Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].ClN([C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32](OC)[CH:33]=2)[N:28]=[CH:27][N:26]=1)C1C=CC=CC=1F.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[N:26]=[CH:25][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ncc2ccccc2n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
Trifluoromethanesulphonic anhydride (0.55 ml, 3.3 mmol) was added to a stirred suspension of 4-(chloro-2-fluoroanilino)-7-hydroxy-6methoxyquinazoline (959 mg, 3 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (2.2 ml) and pyridine (2.2 ml) under argon at 0° C. The reaction mixture was stirred for 1 hour at 0° C., allowed to warm to ambient temperature and stirred for a further 1.5 hours. The volatiles were removed by evaporation, the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether/petroleum ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(trifluoromethylsulphonyloxyquinazoline (270 mg, 60%) as a beige solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:9])[CH3:8].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[CH3:1][N:2]1[CH2:6][CH:5]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]1([CH3:9])[CH3:8]
Reactant: C1CCNC1
Reactant: CN1CCC(=O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CN1CC=C(N2CCCC2)C1(C)C
Temperature: 25 °C

Procedure:
1,2,2-Trimethylpyrrolidin-3-one (1.00 g) was dissolved in cyclohexane (5 mL). Pyrrolidine (1.31 mL) and p-toluenesulfonic acid monohydrate (7.48 mg) were sequentially added thereto, and the mixture was heated under reflux for 3 days, and allowed to cool to room temperature. The resultant mixture was concentrated under reduced pressure to thereby give a crude product of 1,2,2-trimethyl-3-(pyrrolidine-1-yl)-2,5-dihydro-1H-pyrrole (972 mg). To the product dissolved in dimethylformamide (10 mL), formamidine disulfide hydrochloride (1.20 g) was added, followed by stirring at room temperature for 4 days. The resultant mixture was concentrated under reduced pressure. Methanol (50 mL) and sodium carbonate anhydrate (20 g) were added to the residue, and the resultant mixture was stirred at room temperature for 1 hour. The insoluble material was removed through filtration, followed by washing with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (methanol methylene chloride=1:99→1:9), to thereby give the title compound (580 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)CCCN2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCCc4cc(C)ccc43)c2cc1OC
Yield: 94 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 94% yield from 6-methyl-1,2,3,4-tetrahydroquinoline (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 147°-148° C.; LC-MS: 336 (MH+); anal. RP18-HPLC RT: 4.51 min.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[CH3:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>>[CH3:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:16]=1[C:21](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:18]2=[O:19]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: Cc1cccc2c1C(=O)OC2=O
Product: COC(=O)C(CN1C(=O)c2cccc(C)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.39 g, 52%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.54 g, 2.86 mmol) and 3-methylphthalic anhydride (0.56 g, 3.44 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10](I)=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].[NH4+].[Cl-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1C#C[Si](C)(C)C
Temperature: 32 °C
Reaction time: 4 h

Procedure:
Under a stream of Ar the above prepared (5-iodo-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.913 g, 2.68 mmol) was dissolved in 17 mL of acetonitrile and treated successively with triethylamine (1.12 mL, 3 eq.), Cul (0.051 g, 0.1 eq.), (Ph3P)2PdCl2 (0.188 g, 0.1 eq.), and ethynyltrimethylsilane (1.11 mL, 3 eq.). The flask was closed with a septum and allowed to stir for 4 h at 32° C. The reaction mixture was then poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/ethyl acetate=85/15) gave finally 0.592 g of the title compound as light brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:19])[NH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:19])[N:16]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)[CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1noc2c1-c1cc[nH]c(=O)c1C(c1ccc(Cl)cc1)=NC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: Cc1noc2c1-c1ccn(-c3ccc(C#N)cc3)c(=O)c1C(c1ccc(Cl)cc1)=NC2
Temperature: 40 °C
Yield: 82.1 %

Procedure:
6-(4-Chlorophenyl)-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepin-7(8H)-one (0.025 g, 0.077 mmol), 4-cyanophenylboronic acid (0.023 g, 0.153 mmol), copper(II) acetate (0.035 g, 0.192 mmol) and pyridine (1 mL) were charged into a vial equipped with a stir bar. The reaction was heated to 40° C. for 3 h in an open vial (to allow contact with air) before silica gel was added. Then the pyridine was removed under vacuum. The dry silica gel was packed and the adsorbed product was purified by flash chromatography (hexane/EtOAc 19:1 to 4:6) to give 4-(6-(4-chlorophenyl)-1-methyl-7-oxo-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-8(7H)-yl)benzonitrile as an off-white solid (0.027 g). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=6.87 Hz, 1H), 8.02 (td, J=2.10, 8.24 Hz, 2H), 7.66 (td, J=2.10, 8.70 Hz, 2H), 7.49 (td, J=2.10, 8.47 Hz, 2H), 7.35 (td, J=2.30, 8.70 Hz, 2H), 6.84 (d, J=7.32 Hz, 1H), 5.26 (d, J=13.28 Hz, 1H), 4.18 (d, J=13.05 Hz, 1H), 2.56 (s, 3H); LC/MS m/z 427 [M+H]+.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.C[O-].[Na+].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][C:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1>C(#N)C>[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][C:21]2([C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:10][O:9]2)=[CH:17][CH:16]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 162 ml (2.2 moles) of dimethyl sulphide in 400 ml of absolute acetonitrile was added to a solution of 189 ml (2.0 moles) of dimethyl sulphate in 1,200 ml of absolute acetonitrile at room temperature. The reaction mixture was stirred overnight at room temperature. 118.8 g (2.2 moles) of sodium methylate were then added. The mixture was stirred for 30 minutes and a solution of 272 g (1.2 moles) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 600 ml of absolute acetonitrile was then added dropwise in the course of 30 minutes. The reaction mixture was subsequently stirred overnight. It was then concentrated, the residue was partitioned between water and ethyl acetate, the organic phase was separated off, washed twice with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated and the residue was distilled in vacuo. 242.4 g (84% of theory) of 2-(4-chlorophenoxymethyl)-2-tert.-butyl-oxirane of boiling point 115°-22° C./0.003 mm Hg column and of melting point 50°-52° C. were obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:21]([C:20]3[CH:24]=[CH:25][C:17]([I:16])=[CH:18][CH:19]=3)=[O:22])[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Yield: 90.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 161 and using 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (2.46 g) described in Preparation Example 53 and 4-iodobenzoyl chloride (3.36 g), the title compound (4.72 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5](=[O:12])[N:6]([CH2:8][O:9][CH2:10][CH3:11])[CH:7]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[C:14]([O:13][C:3]1[C:2]([Cl:1])=[CH:7][N:6]([CH2:8][O:9][CH2:10][CH3:11])[C:5](=[O:12])[CH:4]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOCn1cc(Cl)c(O)cc1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOCn1cc(Cl)c(OC(=O)c2ccccc2)cc1=O
Yield: 93 %

Procedure:
The general procedure of Example 49 was followed using 200 mg of 5-chloro-1-ethoxymethyl-4-hydroxy-2-pyridone, 0.14 ml of benzoyl chloride, 0.68 ml of triethylamine and 20 ml of dioxane, thereby producing 280 mg of the title compound in a yield of 93%.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[Li]CCCC.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[Br:7][C:5]1[CH:6]=[C:2]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:20])[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccccc1)c1cc(Br)cs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,4 dibromothiophene (3 g, 12.4 mmol) was dissolved in Et2O (50 mL) and cooled to −78° C. BuLi (1.6 M in hexanes)(8.1 mL, 13 mmol, 1.05 eg) was added dropwise over 20 min. then the yellow solution was stirred at −78° C. for 1 hour. Benzaldehyde (1.45 g, 13.64 mmol, 1.1 eg) dissolved in Et2O (15 mL) was added dropwise at a rate to maintain internal temperature <−70° C., then reaction mixture was allowed to warm slowly to 0° C. Quenched with Sat NH4Cl (50 mL) and phases partitioned. Organic fraction was washed with brine, dried, concentrated. Residue was chromatographed with 10% EtOAc/hexane to yield the title compound as a pale yellow solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24]Cl)[CH2:18][CH2:17]1.[OH-].[Na+].C(Cl)(Cl)Cl>CCCCCC>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][S:1][C:2]2[NH:6][C:5]3[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=3[N:3]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Reactant: CN1CCN(CCCCl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc(SCCCN3CCN(C)CC3)[nH]c2cc1C
Yield: 0.1 %

Procedure:
2-[3-(4-Methylpyperazino)propylthio]-5,6-dimethylbenzimidazole (XVII) and its trihydrochloride were synthesized as described above. The reaction of 2,8 g (0,010 mol) 2-mercapto-5,6-dimethylbenzimidazole and 3,74 g (0,015 mol) 3-(4-methylpyperazino)propylchloride dihydrochloride in the presence 1,32 g (0,033 mol) sodium hydroxide gave in 79% yield (2,5 g) compound XVII, m.p. 116-118° C. (with decomp., from chloroform with hexane). 1H NMR (CDCl3), δ: 1,95 (2H, m, CH2CH2CH2); 2,31 (6H, s, 2CH3); 2,35 (3H, s, CH2N); 2,54 (10H, broad m, 8H of pyperazine, 2H, t, CH2S); 3,22 (2H, t, CH2N); 7,50 (2H, broad s, ArH). Trihydrochloride of XVII, yield 78%, m.p. 228-231° C. (with decomp., from ethanol).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([OH:17])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([O:17][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:15]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: BrCCCc1ccccc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2OCCCc2ccccc2)cc1
Yield: 18.4 %

Procedure:
A solution of methyl 1-{4-[(ethylamino)carbonyl]phenyl}-5-hydroxy-1H-1,2,3-triazole-4-carboxylate (580 mg, 2 mmol) obtained in Example 1211a), (3-bromopropyl)benzene (438 mg, 2.2 mmol, 1.1 eq.) and potassium carbonate (332 mg, 2.4 mmol, 1.2 eq.) in DMF (5 ml) was stirred at 90° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform (20 ml), washed with water (10 ml×2) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (150 mg, 18%).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][O:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[C:1](=[O:8])[CH2:2][O:3][CH2:4][C:5]1=[O:7]
Reactant: O=C1COCC(=O)O1
Reactant: NCCCO
Product: O=C1COCC(=O)N1CCCO

Procedure:
A solution of diglycolic anhydride (2.32 g, 2/mmol) in 3-amino-1-propanol (6 ml) was refluxed a 180° C. for 3 hours. The volatiles were removed by evaporation a nd the residue was purified by column chromatography on silica eluting with methylene chloride/methanol (8/2) to give 4-(3-hydroxypropyl)-3,5-dioxomorpholine (3(46 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23].C(O)(=O)C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CCNC1
Reactant: CCI
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 8: 3-(3-chloro-5-fluorophenyl)pyrrolidin-3-ol (0.30 g, 1.4 mmol), acetonitrile (20 mL), sodium carbonate (0.19 g, 3.5 mmol), iodoethane (0.22 g, 1.4 mmol). Yield: 0.17 g. The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 169-170° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 8), 228 (7), 157 (7), 129 (7), 72 (30), 71 (bp).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[Cl:7][CH2:8][C:9](=O)[CH2:10][C:11](OCC)=[O:12]>>[Cl:7][CH2:8][C:9]1[N:6]=[C:2]2[S:1][CH:5]=[CH:4][N:3]2[C:11](=[O:12])[CH:10]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1nccs1
Product: O=c1cc(CCl)nc2sccn12

Procedure:
The intermediate 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one was prepared from 2-thiazolamine and ethyl 4-chloroacetoacetate by the procedure described in EXAMPLE 1. The m.p. was 132°-136° C., and the structure was confirmed by NMR and IR.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([N:16]3[C:20]([CH3:21])=[N:19][N:18]=[N:17]3)[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:22][CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.[ClH:44]>CO.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:44].[F:32][C:30]([F:31])([F:33])[C:28]1[CH:29]=[C:24]([CH2:23][O:22][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:15][C@H:14]3[N:16]2[C:20]([CH3:21])=[N:19][N:18]=[N:17]2)[CH:25]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:27]=1
Reactant: Cc1nnnn1[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cc1nnnn1[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(5-methyl-1H-tetrazol-1-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 110; 134 mg, 0.22 mmol) was dissolved in methanol (10 ml) and hydrochloric acid (2N) (1 ml) and 10% palladium hydroxide (50 mg) added and the mixture hydrogenated at 40 psi overnight. The reaction mixture was then filtered and concentrated in vacuo. The oil was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics dried (MgSO4) and concentrated in vacuo. The solid was purified by flash column chromatography [5% methanol in dichloromethane]. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether to a solution in diethyl ether. The title compound was filtered off and dried in vacuo (32 mg, 26%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:21][C:22]([F:35])([F:34])[C:23]1[N:24]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:31]2[CH2:32][CH2:33][N:28]([C:25]3[S:26][CH:27]=[C:23]([C:22]([F:35])([F:21])[F:34])[N:24]=3)[CH2:29][CH2:30]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1csc(N2CCNCC2)n1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(C(F)(F)F)cs2)CC1)C(F)(F)F
Yield: 48 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(4-trifluoromethyl-thiazol-2-yl)-piperazine (Example 49(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a crystalline white solid (yield 48%). MS (m/e): 531.8 (M+H+, 100%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:10](=[O:11])[O:9][CH:8]1[CH2:12][CH:13]([O:25][C:26]([CH:28]([NH:33][C:34]([CH3:36])=[O:35])[CH2:29][C:30]([NH2:32])=[O:31])=[O:27])[CH2:14][CH:15]=[CH:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CO.[H][H]>[Pt]=O.[Pd].C(O)C>[CH3:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]([O:25][C:26]([C@@H:28]([NH:33][C:34]([CH3:36])=[O:35])[CH2:29][C:30]([NH2:32])=[O:31])=[O:27])[CH2:12][C@@H:8]1[O:9][C:10](=[O:11])[C@H:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCCCCC=CCC=CCC(CC1OC(=O)C1CCCCCC)OC(=O)C(CC(N)=O)NC(C)=O
Agent: O=[Pt]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(N)=O)NC(C)=O
Reaction time: 8 h

Procedure:
In this process of the second aspect of the invention, the starting esterastin may be dissolved in an organic solvent such as a lower alkanol, for example, methanol or ethanol which is inert to the reaction involved. To this solution is added an amount of a known hydrogenation catalyst such as platinum oxide or palladium metal. The amount of the catalyst may be 2~20% by weight of the starting esterastin. The reduction may carried out in a stream of hydrogen gas or in Parr-apparatus at ambient temperature for a period of time of 2 hours to 12 hours. Usually, it suffices that the catalytic reduction is carried out overnight. After the reaction is completed, the reaction mixture is filtered to remove the catalyst, and the filtrate is concentrated to dryness to afford a crude powder of tetrahydroesterastin.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([OH:20])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:21](O)[CH:22]=[CH2:23].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([O:20][CH2:23][CH:22]=[CH2:21])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=CCO
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)c1sc(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Yield: 66 %

Procedure:
To a solution of 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylic acid (0.20 g, 0.67 mmol), allyl alcohol (0.042 g, 0.73 mmol, 1.1 equiv) and DMAP (0.008 g, 0.07 mmol, 10 mol %) in CH2Cl2 (2 mL) was added EDCI.HCl (0.14 g, 0.73 mmol, 1.1 equiv). The CH2Cl2 mixture was stirred at room temp. for 3 d, diluted with CH2Cl2, washed with a 1N HCl solution (5 mL) and a saturated NaHCO3 solution (5 mL), dried (Na2SO4), and concentrated under reduced pressure to afford allyl 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylate (0.15 g, 65%) as a colorless oil: TLC (50% CH2Cl2/hexane) Rf0.63; 1H NMR (CDCl3) δ1.37 (s, 9H), 1.50 (s, 9H), 4.74 (ddd, J=5.5, 1.5, 1.5 Hz, 2H), 5.26 (dd, J=10.3, 1.5 Hz, 1H), 5.37 (dd, J=17.3, 1.5 Hz, 1H), 5.87-5.98 (m, 1H), 7.68, 9.35; 13C NMR (CDCl3) δ28.2 (3C), 31.8 (3C), 35.2, 64.9, 80.8, 104.9, 116.4, 118.1, 132.0, 145.6, 152.1, 164.0, 164.4
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[OH:8][CH:9]([CH2:15][NH:16][OH:17])[CH2:10][P:11](=[O:14])([OH:13])[OH:12]>C(O)=O>[CH:1]([N:16]([CH2:15][CH:9]([OH:8])[CH2:10][P:11](=[O:13])([OH:12])[OH:14])[OH:17])=[O:3]
Reactant: O=P(O)(O)CC(O)CNO
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN(O)CC(O)CP(=O)(O)O
Yield: 16 %

Procedure:
Formic acid (300 mg.) was added dropwise to acetic anhydride (330 mg.) with stirring and the mixture was stirred for half an hour. To this solution were added 2-hydroxy-3-(N-hydroxyamino)propylphosphonic acid (430 mg.) and then formic acid (0.5 ml.), and the mixture was stirred for 1.5 hours at ambient temperature and then evaporated to dryness under reduced pressure. The oily residue was dissolved in methanol (10 ml.) and adjusted to pH 6-7 with conc. aqueous ammonium hydroxide solution to give oily precipitates which was collected by decantation and pulverized by triturating with methanol to give monoammonium salt of 3-(N-formyl-N-hydroxyamino)-2-hydroxypropylphosphonic acid (80 mg.).