Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC[CH:25]([O:28]C(CCl)CCl)CCl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:25]=[O:28])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(c3ccccc3)CC2)cc1
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccc(C=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-methylphenylsulfonyl)-4-phenylpiperidine (1.0 g) and 1,1-dichloromethylmethylether (0. 57 ml) in dichloromethane (5 ml) was added at 0° C. a solution of titanium tetrachloride (0.7 ml) in dichloromethane (5 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was added to stirred ice/water to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:4→1:2) to give pale yellow crystals of 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]benzaldehyde (0.381 g). (469.4 mg of the starting materials were collected).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22].[CH:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:29][CH2:30][NH:31][C:2]2[C:10]3[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=3[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=2[C:21]#[N:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1Cl
Reactant: NCCC1CCCCC1
Product: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1NCCC1CCCCC1

Procedure:
4-Chloro-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole is reacted with 2-cyclohexylethylamine to obtain 4-(2-cyclohexylethylamino)-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole, m.w., 329.3.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].[NH2:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:15][C:14]=1C.NC1C=CC(C(C2C=CC=CC=2)=O)=C([Br:43])C=1>>[C:17]([C:16]1[CH:25]=[CH:26][C:13]([NH:12][C:4](=[O:5])[C:3]([CH:8]([F:10])[F:9])([OH:7])[CH:2]([F:11])[F:1])=[C:14]([Br:43])[CH:15]=1)(=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C(=O)c2ccccc2)ccc1N
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)c(Br)c1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)F)C(F)F)c(Br)c1

Procedure:
Using a procedure similar to that described in Example 1, except replacing the 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid with 3,3-difluoro-2-difluoromethyl-2-hydroxypropanoic acid and the 4-amino-3-methylbenzophenone with 4-amino-2-bromobenzophenone, the title compound was prepared; mp 128°-132° C. Analysis for C17H12BrF4NO3 : Calculated: C, 47.13; H, 2.79; N, 3.23; Found: C, 56.21; H, 2.95; N, 3.14.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([N:21]1[C:31]2[NH:30][C:29]3[N:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:27](=[O:36])[N:26]([CH3:37])[C:25]=2[CH:24]=[CH:23][CH:22]1[C:38]1[CH:42]=[CH:41][N:40]([Si](C(C)C)(C(C)C)C(C)C)[CH:39]=1)[CH3:20]>C1COCC1.CCOCC>[CH2:19]([N:21]1[C:31]2[NH:30][C:29]3[N:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:27](=[O:36])[N:26]([CH3:37])[C:25]=2[CH:24]=[CH:23][CH:22]1[C:38]1[CH:42]=[CH:41][NH:40][CH:39]=1)[CH3:20]
Reactant: CCN1C2=C(C=CC1c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1)N(C)C(=O)c1cccnc1N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN1C2=C(C=CC1c1cc[nH]c1)N(C)C(=O)c1cccnc1N2
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Tetrabutylammonium fluoride in THF (1M, 0.36 mL) was added to a solution of 5,11-dihydro-1-ethyl-5-methyl-2-[1-(triisopropylsilyl)pyrrol-3-yl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.17 g) in dry THF (10 mL). After stirring the resulting mixture for 1 h, it was diluted with ether, washed with water, dried (anhyd Na2SO4), filtered, and evaporated. The residue was chromatographed over silica gel (ethyl acetate/hexanes, 1:1), and then crystallized from chloroform/hexanes to give 0.083 g of the title compound, mp 173°-174° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The reaction sequence is shown in FIG. 5. Nε -(tert-butoxycarbonyl)-L-lysine (2 g, 8.12 mmol) was dissolved in methanol (40 ml) and water (40 ml), and the pH was adjusted to 8 with triethylamine. A solution of N-(benzyloxycarbonyl-oxy)succinimide in dioxane (2.4 g, 9.7 mmol in 20 ml) was added to the above mixture and the pH was maintained at 8-9 with triethylamine. The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation to obtain crude Nα -CBZ-Nε -(tert-butoxycarbonyl)-L-lysine. Nα -CBZ-Nε -(tert-butoxycarbonyl)-L-lysine was treated with 0.2M calcium carbonate (4 ml) and the aqueous layer was removed to obtain a white solid. The solid was resuspended in N,N-dimethylformamide(40 ml) and benzyl bromide (1.16 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was worked up with ethyl acetate and water, and the organic layer was dried over magnesium sulphate. The solvent was removed to obtain crude Nα -CBZ-Nε -(tert-butoxycarbonyl)-L-lysine benzyl ester which was purified by silica gel chromatography using 25% hexane in ethyl acetate as a solvent. To Nα -CBZ-Nε -(tert-butoxycarbonyl)-L-lysine benzyl ester (1 g, 2.2 mmol) in methylene chloride (10 ml) was added trifloroacetic acid at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for further 2.5 hr at room temperature. The solvent was removed and the crude product was obtained. Pure Nα -CBZ-L-lysine benzyl ester was obtained by silica gel chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([N:23]3[C@@H:27]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=4)[C@H:26]([CH2:36][O:37]C4CCCCO4)[O:25][C:24]3=[O:44])=[O:22])[CH2:16]2)[CH2:11][CH2:10]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([N:23]3[C@@H:27]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=4)[C@H:26]([CH2:36][OH:37])[O:25][C:24]3=[O:44])=[O:22])[CH2:16]2)[CH2:11][CH2:10]1)#[N:2]
Reactant: N#Cc1ccccc1N1CCC(N2CC[C@@H](NC(=O)N3C(=O)O[C@@H](COC4CCCCO4)[C@@H]3c3ccc(F)c(F)c3)C2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: N#Cc1ccccc1N1CCC(N2CC[C@@H](NC(=O)N3C(=O)O[C@@H](CO)[C@@H]3c3ccc(F)c(F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-(tetrahydropyran-2-yloxymethyl)oxazolidine-3-carboxylic acid {1-[1-(2-cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl}amide (156 mg, 0.26 mmol) in methanol (5 mL) was added p-toluenesulfonic acid (50 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 17 h. The volatiles were removed under reduced pressure, the residue taken up in ethyl acetate (100 mL), washed with saturated sodium carbonate solution (3×100 mL), brine (1×100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to afford (4S,5R)-4-(3,4-difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2-cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl}amide. The hydrochloride salt was prepared according to standard procedures to provide a white solid (123 mg, 0.22 mmol, 84%)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1.[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][NH:28][CH3:29]>CC(C)=O>[CH3:23][N:24]([CH3:30])[CH2:25][CH2:26][CH2:27][N:28]([CH3:29])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CNCCCN(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC(C)=O
Product: CN(C)CCCN(C)c1ccc(C=O)cc1
Temperature: 50 °C

Procedure:
10 g of 4-fluorobenzaldehyde, 12 g of K2CO3 and 20 ml of NMP are stirred and heated at 50° C. 13 ml of N,N,N′-trimethyl-1,3-propanediamine are added dropwise to the medium kept stirring and heated at 80° C. for 10 h. After the reaction medium has been cooled to ambient temperature, 100 ml of acetone are added. The precipitate obtained is filtered off, and the filtrate is evaporated to dryness and then dried. 21.85 g of powder are recovered. The analyses indicate that the product is in conformity.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.C[O:15][C:16](=[O:26])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[CH:11]([S:10][C:4]1[C:3]([CH2:2][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:16]([OH:26])=[O:15])=[CH:24][CH:23]=2)=[CH:8][C:7]([CH3:9])=[CH:6][N:5]=1)([CH3:13])[CH3:12]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cnc(SC(C)C)c(CCl)c1
Product: Cc1cnc(SC(C)C)c(COc2ccc(CCC(=O)O)cc2)c1
Yield: 55 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-5-methyl-pyridine (0.052 g, 0.24 mmol) obtained in Step D of Preparation Example 30 and 3-(4-hydroxy-phenyl)-propionic acid methyl ester (0.043 g, 0.24 mol) obtained in Preparation Example 4 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (55%).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Br:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([N:15]([CH2:18][C:19](=O)[CH3:20])[CH:16]=O)=[CH:9][CH:8]=1.C(OCC)(=O)C.N>C(O)(=O)C>[Br:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([N:15]2[CH:18]=[C:19]([CH3:20])[N:5]=[CH:16]2)=[CH:9][CH:8]=1
Reactant: COc1nc(Br)ccc1N(C=O)CC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1nc(Br)ccc1-n1cnc(C)c1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A suspension of ammonium acetate (267 g) and N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (199 g) in glacial acetic acid (400 ml) was stirred at 130° C. for one hour and 10 minutes. The reaction solution was returned to room temperature. Ethyl acetate and ice water were added to the reaction solution, and the reaction solution was ice-cooled. Then, concentrated aqueous ammonia (500 ml) was added dropwise and then the organic layer was separated. The resulting organic layer was sequentially washed with water and brine and dried over anhydrous magnesium sulfate. Then, the organic layer was purified by short silica gel column chromatography (carrier: Wakogel C-200; elution solvent: ethyl acetate). The eluted fraction was concentrated. The resulting residue was triturated with ethyl acetate and tert-butyl methyl ether and dried under reduced pressure to obtain 107.7 g of the title compound.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccncc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccncc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 46.7 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (230 mg, 0.78 mmol, 1.0 eq), L-isoleucine pyridin-4-ylmethylamide (266 mg, 1.5 mmol) and dichloromethane (2 mL), was treated with triethylamine (660 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (1.0 mL, 2.0 eq), to provide 180 mg (46%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] pyridin-4-ylmethylamide.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (11%).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](C(C)C)[C:37]=1CC(O)=O)(C)C.C(O)(=O)CCC1C=CC=CC=1>>[O:15]=[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[CH2:13][CH2:33][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: O=C(O)CCc1ccccc1
Product: CC(C)c1ccc(C(=O)CCc2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with hydrocinnamic acid, mp 121°-124° C.
Reaction SMILES: C([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:10]1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(NCc1ccccc1)C2)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)[Si](Oc1cccc2c1CCC(N)C2)(c1ccccc1)c1ccccc1
Yield: 45.9 %

Procedure:
A mixture of 2-benzylamino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.15 g), ammonium formate (4.41 g) and Pd/C (0.15 g) in ethanol (EtOH) (40 ml) was refluxed for 3.5 hours. The insoluble material was filtered off and the solvent was evaporated in vacuo. The residue Has partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 2-amino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.18 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:28]([CH:24]2[CH2:27][CH2:26][CH2:25]2)=[O:29])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)C1CCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCC3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and cyclobutanecarboxylic acid as an off-white solid (61%). MS 400 (MH+).
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[C:6]1([C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)C.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31]C>>[C:15]1([C:14]2[CH:12]=[CH:6][CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][C:4]([C:5]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCC
Reactant: CCOCC
Reactant: O=C(Cc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccccc1-c1ccccc1)c1ccccc1

Procedure:
To a solution the monotetrahydropyranyl ether of the dihydroxydeoxybenzoin (6.87 g, 22 mmole) and 4-hydroxybenzaldehyde (2.44 gm, 20 mmole) in dry benzene (100 ml) was added dry piperidine (0.12 ml). It was refluxed for 30 hours removing water azeotropically adding fresh portions of dry benzene from time to time to replenish the distilled benzene. The reaction mixture was cooled and washed with water (2×40 ml). The organic layer was dried (Na2SO4) and concentrated. The residue left was allowed to stand for 24 hours. The solidified material was filtered off and washed with chloroform to afford the dihydrobenzopyranone. The filtrate was collected, concentrated and residue chromatographed over a silica gel column eluting rapidly with 2% ethyl acetate in hexane, to afford, first, the unreacted THP ether of deoxybenzoin (starting compound). With increasing polarity (20% ethyl acetate in hexane), the 2-phenylchalcone (desired compound) was obtained which was crystallised from benzene-hexane, m.p. 140° C. (6 g, 72.1%).
Reaction SMILES: O[C:2]1[CH:10]=[C:9](O)[CH:8]=[CH:7][C:3]=1C(O)=O.[OH:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].S(OC)(OC)(=O)=O.C1(O)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[OH:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([O:17][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:16]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: COS(=O)(=O)OC
Solvent: Oc1ccccc1
Product: COc1ccc(C(=O)Oc2ccccc2)c(O)c1
Yield: 66 %

Procedure:
2,4-Dihydroxybenzoic acid was converted to 2-hydroxy-4-methoxybenzoic acid by treatment with dimethyl sulfate according to the procedure of M. Gomberg and L. C. Johnson (J. Amer. Chem. Soc., 1917, 39, 1687). Treatment of 2-hydroxy-4-methoxybenzoic acid with phenol and phosphorus oxychloride according to the general method of N. G. Gaylord and P. M. Kamath (Organic Syntheses, Coll. Vol. IV, p. 178, 1963) gave phenyl 2-hydroxy-4-methoxybenzoate in 66% yield. Reaction of this phenyl ester with two molar equivalents of benzamidine in boiling ethanol for 20 hours gave a precipitate of 2,4-diphenyl-6-(2'-hydroxy-4'-methoxyphenyl)-s-triazine, which recrystallised from formdimethylamide as pale yellow needles, m.p. 211°-212° C., in 44% yield. Elemental analysis: C, 74.0%; H, 4.4%; N, 11.6%. C22H17N3O2 requires C, 74.4%; H, 4.8%; N, 11.8%. This compound was then sulfonated by treatment with 1.1 molar equivalents of chlorosulfonic acid in boiling chlorobenzene for one hour. The resultant precipitate was collected, rinsed with light petroleum, and treated with sodium hydroxide solution to give the sodium salt of 2,4-diphenyl-6-(2'-hydroxy-4'-methoxy-5'-sulfophenyl)-s-triazine. It was obtained in 87% yield after recrystallisation from 30% aqueous ethanol. Elemental analysis: C, 55.6%; H, 3.6%; N, 9.0%; S, 6.4%. C22H16N3O5SNa.1H2O requires C, 55.6%; H, 3.6%; N, 8.8%; S, 6.7%.
Reaction SMILES: [C:1]([N:5]1[C:17]2[C:16]3[N:15]=[C:14]([S:18][CH3:19])[N:13]=[CH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:7]([C:20]([O:22]CC)=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:26].[Li][N:28]([Si](C)(C)C)[Si](C)(C)C>C1COCC1>[C:1]([N:5]1[C:17]2[C:16]3[N:15]=[C:14]([S:18][CH3:19])[N:13]=[CH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:7]([C:20]([NH2:28])=[O:22])=[N:6]1)([CH3:2])([CH3:4])[CH3:3].[NH2:26][C:12]1[C:11]2[CH:10]=[CH:9][C:8]3[C:7]([C:20]([NH2:28])=[O:22])=[N:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:17]=3[C:16]=2[N:15]=[C:14]([S:18][CH3:19])[N:13]=1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: CCOC(=O)c1nn(C(C)(C)C)c2c1ccc1cnc(SC)nc12
Reactant: [NH4+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CSc1nc(N)c2ccc3c(C(N)=O)nn(C(C)(C)C)c3c2n1
Product: CSc1ncc2ccc3c(C(N)=O)nn(C(C)(C)C)c3c2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
Ethyl 1-tert-butyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (170 mg 0.494 mmol) was suspended in 4 ml of anhydrous THF and ammonium chloride (80 mg 1.48 mmol) was added. The reaction mixture was cooled to 0° C. and LiN(TMS)2 1M in THF (3 ml, 3 mmol) was added; the reaction was stirred for 2 hours. The solvent was then evaporated to dryness, the residue suspended in water and filtered. The crude was purified via silica gel column chromatography eluting with DCM/MeOH 97/3 to give 1-tert-butyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 100 mg (65% yield), and 6-amino-1-tert-butyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 10 mg (6%). LC/MS (254 nm) HPLC method 2 Rt 6.07 min. 1H NMR (401 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.42 (d, J=8.54 Hz, 1H), 7.80 (d, J=8.79 Hz, 1H), 7.75 (br. s., 1H), 7.53 (br. s., 1H), 2.74 (s, 3H), 2.00 (s, 9H). HRMS (ESI) calcd for C15H17N5OS [M+H]+ 316.1227 found 316.1224.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8](I)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:18]=[N+:19]=[N-:20])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1CC(I)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 4-iodo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (20 mmol, 1 equiv) in DMF was added NaN3 (2.5 equiv, 50 mmol), the resulting mixture was heated to 65 centigrade and stirred overnight. The mixture was diluted with water, extracted with AcOEt and dried over Na2SO4. After removal of solvent, the residue was purified by chromatography on silica gel to give title product (4.94 g) as colorless oil in 90% yield. MS m/e=271.5 [M+H]+.