0.5 h, iodomethane (0.21 ml; 3.41 mM) in dimethylformamide (1 ml) was added, and stirring was continued for 1 h. The reaction mixture was then quenched with water, and poured onto excess water with stirring. Filtration afforded the title compound (0.5 g; 92%).
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:14][CH3:15])([CH3:13])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:17]1[C:18]([CH3:27])=[CH:19][C:20]2[N:21]([N:23]=[C:24]([CH3:26])[N:25]=2)[N:22]=1>>[CH2:14]([C:10]([CH3:13])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:17]1[C:18]([CH3:27])=[CH:19][C:20]2[N:21]([N:23]=[C:24]([CH3:26])[N:25]=2)[N:22]=1)[CH3:15]
Reactant: CCC(C)(CO)CS(=O)(=O)N=CN(C)C
Reactant: Cc1nc2cc(C)c(Cl)nn2n1
Product: CCC(C)(COc1nn2nc(C)nc2cc1C)CS(N)(=O)=O

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2-ethyl-2-methyl-1-propanol and 6-chloro-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 194°-195° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([NH2:22])[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:30][N:31]=[C:32]=[O:33].C(Cl)Cl.C(OCC)(=O)C>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([NH:22][C:32]([NH:31][CH3:30])=[O:33])[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)NC1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a mixture of the intermediate obtained in Step A (263 mg, 0.865 mmol) and triethylamine (0.145 ml, 1.03 mmol) in methylene chloride was added methylisocyanate (0.061 ml, 1.03 mmol). The reaction mixture was stirred overnight and then applied to a flash chromatography column. Flash chromatography (silica gel, methylene chloride/ethyl acetate 1:1) provided the title compound (206 mg, 0.57 mmol).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH3:10])=[O:7])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2ccc(F)cc2)cc1

Procedure:
The title compound (D145) (22 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D103) (50 mg) and 4-Fluorobenzyl bromide (0.045 ml). (Na2CO3; reaction time: 5 hrs; 70° C.).
Reaction SMILES: [CH2:1]([NH:9][N:10]=[C:11]([CH3:17])[C:12]([O:14]CC)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].C(O)C.Cl>C(OCC)C.O>[CH2:1]([NH:9][N:10]=[C:11]([CH3:17])[C:12]([OH:14])=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)=NNCCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(=NNCCc1ccccc1)C(=O)O
Reaction time: 30 h
Yield: 47 %

Procedure:
6 g. Ethyl 2-(phenethylhydrazono)-propionate (prepared according to Example 2) are dissolved in a solution of 1.4 g. potassium hydroxide in 28 ml. 80% ethanol and saponified at ambient temperature. After stirring for 30 hours, the reaction mixture is mixed with 25 ml. water and shaken out twice with 50 ml. amounts of diethyl ether. The aqueous phase is acidified with dilute hydrochloric acid. The crystals which precipitate out are filtered off and recrystallized from toluene. There is obtained 2-(phenethylhydrazono)-propionic acid in a yield of 47% of theory; m.p. 74°-76° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.P(=O)(O)(O)O>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Yield: 24.2 %

Procedure:
A N,N-dimethylformamide mixture (0.6 mL) of tert-butyl 4-(4-{[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}phenyl)piperazine-1-carboxylate (50 mg, 0.087 mmol) and concentrated phosphoric acid (0.6 mL) is heated at 60 C for 2 h. After evaporating to dryness, the residue is partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer is washed with water, dried, and evaporated to yield 10 mg (24%) of the title compound as an orange solid. MS (ESI) m/z 475.2 (M+H)+1
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11](/[CH:13]=[CH:14]\[CH:15]([C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].I[Si](C)(C)C>CC#N>[Br:1][C:2]1[CH:12]=[C:11](/[CH:13]=[CH:14]\[CH:15]([C:20]2[CH:21]=[C:22]([Cl:28])[C:23]([Cl:27])=[C:24]([Cl:26])[CH:25]=2)[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=C(O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a stirred solution of (Z)-ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate (360 mg, 0.70 mmol) in CH3CN (1.0 mL) was added iodotrimethylsilane (0.28 mL, 2.8 mmol). The reaction mixture was heated to reflux for 20 h, allowed to cool to ambient temperature and partitioned between CH2Cl2 and aq. 10% Na2S2O3. Organic phase was washed once with aq. 10% Na2S2O3 and dried over MgSO4 and concentrated in vacuo. Passing the material through a silica plug with 10% EtOAc in hexanes, followed by 20% MeOH in CH2Cl2) as the eluting solvents afforded the title compound as a yellow foam (143 mg, 42%): mp 54-64° C.; 1H NMR (400 MHz, CDCl3) δ 11.36 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 2H), 7.14 (d, J=7.9 Hz, 1H), 6.85 (d, J=11.4 Hz, 1H), 6.15 (t, J=10.9 Hz, 1H), 4.36-4.09 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −69.30.