Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][CH2:25][NH2:26])=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:18])([CH3:17])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][CH2:25][NH:26][C:34](=[O:36])[CH3:35])=[CH:5][C:4]=2[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC(C)(C)O
Solvent: CCN(CC)CC
Product: COCc1nc2c(N)nc3cc(CCCNC(C)=O)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
A solution of 1-[4-amino-7-(3-aminopropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (1.25 g, 3.50 mmol) in triethylamine (2.4 mL, 17.5 mmol) was cooled to 0° C. in an ice water bath and acetic anhydride (393 mg, 3.85 mmol) was added. The solution was stirred for approximately 18 hours while warming to ambient temperature. The solution was concentrated under reduced pressure and the residue was partitioned between 1% aqueous sodium carbonate (125 mL) and chloroform (50 mL). Successive chloroform extractions were performed until no product was present in the aqueous layer. The combined organic fractions were concentrated under reduced pressure and dissolved in methanol (100 mL). To this solution was added solid potassium carbonate (3 tsp) and the reaction was heated to reflux temperature for 2 hours. After cooling to ambient temperature, the mixture was filtered, concentrated and partitioned between water (50 mL) and chloroform (50 mL). Crude product was extracted from the aqueous fraction through successive chloroform extractions until no product remained in the aqueous layer. The combined organic extracts were concentrated and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-30% CMA over 1500 mL, followed by 30% CMA over 1000 mL) to provide 578 mg of N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}acetamide as a white semi-solid.
Reaction SMILES: [CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:27])[N:15]([CH2:20][CH2:21][C:22](OCC)=[O:23])[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O1CCCC1.O.ClCCl>[CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:27])[N:15]([CH2:20][CH2:21][CH2:22][OH:23])[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:9])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCn1c(C)cnc(NNS(=O)(=O)Cc2ccccc2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCO
Reaction time: 5 h

Procedure:
To a solution of 3-(2-benzylsulfonylhydrazino)-1-[(2-ethoxycarbonyl)ethyl]-6-methylpyrazinone, the product of Example 30 (0.398 g, 1.01 mmol), in tetrahydrofuran (10 mL) containing 5% methanol, is added sodium borohydride (0.229 g, 6.07 mmol) at room temperature. The reaction mixture is stirred for 5 hours. Water (2 mL) is then added and the mixture is fractionated between dichloromethane and water. The organic phase is dried over anhydrous sodium sulfate and is concentrated under reduced pressure. The crude residue is purified using silica gel column chromatography with ethyl acetate/n-hexane as eluent to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:14][C:15]([CH3:31])([O:17][C:18](=[O:30])[NH:19][C:20](=S)[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:16]>C(Cl)Cl>[C:24]([O:23][C:22]([NH:21]/[C:20](=[N:19]/[C:18](=[O:30])[O:17][C:15]([CH3:31])([CH3:16])[CH3:14])/[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:3]=1)=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: Nc1cccc(N2CCCC2=O)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1cccc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a 500 mL round bottom flask was charged 1-(3-aminophenyl)pyrrolidin-2-one (5 g, 28.4 mmol), 2,2,10,10-tetramethyl-6-thioxo-3,9-dioxa-5,7-diazaundecane-4,8-dione (9.80 g, 35.5 mmol), polystyrene-carbodiimide (Argonaut P/N 800371, 1.42 mmole/g, 30.0 g, 42.6 mmol) and CH2Cl2 (300 mL). The resulting suspension was stirred at room temperature for 14 hours. The reaction was filtered and the collected solid was washed with 2×30 mL CH2Cl2. The filtrate was concentrated. The concentrate was purified by flash chromatography on a 140 g silica gel plug eluting with CH2Cl2 then 1:1 ethyl acetate/hexanes to provide the title compound. MS (ESI+) m/e 419.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[CH2:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([NH:20][C:21]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc2sc(NC(=O)NCc3ccccc3)nc12
Temperature: 60 °C

Procedure:
To a stirred solution of 2-amino-4-methoxy-benzothiazole (180 mg, 1 mol) in THF (5 ml) was added benzylisocyanate (166 mg, 1.25 mmol) and the mixture heated to 60° C. for 3 h. After evaporation of the solvent, ether (5 ml) was added and the suspension ultra-sonnicated for 10 min with addition of nHexane (5 ml). This suspension was filtered and washed further with ether/nHexane (1:1) to afford the title compound, after drying under vacuum, as a white solid (220 mg, 70% yield), MS: m/e=313 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13]>[Cu](I)I.C(N(CC)CC)C>[OH:14][CH2:10][CH2:11][C:12]1[O:9][C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH:13]=1
Reactant: C#CCCO
Reactant: Oc1cccc(Br)c1O
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: OCCc1cc2cccc(O)c2o1

Procedure:
As shown in Scheme 17, 3-bromo-1,2-benzenediol is treated with bis-triphenylphosphine palladium dichloride, copper iodide, triethylamine, and 3-butyn-1-ol and heated at between 40° C. and 80° C. for several hours or until TLC (thin layer chromatography) indicates the reaction is complete to provide 2-(2-hydroxyethyl)-1-benzofuran-7-ol. 2-(2-Hydroxyethyl)-1-benzofuran-7-ol is then processed according to procedures described for Examples 203-224 as shown as in Scheme 15 to provide 2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-7-yl trifluoromethanesulfonate, which is processed as described in Murata, et al., Journal of Organic Chemistry (2000) 65, 164-168 and followed by treatment with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides, a palladium catalyst, such as palladium (II) acetate, a trivalent phosphine such as biphen-2-yl-dicyclohexylphosphine, and aqueous sodium carbonate or potassium phosphate in an organic solvent such as ethanol or tetrahydrofuran at 25° C. to 120° C. to provide compounds formula (53). Compounds of formula (53) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (53) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[N:22]=[N:23][N:24]([CH3:38])[C:25]=4[NH:26][C:27]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])=[O:28])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C.O>[CH3:38][N:24]1[C:25]([NH:26][C:27]([O:29][C@@H:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31])=[O:28])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)[CH:10]=3)=[CH:16][CH:17]=2)[N:22]=[N:23]1
Reactant: CCOC(=O)C1(c2cccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3cccc(C4(C(=O)O)CC4)c3)cc2)nnn1C)c1ccccc1
Reaction time: 20 h
Yield: 88.3 %

Procedure:
To a solution of (R)-1-(4′-(1-methyl-5-((1-phenylethoxy)carbonylamino)-1H-1,2,3-triazol-4-yl)biphenyl-3-yl)cyclopropanecarboxylic acid ethyl ester (90 mg, 0.176 mmol) in THF (5 mL) and ethanol (5 mL) was added an excess of sodium hydroxide (1.76 mL, 1.76 mmol, 1.0 M) in water at room temperature. The resulting colorless solution was stirred for 20 h at which time LCMS analysis indicated the absence of starting material. Then, the solvent was removed under vacuum and the basic aqueous layer was neutralized with 1.0 N HCl. The resulting white solids were collected by filtration and washed with water and hexanes. After air drying, 75 mg (88% yield) of the (R)-1-(4′-(1-methyl-5-((1-phenylethoxy)carbonylamino)-1H-1,2,3-triazol-4-yl)biphenyl-3-yl)cyclopropanecarboxylic acid was isolated as a white solid. LC/MS calcd. for C28H26N4O4 (m/e) 482.0, obsd. 483.1 (M+H, ES+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:7]([CH2:10][O:11]C(=O)C)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(COC(C)=O)n1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Yield: 81 %

Procedure:
A solution of crude 2-n-butyl-5-acetoxymethyl-1-(2chlorophenyl)methyl-1H-imidazole (250 g) in methanol (200 mL) was treated with 10% sodium hydroxide solution (700 mL) and the mixture was heated on a steam bath for 4 hours. After cooling, methylene chloride was added, the organic phase was separated, washed with water, dried and concentrated. The residue was dissolved in ether, cooled, and seeded to give the crude product. Recrystallization from ethyl acetate gave 176 g of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 86-88° C. This material was identical in all respects to the product prepared by Method 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[CH:26]1[CH:31]=[C:30]([CH2:32]Br)[C:29]([CH2:34]Br)=[CH:28][CH:27]=1>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH2:32][C:30]3[CH:31]=[CH:26][CH:27]=[CH:28][C:29]=3[CH2:34][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:23]
Reactant: BrCc1ccccc1CBr
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1N(S(=O)(=O)c1ccc(OC)cc1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
To a solution of 0.350 g (1.039 mmol) of the product of Example 31 in 35 mL of DMF was added 0.104 g (2.596 mmol) of 60% sodium hydride and the solution was stirred at room temperature for 15 minutes. To the resulting mixture was then added 0.384 g (1.454 mmol) of a,a'-dibromo-o-xylene and the reaction mixture was then heated to 80° C. for 18 h, cooled to room temperature, diluted with ether and washed with water. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with EtOAc/hexanes (1:3) to provide 0.358 g (79%) of the desired product as a white solid. Electrospray Mass Spec: 440 (M+H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:32]([Cl:31])=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2c(Cl)cccc2Cl)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,6-dichlorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.37 (m, 3 H), 7.28-7.21 (m, 2 H), 6.91 (t, J=8.3 Hz, 1 H), 6.83-6.78 (m, 1 H), 6.19-6.13 (m, 1 H), 5.83-5.68 (m, 2 H), 5.62-5.56 (m, 1 H), 4.27 (t, J=5.2 Hz, 2 H), 2.94-2.77 (m, 2 H), 2.75 (s, 3 H), 2.12-2.06 (m, 2 H), 0.97 (s, 9 H); LC/MS (m/z) ES+=553.30 (M+1).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=2[O:18][CH3:19])=[C:4]([CH2:20][N:21]2[C@@H:25]([CH3:26])[C@@H:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[O:23][C:22]2=[O:41])[CH:3]=1.N(OC(C)(C)C)=O.[CH3:49][S:50]SC>>[F:34][C:33]([F:35])([F:36])[C:31]1[CH:32]=[C:27]([C@H:24]2[O:23][C:22](=[O:41])[N:21]([CH2:20][C:4]3[CH:3]=[C:2]([S:50][CH3:49])[CH:7]=[CH:6][C:5]=3[C:8]3[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[C:11]([F:17])=[CH:10][C:9]=3[O:18][CH3:19])[C@H:25]2[CH3:26])[CH:28]=[C:29]([C:37]([F:39])([F:38])[F:40])[CH:30]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CSSC
Agent: CC(C)(C)ON=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(SC)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution (4S,5R)-3-[(4-amino-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (200 mg, 0.34 mmol) in methyl disulfide (2 mL) was added tert-butyl nitrite (70 mg, 0.68 mmol). The resulting mixture was stirred at 80° C. for 30 min. An aliquot indicated completion of the reaction. The titled compound was obtained as a glassy material after two preparative TLC plates using respectively 20% EtOAc in hexanes and 10% EtOAc in dichloromethane as the eluent. LC-MS: 616.21 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.84 (s, 1H), 7.67 (s, 2H), 7.35 (s, 0.5H), 7.22-7.28 (m, 1.5H), 7.12-7.19 (m, 1H), 6.94-7.02 (m, 1H), 6.61-6.68 (m, 1H), 5.55 (d, J=8.0 Hz, 0.5H), 5.31 (d, J=9.5 Hz, 0.5H), 4.85 (d, J=16.0 Hz, 0.5H), 4.83 (d, J=15.5 Hz, 0.5H), 3.99 (d, J=15.5 Hz, 0.5H), 3.69-3.81 (m, 4.5H), 3.12-3.24 (m, 1H), 2.54, (s, 1.5H), 2.53 (s, 1.5H), 1.11-1.27 (m, 6H), 0.50 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=7.0 Hz, 1.5H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:11]2)=[CH:5][CH:4]=1)#[N:2].[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:11]1[C:12]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][S:14][C:10]1=[N:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: N#Cc1ccc(N=C2NC3(CCCC3)CS2)cc1
Reactant: CC(C)CBr
Product: CC(C)CN1C(=Nc2ccc(C#N)cc2)SCC12CCCC2

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-cyanophenyl isothiocyanate according to Method C1a to give 2-(4-cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-cyanophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2.[CH3:22]O>>[CH3:22][O:19][C:18](=[O:20])[CH:17]([C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([OH:6])[CH:8]=2)[CH:13]=1)[CH3:21]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Yield: 89.5 %

Procedure:
To a solution of methanol (2100 ml) and sulphuric acid (84 ml) was added 2-(6-Hydroxynaphthalen-2-yl)-propionic acid 5 (420 g, 1.944 mmol), and refluxed for 6 hours. Methanol (1000 ml) was distilled off and the cooled reaction mass was poured onto ice water (3000 ml). Crude 6 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:5) to give pure 6 (400 g, 89.5%) as a white fluffy powder. The melting point found to be 89.5-92° C. The structure was confirmed with IR and NMR.
Reaction SMILES: C([O:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[NH:15])[NH2:14])[CH:8]=1)(C)(C)C.CN([CH:20]=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=O)C.[H-].[Na+]>C(O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[CH:21]=[CH:20][N:14]=[C:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:5])=[O:16])[N:15]=2)=[CH:25][CH:26]=1
Reactant: CN(C)C=CC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=N)N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cccc(-c2nccc(-c3ccc(F)cc3)n2)c1
Yield: 49.8 %

Procedure:
Part B. To a mixture of 3-carbamimidoyl-benzoic acid tert-butyl ester (220.2 mg, 0.94 mmol), 3-dimethylamino-1-(4-fluoro-phenyl)-propenone (182.6 mg, 0.95 mmol) and sodium hydride (39.2 mg, 1.63 mmol, 60% in hexanes) is added dry ethanol (5.0 mL). The resulting mixture is stirred at refluxing for 8 h until complete consumption of the starting material as determined by TLC. The solvent is removed, and the residue is added to 1N HCl (15 mL) to precipitate a yellow solid. The title product (137.8 mg, 41.3% yield) is produced after washing with water, then ethyl ether in sequence, m.p. 239-241° C. 1H NMR (300 MHz, DMSO-d6): δ 9.05 (1H, s), 8.97 (1H, d, J=5.0 Hz), 8.73 (1H, dd, J=7.7, 1.2 Hz), 8.38 (2H, m), 8.11 (1H, dd, J=8.0, 1.2 Hz), 8.04 (1H, d, J=5.3 Hz), 7.68 (1H, t, J=7.8 Hz), 7.43 (2H, m). MS (ES+): m/e 295.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[N:10][C:11]([O:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[C:12]([CH:15]=2)[C:13]#[N:14])=[CH:4][CH:3]=1.C(#N)C.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][O:16][C:11]1[N:10]=[C:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCN
Temperature: 80 °C

Procedure:
To the product of Example 25 (971 mg) was added acetonitrile (14 mL) and ethanol (5 mL). The mixture was heated to 80° C. to dissolve the material before adding hydrazine hydrate (0.60 mL, 12.24 mmol). After 2.3 hours the mixture was filtered through Celite®545 diatomaceous earth and then concentrated. The residue was purified by flash chromatography (silica gel) eluting with 2% triethylamine/4% methanol/94% dichloromethane affording the product. MS (electrospray) m/e 418.0 MH+ (retention time=3.0 min LC/MS).
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:21]>O>[Cl:21][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1ccc2onc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2onc(Cl)c2c1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
3-Hydroxy-5-methyl-1,2-benzisoxazole (15.0 g, 100.6 mmol; preparation: Australian Journal of Chemistry (1977), 30(8), 1847-50) were suspended in triethylamine (15.4 ml, 110.6 mmol), and phosphorus oxytrichloride (37.0 g, 22.5 ml, 241.4 mmol) was added dropwise with cooling to this mixture at room temperature. Since stirring of the reaction mixture became almost impossible after about half the amount of phosphorus oxytrichloride had been added dropwise, the temperature was raised to 50° C. After dropwise addition of the total amount of phosphorus oxytrichloride, the reaction mixture was heated at 130° C. for 5 h, after which the reaction was complete according to TLC. After cooling, the mixture was slowly added dropwise to water (200 ml) while cooling, the aqueous phase was extracted 3 times with MtB ether, the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. This resulted in 14.6 g of 3-chloro-5-methyl-1,2-benzisoxazole (yield: 87%) as viscous oil which solidified overnight. MS (MSD) m/z 168 [M+H+].
Reaction SMILES: [H-].[Na+].[N:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[C:4]=[O:5].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[C:17]([O:24][CH2:25][CH3:26])[CH:16]=1>C1COCC1>[C:9]([C:8]1[CH:7]=[C:6]([NH:3][C:4](=[O:5])[O:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][C:17]=2[O:24][CH2:25][CH3:26])[CH:13]=[CH:12][CH:11]=1)#[N:10]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: CCOc1cc(Br)ccc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
NaH (346 mg, 8.7 mmol, 60% dispersion in oil) was added in one portion to a solution of 3-isocyanatobenzonitrile (567 mmol, 3.9 mmol) and 62E (960 mg, 3.9 mmol) in THF (40 mL) and the cooling bath was removed. After stirring for 2 h at ambient temperature 1.0 N citric acid (50 mL) was added and the mixture was extracted with diethyl ether. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography (0% to 60% EtOAc in hexanes) to yield 62F (611 mg, 50%) as a pale, yellow solid. MS (ESI) m/z 411.0/413.0 (M+H)+.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O>[CH3:22][CH:23]1[CH2:28][CH2:27][N:26]([C:4]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:5]=2[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])[CH2:25][CH2:24]1
Reactant: CC1CCNCC1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2)CC1
Yield: 93.9 %

Procedure:
A mixture of 0.024 mole (0.96 g) of NaOH, 25 ml of water, 0.02 mole (5.92 g) of 2,4'-dichloro-5-nitro-benzophenone and of 0.022 mole (2.6 ml) of 4-methylpiperidine is heated to 80° C. for three and a half hours. After cooling the reaction medium to normal temperature the resulting precipitate is filtered, washed in water and dried giving 6.74 g (Yield: 94%) of the expected product. M.P.=138° C. (Ex. 25) The compounds listed hereunder are obtained by reacting, in the same conditions as above, the 2,4'-dichloro-5-nitro-benzophenone with other piperidine derivatives (2-methyl, 3-methyl, 3,5-dimethylpiperidine):