Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1>N1CCCCC1>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:2]2\[S:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[NH:4][C:3]\2=[O:11])=[CH:13]1
Reactant: O=C1CSc2ccccc2N1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2ccccc12

Procedure:
A solution of 2H-1,4-benzothiazin-3(4H)-one (1.65 g, 10 mmol) and indole-3-carboxaldehyde (1.45 g, 10 mmol) in piperidine (30 ml) was heated under reflux for 5 days. The solvent was removed in vacuo, ethanol (20 ml) was added to the residue and the solid was filtered off. This solid was boiled in ethanol (20 ml) and filtered hot to give a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=1>CN(C)C=O.Cl.C(N=C=NCCCN(C)C)C>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])[CH:21]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 53.8 %

Procedure:
To a solution of 150 mg of 3-(4-fluorophenyl)-1H-5-indazolecarboxylic acid produced in Production Example I-14 in 2.5 ml dimethylformamide were added a solution of 70 mg of 3-picolylamine in 0.5 ml dimethylformamide and 124 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (=WSC.HCl), and the mixture was stirred at room temperature for four days. After removing the solvent by distillation, the residue was dissolved in 25 ml of ethyl acetate. The mixture was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether, to give 109 mg of the title compound as pale yellow crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6][CH2:5]2.[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[C:10]([CH3:12])[CH:11]=3)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6][CH2:5]4)[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1
Reactant: Cc1cc(I)cc2c1N(C)C(=O)CC2
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Product: Cc1cc(Sc2cc([C@@]3(O)CCO[C@@H](C)C3)cs2)cc2c1N(C)C(=O)CC2
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1,8-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]tetrahydropyran in 60% yield as a foam;
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](O)(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>N1C=CC=CC=1>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])=[O:29])([OH:28])=[O:27]
Reactant: O=C(O)CCCCC(=O)O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2[C@]2(C(=O)CCCCC(=O)O)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 500 mg of guanosine in anhydrous pyridine was added adipic acid (5 mol eq) and bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOPDC) (1.0 mol eq.). The mixture was allowed to stir at room temperature for 18 h, then the solvent was removed in vacuo. The residue was added to 100 mL of ice-cooled water and the aqueous layer adjusted to pH 3.0 and then extracted three times with 60 mL of ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on a silica gel column and eluted with a mixture of chloroformethanol, whereupon the eluate was evaporated in vacuo.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C[O-].[Na+].[C:22](OCC)(=O)[CH3:23]>CO>[CH3:22][C:23]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 87 %

Procedure:
5.04 g. of 2-(theophyllin-7-yl)-acetamidoxime, 2.16 g. of sodium methylate and 10 cm3 ethyl acetate are heated under shaking and under pressure in 150 cm3 methanol at 100° C. for 8.5 hours. After processing 4.8 g. (87% yield) of 7-[(5-methyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. M.p.: 135°-136° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:14]OS(C3C=CC(C)=CC=3)(=O)=O)[O:13][C:9]=2[CH:8]=[C:7]([C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH:6]=1)([CH3:3])[CH3:2].Cl.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C>C1COCC1>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:26]([C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:10]3[CH2:11][CH:12]([CH2:14][N:37]([CH3:38])[CH3:36])[O:13][C:9]=3[CH:8]=2)=[O:34])=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CN(C)C)O2
Temperature: 50 °C
Yield: 9.8 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in THF (2 mL) was added dimethyl amine hydrochloride (190 mg) and triethylamine (0.4 mL). The mixture was heated at 50° C. for 2 days, then concentrated, and purified by reverse phase HPLC to give a white solid (6 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1 H) 7.25-7.32 (m, 1 H) 7.04 (s, 1 H) 6.90 (d, J=1.01 Hz, 1 H) 6.84 (d, J=2.27 Hz, 1 H) 5.03-5.14 (m, 1 H) 4.61-4.71 (m, 1 H) 3.81 (s, 3 H) 3.29 (dd, J=16.42, 9.35 Hz, 1 H) 2.75-2.92 (m, 2 H) 2.60-2.70 (m, 1 H) 2.47 (s, 6 H) 1.34 (d, J=6.06 Hz, 6 H); LCMS for C19H26N4O3 m/z 359.20 (M+H+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([OH:15])(C)C.C1(=O)OC(=O)C2=CC=CC=C12>C(O)(C)C>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:15])=[O:5]
Reactant: CC(C)O
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
Phthalamic acids have been prepared by addition of a solution of secondary amine in isopropanol at 78° C. to a phthalic anhydride/isopropanol slurry at 78° C. in a one to one phthalic anhydride/amine molar ratio with subsequent vacuum stripping of the solvent. This method utilizes isopropanol as the solvent for the reaction. Isopropanol, a secondary amine, reacts with phthalic anhydride to yield isopropyl mono ester of phthalic acid. At 78° C., as much as 40% of the product may be this ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.CO.[NH3:17]>>[Cl:1][C:2]1[CH:11]=[C:10]([NH2:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: N
Solvent: CO
Product: COc1ccc2nc(Cl)cc(N)c2c1
Temperature: 150 °C
Yield: 55 %

Procedure:
A suspension of 2,4-dichloro-6-methoxyquinoline (5.00 g, 22.0 mmol) in NH3 (g)/MeOH (saturated, 40 mL) was heated to 150° C. for 16 hours in a sealed tube. The solvent was removed in vacuo and the residue was diluted with MeOH (20 mL). The mixture was filtered off and the filtrate was concentrated to give the crude product, which was purified by column chromatography on silica gel (PE/EtOAc=2/1) to give 2-chloro-6-methoxyquinolin-4-amine (7.50 g, yield: 55%) as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH:30]4[CH2:32][CH2:31]4)=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:37])[CH:11]=1>>[CH:30]1([C:29]2[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[F:37])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=[C:27]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[CH2:32][CH2:31]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Product: C[C@H]1CN(c2ccc(C(=O)N3CCN(c4ncc(C(F)(F)F)cc4C4CC4)CC3)c(F)c2)S(=O)(=O)C1
Yield: 57.5 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (256 mg) described in Preparation Example 123 and by the reaction and treatment in the same manner as in Example 4, the title compound (164 mg) was obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>O>[Cl:1][S:2]([C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:8]([O:7][CH3:6])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc(C(=O)O)c1OC
Solvent: O
Product: COc1cc(S(=O)(=O)Cl)cc(C(=O)O)c1OC
Yield: 81.1 %

Procedure:
To a solution, cooled to -5° C., of 511.7 g (200 ml) of chlorosulfonic acid (ClSO3H) are slowly added 80 g of 2,3-dimethoxy benzoic acid. Then the temperature is allowed to rise to 15° C., the mixture is poured into a solution of water and ice, and the precipitate formed is filtered. Thus, 100 g (yield: 80%) of 5-chlorosulfonyl 2,3-dimethoxy benzoic acid are obtained [(IIb), Melting point: 157° C⟧
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1.[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]=[CH:16][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:7]=1
Reactant: Nc1ccc(Br)cc1Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Product: Brc1ccc2ncn(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 5-bromo-N1-phenylbenzene-1,2-diamine (650 mg, 2.47 mmol) in HC(OMe)3 (15 mL) was added TsOH.H2O (38 mg, 0.2 mmol). The mixture was stirred at 100° C. for 4 h. Upon completion, the reaction solution was concentrated, the residue was extracted with EtOAc and washed with water. The organic layer was concentrated to give the crude 6-bromo-1-phenyl-1H-benzo[d]imidazole which was used in next step without further purification. LCMS (m/z): 273.1/274.1 [M+H]+/[M+2H]+
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH2:12][C@H:11]1[C:14](O)=[O:15])=[O:9])([CH3:6])([CH3:5])[CH3:4].II.CO>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH2:12][C@H:11]1[CH2:14][OH:15])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 699 mg (18.48 mmol) sodium borohydride in 20 mL dry THF under nitrogen, was added 1.15 g (5.74 mmol) (S)-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester and the reaction was cooled to 0° C., 1.72 g (6.78 mmol) iodine in 10 mL dry THF was added dropwise over 30 minutes, the reaction mixture was allowed to warm to room temperature, and was heated under reflux for 19 hours. The mixture was cooled to room temperature and 25 mL MeOH was added dropwise over 15 minutes. After evaporation of the solvent, 30 mL KOH (1 M) was added and the mixture was stirred at room temperature for 2 hours. The aqueous phase was extracted with DCM (2×75 mL) and the combined organic layers were washed with saturated brine (3×50 mL), then dried over MgSO4. After filtration, the solvent was evaporated to give the desired product, which was used for the next step without further purification.
Reaction SMILES: O.NN.[C:4]1([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:16][CH2:15]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH2:19]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2cccc3ccccc23)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1CCN(c2cccc3ccccc23)CC1

Procedure:
0.17 ml (3.55 mmol) of hydrazine monohydrate is added slowly at room temperature to a solution of 1.14 g (2.96 mmol) of 2-{2-[4-(1-naphthyl)-1-piperazinyl]ethyl}-1H-isoindole-1,3(2H)-dione, prepared in step 1.1, in 15 ml of ethanol. The reaction mixture is then refluxed for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([OH:16])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N+:7]([O-:25])=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([OH:16])[CH:3]=1
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1Oc1n[n+]([O-])c(Cl)cc1O
Reaction time: 48 h
Yield: 22.6 %

Procedure:
135 mg (0.572 mmol) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 128) obtained in Example 1 and methylene chloride (6 mL) were mixed, 247 mg (purity 80%, 1.14 mmol) of m-chloroperbenzoic acid was added to the mixture and the resulting mixture was refluxed for 16 hours with stirring. The mixture was allowed to stand at room temperature for 2 days, the reaction mixture was poured in a saturated aqueous sodium-sulfite solution, and washed with methylene chloride. The aqueous layer was made acidic with hydrochloric acid, extracted with methylene chloride, then washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (YMC GEL, SIL60, 350/250 mesh, eluted with ethyl acetate) to obtain 32.6 mg (0.129 mmol, Yield: 22.6%) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol 1-oxide (Compound No. 129).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:65])[NH:5][C:6](=[O:64])[C@H:7]([CH2:58][C:59]1[N:63]=[CH:62][NH:61][CH:60]=1)[NH:8][C:9](=[O:57])[C@H:10]([CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:11][C:12](=[O:47])[C@H:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[NH:14][C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:67]([NH2:69])[CH3:68]>CO>[CH2:67]([NH:69][C:3](=[O:2])[C@@H:4]([CH3:65])[NH:5][C:6](=[O:64])[C@H:7]([CH2:58][C:59]1[N:63]=[CH:62][NH:61][CH:60]=1)[NH:8][C:9](=[O:57])[C@H:10]([CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:11][C:12](=[O:47])[C@H:13]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:35][CH:34]=1)[NH:14][C:15](=[O:31])[C@H:16]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:68]
Reactant: CCN
Reactant: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]cn1)NCc1ccccc1
Solvent: CO
Product: CCNC(=O)[C@@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]cn1)NCc1ccccc1

Procedure:
Nα -Butoxycarbonyl-Nim -benzyl-L-histidyl-O-benzyl-L-tyrosyl-O-benzyl-L-seryl-L-histidyl-D-alanine methyl ester, 0.3 g., (Example 18) is treated with 200 ml. of methanol and 5 ml. of ethylamine at room temperature for three days. The above named product is isolated after evaporation of the solvent and the chromatographing of the residue on a silica gel column with ten percent methanol in benzene; 0.21 g.; m.p. 83°-88° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl.N1C=CC=CC=1>[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:13](=[O:14])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.02 h
Yield: 97.4 %

Procedure:
To a solution of 4-isopropoxyaniline (9.06 g, 60.0 mmol) in DCM (120 mL) and pyridine (30 mL) was added 4-nitrophenyl chloroformate (10.9 g, 54.0 mmol) portionwise with stirring over ˜1 min with brief ice-bath cooling. After stirring at rt for 1 h, the homogeneous solution was diluted with DCM (300 mL) and washed with 0.6 M HCl (1×750 mL) and 0.025 M HCl (1×1 L). The organic layer was dried (Na2SO4) and concentrated to give the title compound as a light violet-white solid (16.64 g, 98%). 1H-NMR (300 MHz, CDCl3) δ 8.26 (m, 2H), 7.40-7.28 (m, 4H), 6.98 (br s, 1H), 6.87 (m, 2H), 4.50 (heptet, J=6.0 Hz, 1H), 1.33 (d, J=6.0 Hz, 6H). LC/MS (ESI): calcd mass 316.1, found 633.2 (2 MH)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1)=O.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+].O>CO>[CH2:18]([NH:26][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:7][CH:8]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cn2)c1
Reactant: NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc(-c2ccc(CNCCc3ccccc3)cn2)c1
Reaction time: 16 h

Procedure:
To a solution of 3-(5-formylpyridin-2-yl)benzamide (40 mg, 0.18 mmol) in MeOH (2.5 mL) was added phenethylamine (27 μL, 0.21 mmol). The mixture was stirred for 16 h before adding sodium borohydride (33 mg, 0.88 mmol). After 16 h water (1 mL) was added and the solvent removed in vacuo. Purification of the residue by column chromatography (0.5% NH3: 5% MeOH:DCM) gave the title compound: RT=2.32 min; m/z (ES+)=332.1 [M+H]+.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:30]C(=O)[O-])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH2:27][S:26](=[O:29])(=[O:28])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[ClH:1].[NH2:30][C@H:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20]3[CH2:27][S:26](=[O:29])(=[O:28])[CH2:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C([O-])NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CS(=O)(=O)C3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CS(=O)(=O)C3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
HCl in dioxane (4M, 2 mL) was added to a solution of 3-(4-chlorophenyl)-1-(4-(6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (58 mg, 0.11 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 4 hours, and the solvent was removed to afford (R)-2-amino-3-(4-chlorophenyl)-1-(4-(6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (47 mg, 100%). LCMS: 436.0 [M+H+] (APCI+).
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[O:9]=[C:7]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1
Reactant: CCCOc1ccc(/C=C(\CSC(C)=O)C(=O)O)cc1
Reactant: NCCC(=O)OCc1ccccc1
Product: CCCOc1ccc(/C=C(\CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1
Yield: 66 %

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-propoxyphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield=66% (purification by flash chromatography, eluent: ether/petroleum ether 65/35)-oil IR: 3280, 1740, 1690, 1645, 1620 cm-1 1H NMR (CDCl3 /TMS): 7.50 (s, 1H); 7.35 to 7.15 (m, 7H); 6.95 to 6.75 (m, 3H); 5.15 (s, 2H); 4.00 to 3.50 (m, 6H); 2.65 (t, 2H, J=6 Hz); 2.30 (s, 3H); 1.80 (m, 2H, J app.=8 Hz); 1.00 (t, 3H, J=8 Hz). Microanalysis: C25H29O5NS Calc. % C=65.91 H=6.42 N=3.07 Found. % C=65.80 H=6.38 N=2.91
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18](COCC[Si](C)(C)C)[CH:19]=3)[N:12]3[CH:28]=[CH:29][N:30]=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[N:12]3[CH:28]=[CH:29][N:30]=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Yield: 53 %

Procedure:
To a solution of 7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.191 g, 0.451 mmol) in 2.5 mL of DCM was added 2,2,2-trifluoroacetic acid (1.5 mL, 19.5 mmol) slowly at ambient temperature with stirring under an inert atmosphere. After 4 hours the reaction mixture was concentrated under reduced pressure and then allowed to dry on high vacuum over the weekend. The crude residue was taken up in 5 mL of 1M NaOH and stirred for 10 minutes before solid sodium chloride was added in sufficient amount to saturate the aqueous. The aqueous was then extracted with chloroform and then extracted with 10% MeOH in DCM (50 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was dissolved in DCM in preparation for silica gel chromatography and a short time later a large amount of precipitate was observed. This solid was collected by means of vacuum filtration and the solid was rinsed with DCM to afford 7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.070 g, 0.239 mmol, 52.9% yield). MS (apci) m/z=294.1 (M+H).
Reaction SMILES: [CH2:1]([CH:4]1[N:8]([CH2:9][CH3:10])[S:7](=[O:12])(=[O:11])[NH:6][C:5]1=[O:13])[CH2:2][CH3:3].[C:14]1([S:20][CH2:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CN(C=O)C>[C:14]1([S:20][CH2:21][N:6]2[C:5](=[O:13])[CH:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][CH3:10])[S:7]2(=[O:12])=[O:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC1C(=O)NS(=O)(=O)N1CC
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1CC
Yield: 73.5 %

Procedure:
A mixture of 4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3.7 g, 16.6 mmol), phenylthiomethyl chloride (2.9 g, 18.28 mmol) and tetrabutylammonium bromide (0.53 g, 3.1 mmol) suspended in toluene/DMF (90 ml/10 ml) was refluxed for 8 hours, cooled, and concentrated in vacuo. The residue was diluted with water, extracted with ether/ethyl acetate (500 ml, 1:1), and the organic layer was washed with water and brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 4.01 g of 2-phenylthiomethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =propyl; R3 =ethyl) as an oil.