Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[H-].COCCO[Al+2].[H-].[OH:10][CH:11]([CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:12]#[C:13][C:14]1[N:19]=[C:18]([CH2:20][C:21]2[O:26][C:25](=[O:27])[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[OH:10][CH:11]([CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:12][CH2:13][C:14]1[N:19]=[C:18]([CH2:20][CH:21]([OH:26])[CH2:22][CH2:23][CH2:24][CH2:25][OH:27])[CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCC=CCC(O)C#Cc1cccc(Cc2cccc(=O)o2)n1
Agent: COCCO[Al+2]
Agent: [H-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCCC=CCC(O)CCc1cccc(CC(O)CCCCO)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium (bis) 2-methoxyethoxy-aluminum hydride (24 ml, 82 mmol) is dissolved in 150 ml dry toluene in a flame-dried, 500 ml 3-neck round bottom flask under nitrogen at 0° C. 6-[1-[6-(3-hydroxyl-5-undecen-1-ynyl)pyridinyl]methyl]pyran-2-one (5.83 g, 14 mmole), in 4×10 ml dry toluene, is added slowly dropwise to the reaction mixture at 0° C. The reaction is stirred 20 minutes at 0° C. and then an additional 7 hours at room temperature. The reaction is quenched by the careful addition of 3 ml water. The mixture is stirred vigorously overnight with 1×160 ml 0.5M sodium potassium tartrate. The mixture is extracted with 3×100 ml ethyl acetate. The combined organics are washed with 1×100 ml saturated sodium chloride and dried over magnesium sulfate. The organics are concentrated in vacuo to a crude amber oil (35 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:16]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(OCC(F)(F)C(F)F)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(OCC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Yield: 88.3 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)-1,3-oxazolidin-2-one (1.0 g, 2.49 mmol) in ethanol (10 ml) was added 8N aqueous sodium hydroxide solution (1.56 ml, 12.5 mmol) and the mixture was heated under reflux for 3 hrs. The reaction solution was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,3,3-tetrafluoropropyloxy)phenyl)-1-propanol (825 mg, 88%).
Reaction SMILES: [F:1][C:2]1[C:27]([F:28])=[CH:26][C:5]2[N:6]([CH2:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:25])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])=[N:8][C:4]=2[CH:3]=1.I[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([CH2:30][O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:7]2[N:6]([CH2:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:25])[C:5]3[CH:26]=[C:27]([F:28])[C:2]([F:1])=[CH:3][C:4]=3[N:8]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ICC1CCCC1
Reactant: N#Cc1ccc(Cn2c(-c3ccccc3O)nc3cc(F)c(F)cc32)c(F)c1
Product: N#Cc1ccc(Cn2c(-c3ccccc3OCC3CCCC3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 4-[5,6-difluoro-2-(2-hydroxy-phenyl)-benzoimidazol-1-ylmethyl]-3-fluoro-benzonitrile and iodomethyl-cyclopentane (CAS Reg. No. 27935-87-1). Off-white solid (51%). MS (Turbo Spray): m/z=462.2 (M+H).
Reaction SMILES: [N+](C1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1)([O-])=O.[OH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32](=O)[CH2:33][CH:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:35]2)=[CH:30][CH:29]=1>>[C:38]1([CH:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][C:28]([OH:27])=[CH:29][CH:30]=3)[O:35]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C1CC(c2ccccc2)Oc2cc(O)ccc21
Agent: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Oc1ccc2c(c1)OC(c1ccccc1)CC2

Procedure:
2-Phenyl-chroman-7-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(a) starting from 1.0 g of 7-hydroxy-flavanone. The product was purified by column chromatography using heptane-ethyl acetate (2:1) as an eluant. 1H NMR (400 MHz, CD3OD) δ: 7.41-7.28 (m, 5H), 6.86 (d, 1H, J 8.2 Hz), 6.32 (dd, 1H, J 8.2, 2.4 Hz), 6.29 (d, 1H, J 2.4 Hz), 5.00 (dd, 1H, J 9.9, 2.4 Hz), 2.84 (m, 1H), 2.64 (m, 1H), 2.15 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[CH2:13][N:12]([C@H](C3C=CC=CC=3)C)[CH2:11][C:10]2([F:23])[F:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:28]([O:27][C:25]([N:12]1[CH2:13][C@@H:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]2)[C:10]([F:22])([F:23])[CH2:11]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)CC2(F)F)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)CC2(F)F)CC1
Temperature: 25 °C
Reaction time: 44 h
Yield: 82.8 %

Procedure:
4-(R)-(1-Ethoxycarbonylcyclopropyl)-3,3-difluoro-1-[1-(S)-phenylethyl]pyrrolidine-(2.536 g, 7.842 mmol) was dissolved in dry dichloromethane (80 ml), and benzyl chloroformate (2.80 ml, 19.6 mmol) was added dropwise to the thus prepared solution which was cooled in an ice bath. The reaction solution was stirred at room temperature for 44 hours and then dichloromethane was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 2.294 g (82.8%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([OH:23])=O)[CH:4]=1.C(N(CC)CC)C.C1(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([N:45]=[N+:46]=[N-:47])=[O:23])[CH:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C(=O)O)cc1C2=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)c1c(OC)cc(C(=O)N=[N+]=[N-])cc1C2=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
9,10-Dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carboxylic acid (10 g) was suspended in dry DMF (130 ml) and cooled to 0° C. Triethylamine (3.89 g) was then carefully added, followed by a solution of diphenylphosphoryl azide (10.57 g) in dry DMF (20 ml). A yellow precipitate was generated during 12 hours stirring at room temperature. The precipitate was collected by filtration and washed with saturated sodium bicarbonate solution (1×100 ml) and water (5×100 ml). Drying in vacuo over silica gel yielded 9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carbonyl azide as a signal yellow powder. Decomposition point: 139° C.
Reaction SMILES: C([O-])(=O)C.[Na+].C1(C)C=CC(S(NN)(=O)=O)=CC=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:29][S:30](/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[O:42][CH3:43])(=[O:32])=[O:31])=[C:23]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:24]=1>O1CCCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:29][S:30]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[O:42][CH3:43])(=[O:32])=[O:31])=[C:23]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:24]=1
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1ccc(Cl)cc1S(N)(=O)=O
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1CCS(=O)(=O)Nc1ccc(Cl)cc1S(N)(=O)=O
Temperature: 180 °C
Yield: 44.3 %

Procedure:
Sodium acetate (64 mg, 0.78 mmol) and para-toluenesulfonhydrazide (145 mg, 0.78 mmol) was added to a solution of (E)-5-chloro-2-(2-(4-chloro-2-methoxyphenyl)vinylsulfonamido)benzenesulfonamide (85 mg, 0.19 mmol) in tetrahydrofuran (3 mL). The reaction mixture was heated at 180° C. for 15 min in a microwave reactor. The solids were removed by filtration, washed with tetrahydrofuran and the combined filtrates were evaporated. Purification by preparative HPLC gave 0.037 g (43% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:21][CH2:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(CCc2cc(C)ccc2C2=NC(C)(C)CO2)c1

Procedure:
The subtitle compound was prepared from the product of example 15 step (iii) (20 g) and 3-methoxybenzyl chloride (17.4 ml) by the method of example 15 step (iv). Purification was by chromatography eluting with 5-10% ethyl acetate in isohexane. Yield 20.53 g. MS: APCI(+ve): 324 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.[N:18]1[C:27]2[C:22](=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](O)=[O:29].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CCOC(C)=O.CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:28]([C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[N:24][CH:23]=2)[N:18]=1)=[O:29]
Reactant: NCc1cccc(Br)c1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(Br)c1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
To a stirring solution of 3-bromobenzylamine hydrochloride (77.5 mg, 0.345 mmol) in anhy. DMF (5 ml) was added triethylamine (51.8 ul. 0.345 mmol.), After 5 min, 2-[1,6]naphthyridinecarboxylic acid (40 mg, 0.229 mmol), 1-hydroxybenzotriazole hydrate (34.2 mg, 0.253 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (48.5 mg, 0.253 mmol) was sequentially added. The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aq. NaHCO3, dried over anhy. MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex:EtOAc=1:1 to pure EtOAc) afforded desired product as white solid (64 mg, 81%): m.p. 112-113° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].F[C:11](F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:11][O:8][C:1](=[O:9])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3]
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)[C@@H](O)CC(=O)O
Yield: 100 %

Procedure:
L-malic acid (10 g., 74.6 mmole) was placed in a 100 ml. round-bottom flask and cooled in an ice bath. Trifluoroacetic anhydride, TFAA, (25 ml.) was added to the flask and the suspension was stirred in the cold. Within 15 minutes a homogeneous solution was obtained. After stirring for 2 hours at a temperature of about 0° C., the TFAA and trifluoroacetic acid were removed by vacuum distillation at 0° C. The solid residue of L-malic anhydride trifluoroacetate represented by the formula ##STR84## was dissolved in 50 ml. of anhydrous methyl alcohol and the solution stirred at room temperature for 3.5 hours. The solvent was removed by evaporation to provide in 100% yield L-malic acid monomethyl ester melting at about 75° to about 79° C. After recrystallization from ethyl acetate-hexane the product melted at about 79° to about 80° C. [α]D20 =5.8±1° (C=9.5, methanol).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:32])[C:13]=2[NH:17][C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=2)[C:8]1=[O:33])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:32][C:12]1[C:13]([NH:17][C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:29])([F:30])[F:28])[CH:21]=2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:33])[N:7]([CH2:6][CH2:5][OH:4])[CH:16]=[CH:15]2
Reactant: CC(=O)OCCn1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Cc1ccc(F)c(C(F)(F)F)c1)Nc1c(Cl)ccc2c(=O)n(CCO)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with 2-(6-chloro-5-(2-(4-fluoro-3-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (80.0 mg, 0.000165 mol), potassium carbonate (34.2 mg, 0.000248 mol), methanol and 2 drops of water and the reaction was stirred for 20 minutes at room temperature. The reaction was filtered over sodium sulfate and celite and washed with methanol. The solvent was removed under reduced pressure and the residue purified by reverse phase preparative HPLC to afford the product as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH:25]([C:28]([O:30]C(C)(C)C)=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nnc(Cc2ccccc2)s1)c1ccc(C2CCC(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
85 mg of tert-butyl 4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexanecarboxylate (0.18 mmol, 1 eq.) are placed in 1 mL of dichloromethane. 1 mL of trifluoroacetic acid (13.46 mmol, 76 eq.) is added and the reaction medium is stirred for 3 hours at room temperature. The solvents are evaporated off and the residue is taken up in ethyl acetate and ethanol to give, after filtration, 30 mg of 4-[4-(5-benzyl[1.3.4]-thiadiazol-2-ylcarbamoyl)phenyl]cyclohexanecarboxylic acid.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3].O[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(Cl)CCl>C(Cl)Cl.C(Cl)Cl.CO.CN(C1C=CN=CC=1)C>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)NCc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 4-(methylsulfonamidomethyl)benzoic acid (0.4 g, 1.745 mmol) and benzyl 2-hydroxyacetate (0.290 g, 1.745 mmol) in a mixture of DCM and THF 1/1 (50 ml), EDC (0.334 g, 1.745 mmol) and DMAP (0.256 g, 2.094 mmol) were added in one portion. The reaction was stirred at RT for 3 hours. The solvent was removed under vacuum and the resulting crude was portioned between EtOAc and HCl 2N. The organic phase was separated, washed with brine and dried over Na2SO4. The solvent was removed under vacuum affording 2-(benzyloxy)-2-oxoethyl 4-(methylsulfonamido-methyl)benzoate (0.4 g, 1.060 mmol, 60.7% yield, MS/ESI+ 377.9 [MH]+). This product was employed in the following step without any further purification.
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: CCCCCC=CCC=CCC(CC1OC(=O)C1CCCCCC)OC(=O)C(CC(N)=O)NC(C)=O
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Pd]
Solvent: CCO
Solvent: CO
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: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>C(N(CC)CC)C>[S:6]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In 100 ml of triethylamine was dissovled 76 g (1.0 mole) of 1,3-propanediol, and 95 g (0.50 mole) of tosyl chloride was added to the solution, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 800 ml of dichloromethane was added to the residue. The resulting mixture was washed with 150 ml of water, 120 ml of 1N hydrochloric acid and 150 ml of water, successively, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography of silica gel (600 g), and eluted with dichloromethane-methanol (96:4). The desired fracticns were concentrated under reduced pressure to give 1,3-propanediol monotosylate as a colorless oily material. Yield 86.9 g (yield: 78%).
Reaction SMILES: [CH2:1]([S:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[C:7]([C:15](O)=[O:16])[C:6]1=[O:18])[CH3:2].C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>ClCCl>[CH2:1]([S:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[C:7]([C:15]([Cl:22])=[O:16])[C:6]1=[O:18])[CH3:2]
Reactant: CCSCn1c(=O)c(C(=O)O)cc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCSCn1c(=O)c(C(=O)Cl)cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.20 g (8.3 mmol) of 1-(ethylthiomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (80 mL), and 5.0 mL (60 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure, and thus 1-(ethylthiomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (80 mL), and 1.02 g (9.1 mmol) of 1,3-cyclohexanedione and 1.40 mL (10.0 mmol) of triethylamine were added to the above solution under ice cooling. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and 2.99 g of the title compound was obtained as a light yellow solid (yield: quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=3[N+:25]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O1CCC[CH2:31]1.C(OCC)(OCC)OCC>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=4[N:25]=[CH:31]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: NC(=O)c1sc(-n2cnc3ccc(C=O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of the 1.00 g (2.49 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b), 40 mL of saturated aqueous ammonium chloride solution and 40 mL of tetrahydrofuran was added 1 g of zinc powder. The mixture was stirred room temperature for 15 minutes, then another 1 g of zinc powder was added. The mixture was stirred at room temperature for 15 minutes, then 1 g of zinc powder was added, and the mixture was stirred at room temperature for 15 minutes until the organic layer became straw yellow in color. Subsequent manipulations were performed under nitrogen. The mixture was filtered, and the filtrate was partitioned between 30 mL of saturated ammonium chloride solution and tetrahydrofuran (1:1). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a reddish yellow solid. The solid was mixed with 40 mL of acetic acid and 0.82 ml, (4.98 mmole) of triethyl orthoformate, and the mixture was stirred at room temperature for 30 minutes, during which time the mixture became mostly homogeneous. The mixture was filtered and the filtrate was poured into 200 mL of water. The precipitate was collected by filtration, washed with water and air-dried to give 0.73 g of 4-(3-chloro-phenyl)-2-(6-formyl-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.2a) as a pink solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[CH:15]=1.CCN=C=NCCCN(C)C.[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:37]([S:41]([NH:44][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][C:16]=12)=[O:24])(=[O:43])=[O:42])([CH3:40])([CH3:39])[CH3:38]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: CC(C)(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (170 mg, 0.49 mmol) in dry DCM (10 mL) was added EDCI (288 mg, 1.5 mmol) followed by DMAP (0.18 g, 1.4 mmol) and stirring was continued at 25° C. for 2 h. To the reaction mixture was added tert-butyl sulfonamide (67 mg, 0.49 mmol) and the stirring was continued at 25° C. for 72 h. Reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with saturated aqueous KHSO4 solution followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by combiflash chromatography followed by re-crystallization from EtOH to afford (R)—N-(tert-butylsulfonyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide as white solid. MS (ESI): m/z 463.2 (M+H).