Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]23[CH2:14][CH:13]4[CH2:15][C:9]([CH2:16][OH:17])([CH2:10][CH:11]2[CH2:12]4)[CH2:8]3)[O:6][CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C1COCC1.CN(C1C=CN=CC=1)C.O>[CH3:25][S:26]([O:17][CH2:16][C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:10]1)[C:7]([C:2]1([CH3:1])[O:3][CH2:4][CH2:5][O:6]1)([CH2:14]3)[CH2:8]2)(=[O:28])=[O:27]
Reactant: CC1(C23CC4CC2CC(CO)(C4)C3)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C23CC4CC2CC(COS(C)(=O)=O)(C4)C3)OCCO1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of [3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methanol (2.0 g, 8.47 mmol) obtained in step IV, in THF (35 mL) at ice bath temperature, was sequentially added triethylamine (3.5 mL, 25.4 mmol), DMAP (52 mg, 0.42 mmol), and methanesulfonyl chloride (0.97 mL, 12.7 mmol). After stirring the reaction mixture at the same temperature for 0.5 h, it was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain title compound [3-(2-Methyl-1,3-dioxolan-2-yl) tricyclo[3.3.1.03,7]non-1-yl]methyl methane sulfonate (2.4 g) in 90% yield as viscous liquid. m/z (M+1) 317. IR cm−1 2954, 1461, 1356, 1216, 1174, 1048, 756. 1H NMR (CDCl3) 300 MHz δ 4.15-3.90 (m, 4H), 3.00 (s 3H), 2.44-2.36 (m 2H), 1.89-1.79 (m, 2H), 1.78-1.42 (m, 8H), 1.29 (s, 3H). 13C NMR (CDCl3) 75 MHz δ 112.1, 76.3, 64.95, 64.9, 57.3, 46.6, 45.3, 44.9, 44.5, 42.9, 39.8, 36.9, 36.7, 36.3, 20.
Reaction SMILES: CC(NC1C([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)OC(CO)C(O)C1O)=O>C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+]>[CH:14]1[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=[C:12]([OH:11])[CH:13]=1
Reactant: CC(=O)NC1C(Oc2ccc([N+](=O)[O-])cc2)OC(CO)C(O)C1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
The method may be carried out in solution by first mixing a sample of a female fluid, such as 0.1 ml of saliva, with 0.1 ml of 0.1 M p-nitrophenyl-N-acetyl-β-d-glucosaminide dissolved in 0.1 M sodium citrate-citric acid buffer and 0.2 ml of 0.1 M sodium citrate buffer, pH 4.5. Then, after shaking until the reagents are mixed, the reagents are permitted to incubate for 30 minutes at room temperature, to allow the N-acetyl-β-glucosaminidase present in the saliva to hydrolytically act on the p-nitrophenyl-N-acetyl-β-d-glucosaminide to remove the p-nitrophenyl group therefrom and form p-nitrophenol. At the end of the incubation period, a second buffer consisting of 1.0 ml of 1.0 M sodium glycinate buffer, pH 10.3, is added to the reaction mixture to stop the hydrolytic activity and to develop the yellow color characteristic of p-nitrophenol at alkaline pH's. The absorbence of the reaction mixture is measured at 400 nm and compared to a standard absorbence curve prepared with solutions of known concentrations of p-nitrophenol at pH 10.3. In a similar manner other phenolic derivatives of N-acetyl-β-d-glucosamine may be used in the method. For instance 0.1 M 3,3-bis(p-hydroxyphenyl)phthalid-N-acetyl-β-d-glucosaminide may be substituted for p-nitrophenyl-N-acetyl-β-d-glucosaminide in the above described example. In that instance phenophthalein is the reaction product that is formed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])=[O:4].[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=[C:19]([CH3:27])[N:18]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]([NH:16][C:17]1[N:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=[C:19]([CH3:27])[N:18]=1)=[O:15])(=[O:12])=[O:11])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(OC(F)F)nc(N)n1
Solvent: C1CCOC1
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC(F)F)n1
Yield: 50 %

Procedure:
A solution of 6.2 g of 2-methoxycarbonyl-3-thienylsulfonylisocyanate in 50 ml of absolute tetrahydrofuran is stirred dropwise into a solution of 4.4 g of 2-amino-4-difluoromethoxy-6-methylpyrimidine in 80 ml of absolute tetrahydrofuran. During the course of this addition, the temperature of the reaction mixture rises from 20° to 26° C. After it has been stirred for another hour, the raction mixture is filtered and the filtrate is concentrated. The residue is crystallised from ethyl acetate, affording 5.3 g (50%) of N-(2-methoxycarbonyl-3-thienylsulfonyl)-N'-(4-difluoromethoxy-6-methylpyrimidin-2-yl)urea (compound 2.1) with a melting point of 178°-179° C.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[N:7]O)[CH2:5][C:4]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[O:3]1.COCCO[AlH2-]OCCOC.[Na+]>>[CH3:14][N:11]1[CH2:12][CH2:13][C:4]2([O:3][CH:2]([CH3:1])[CH:6]3[CH:5]2[NH:7]3)[CH2:9][CH2:10]1
Reactant: CC1OC2(CCN(C)CC2)CC1=NO
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Product: CC1OC2(CCN(C)CC2)C2NC12

Procedure:
The precursor amine compounds may in turn be prepared as described in greater detail below. Thus, for example, 2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane may be obtained by reaction of 4-aminomethyl-1-methyl-piperidin-4-ol with acetaldehyde in dry dichloromethane. 2,8-Dimethyl-1-oxa-4,8-diazaspiro[4.5]decane may be obtained by reaction of 1-amino-2-propanol with 1-methyl-4-piperidone under reflux. 1′,4-Dimethylspiro[3-oxa-6-azabicyclo[3.1.0]hexane-2,4′-piperidine] may be obtained by first preparing 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime from 1-methyl-4-piperidone via 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one per the procedure of Tsukamoto et. al., Chem. Pharm. Bull. 1995, 43, 842-852, followed by reduction of the oxime with Red-Al (sodium bis(2-methoxyethoxy)aluminumhydride) and then basic workup to yield 1′,4-Dimethylspiro[3-oxa-6-azabicyclo[3.1.0]hexane-2,4′-piperidine]. 2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]dec-3-ylamine may be obtained by first preparing 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime from 1-methyl-4-piperidone via 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one per the procedure of Tsukamoto et. al., Chem. Pharm. Bull. 1995, 43, 842-852, followed by reduction of the oxime with lithium aluminum hydride/aluminum chloride. Compounds of formula I may then be prepared from these amines by an appropriate coupling reaction.
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=[C:5](F)[N:4]=1>C(N)=O>[NH2:1][C:5]1[N:4]=[C:3]([F:2])[C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1ccc(F)nc1F
Reactant: N
Solvent: NC=O
Product: Nc1ccc(C(=O)OCc2ccccc2)c(F)n1
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a stirred solution of ammonia (15 g) in formamide (250 ml) was added all at once benzyl 2,6-difluoropyridine-3-carboxylate (20 g, 0.08 mole). The mixture slowly became homogeneous, then a solid began to separate. After two hours, the mixture was poured into water (1000 ml) and the solid filtered. The solid was washed with several portions of water then air dried. Continuous extraction for one hour via a Soxhlet extraction apparatus using hexane as the solvent gave, after concentrating to 250 ml and cooling, 6.0 g (30%) of the desired benzyl 2-amino-6-fluoropyridine-3-carboxylate: m.p.=92°-94° C. The hexane insoluble material was recrystallized from a small volume of acetone to give 5.5 g (28%) of the isomeric benzyl 6-amino-2-fluoropyridine-3-carboxylate: m.p.=157.5°-159.5° C.
Reaction SMILES: [BH4-].[Na+].C(N(CC)[C:6](=[O:17])[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:15]=[O:16])C>CO>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[C:6](=[O:17])[O:16][CH2:15]2
Reactant: CCN(CC)C(=O)c1c(C=O)cccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1C(=O)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
Solid sodium borohydride (14.02 g, 370.5 mmol, 1.75 equiv) was added in portions to a solution of N,N-diethyl-2-formyl-6-methoxy-benzamide (49.81 g, 211.7 mmol) in methanol (800 ml) at 0° C. After complete addition, stirring was continued at room temperature for 30 minutes, until TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to 0° C., and 6N aqueous HCl (134 ml) was carefully added. The solution was heated to 90° C. for 90 minutes. After cooling, volatiles were removed in vacuo. The residue was taken up in water (500 ml) and extracted four times with EtOAc (1.6 liter in total). The combined organic layers were washed with brine (2×100 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (33.92 g, 98%) in adequate purity for direct use in the next transformation. 1H NMR (400 MHz, CDCl3): δ=7.60 (t, J=8.4 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 5.22 (s, 2H), 3.98 (s, 3H). MS (ES+): 165 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: COCCN
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: COCCNc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 2-methoxyethylamine in DME. ES-MS m/e (%): 280 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]Br>>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)n1
Reactant: C[Mg]Br
Product: Cc1cccc(C(C)O)n1

Procedure:
Use a method similar to the Preparation 198 (Step 1), using 6-methyl-2-pyridinecarboxaldehyde and methylmagnesium bromide, to give the desired intermediate.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].[CH3:12][C:13]([C@@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])=[O:14]>>[CH3:1][C:2]([C@@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])=[O:3].[CH3:12][C@H:13]([C@H:15]([C@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]
Reactant: C[C@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Agent: CC(=O)[C@H](O)[C@H](O)[C@H](O)CO
Product: C[C@@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
As shown in FIG. 23, first, 6-deoxy L-psicose was prepared from L-rhamnose, using L-rhamnose isomerase and D-tagatose 3-epimerase (The Annual Meeting of the Japan Society of Bioscience, Biotechnology and Agrochemistry 2007). As a consequence of the hydrogenation with a nickel catalyst under high-pressure conditions, a mixture of 1-deoxy D-allitol (6-deoxy-L-allitol) and 1-deoxy D-talitol (6-deoxy-L-tallitol) was obtained (FIGS. 24 and 26). The mixture as a substrate was subjected to a bacterial cell reaction with the bacterial strain IK7 (NITE BP-271) of the genus Enterobacter (FIGS. 25 and 27). Consequently, only 1-deoxy D-allitol was selectively oxidized to 1-deoxy D-psicose. Almost no reduction of the total weight of both the substrates with the bacterial strain IK7 of the genus Enterobacter was observed. The productivity of 1-deoxy D-psicose from 1-deoxy D-allitol was about 90%. The reaction products were separated from each other. Consequently, 1-deoxy D-psicose and 1-deoxy D-talitol were obtained individually as pure products. A photograph of the crystal of the resulting 6-deoxy L-psicose is shown in FIG. 28. The product was identified by comparison with the chemically synthesized 1-deoxy D-psicose and confirmed on the basis of the coincidence of the 13C NMR spectra (FIG. 29) of the two and the optical rotation degrees of the two.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19].O>CN(C)C=O.C(O)(=O)C>[CH2:19]([CH:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:18]=[CH2:17]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OCC)C(=O)c1ccccc1
Yield: 84.1 %

Procedure:
Ethyl benzoylacetate (6 grams) is dissolved in 40 ml of dimethyl formamide and 1.5 grams of sodium hydride is added thereto with ice cooling and stirring. Ten minutes thereafter, 4 grams of allyl bromide is added thereto, the mixture is stirred at room temperature for one hour, and poured into water. The mixture is neutralized with acetic acid, and extracted with ether. The ether extract is washed with water, dried with anhydrous magnesium sulfate, and ether is evaporated therefrom to give 6.1 grams of colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:9][Cl:10])=[O:6].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.C(OCC)(=O)C.CCCCCC>CN(C=O)C.O>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:9][Cl:10])=[O:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C(OCCCl)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCl)c1
Reaction time: 8 h

Procedure:
To a solution of 2-chloroethyl 3-hydroxybenzoate (4.0 g, 0.02 mol) and tert-butyldimethylsilyl chloride (4.5 g, 0.029 mol) in 5 mL of dry DMF was gradually added imidazole (92.7 g, 0.04 mol). The solution was then stirred overnight. TLC analysis (silica gel, 20% ethyl acetate/hexane) showed clean conversion to a new material. The solution was poured into a 25 mL of water and extracted with 3×25 mL of ether. The combined ether solutions were dried over anhydrous MgSO4. Evaporation of the solvent gave an oil which was chromatographed on silica using 10% ethyl acetate/hexane to give the product quantitatively as a colorless liquid: 1H NMR (CDCl3) δ 0.218 (s, 6H), 0.994 (s, 9H), 3.81 (t, 2H, J=5.7 MHz), 4.56 (t, 2H, J=5.7 MHz), 7.05-7.65 (m, 4H); 13C NMR (CDCl3) δ -4.97, 17.66, 25.12, 41.06, 63.91, 120.61, 122.19, 124.60, 128.95, 130.53, 155.31, 165.35; MS m/e (rel intensity) 314 (14), 257 (9), 235 (9), 213 (100), 185 (6) 149 (7), 135 (10), 120 (6), 93 (13), 83 (6), 69 (9), 55 (9); Exact mass: calcd 314.1104, found 314.1110. ##STR28##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1F
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: O=c1[nH]ccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To a mixture of 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (50.0 mg) and sodium iodide (35.5 mg) in acetonitrile (3 mL) was added chloro(trimethyl)silane (0.0760 mL) at room temperature, and the mixture was stirred at 50° C. for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (36.5 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1.[OH:25]C(CCCCC)/C=C/C1N(CCCCCCC(O)=O)C(=O)CS1>>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1=[O:25]
Reactant: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Reactant: CCCCCC(O)/C=C/C1SCC(=O)N1CCCCCCC(=O)O
Product: CCCCCC(O)/C=C/C1N(CCCCCCC(=O)O)C(=O)CS1=O

Procedure:
This compound is prepared essentially by the method as described in Example 2 except that the 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid is replaced by 7-[2-(3-hydroxy-1-trans-octenyl)-4-oxo-3-thiazolidinyl]-heptanoic acid. This method affords the title compound as a viscous, essentially colorless oil after purification by column chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1)([CH2:5][CH:6]([C:11](=[O:27])[NH:12][CH:13]([C:23](=[O:26])[NH:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][P:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1)([CH2:5][CH:6]([C:11](=[O:27])[NH:12][CH:13]([C:23](=[O:26])[NH:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(N)c1)OC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(NCc2ccccc2)c1)OC
Yield: 74.7 %

Procedure:
(3-Aminobenzyl){2-[2-(4-methoxyphenyl)-1-methylcarbamoyl ethylcarbamoyl]-4-methylpentyl}phosphinic acid methyl ester (prepared as described in Example 4/Step A) (150 mg, 0.30 mmole), benzaldehyde (38 mg, 0.36 mmole), sodium cyanoborohydride (23 mg, 0.357 mmole) and acetic acid (1 drop) in methanol were stirred at room temperature for 3 hours. The reaction was quenched with 1N hydrochloric acid (few ml's) and the reaction mixture concentrated. The residue was dissolved in ethyl acetate (20 ml) and washed with 1N hydrochloric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and dried with magnesium sulfate. Filtration and concentration gave the crude product which was purified by chromatography (3:97--methanol:methylene chloride) yielding 133 mg (75%) of (3-Benzylamino benzyl)-{2-[2-(4-methoxyphenyl)-1-methylcarbamoylethylcarbamoyl]-4-methylpentyl}phosphinic acid methyl ester as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:17]([C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][N:46](C)[C:47](=O)OC(C)(C)C)=[CH:41][C:40]=3[CH3:55])[CH:35]=2)=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=O)(C)(C)C>ClCCl>[CH:31]([S:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[N:18]=[C:17]([C:34]3[O:38][N:37]=[C:36]([C:39]4[CH:44]=[CH:43][C:42]([CH2:45][NH:46][CH3:47])=[CH:41][C:40]=4[CH3:55])[CH:35]=3)[C:16]([NH2:15])=[N:21][CH:20]=2)=[CH:27][CH:26]=1)(=[O:29])=[O:30])([CH3:33])[CH3:32]
Reactant: Cc1cc(CN(C)C(=O)OC(C)(C)C)ccc1-c1cc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)on2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
TFA (556.9 mg, 376.3 μL, 4.884 mmol) was added to a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]-3-methyl-phenyl]methyl]-N-methyl-carbamate (190 mg, 0.2442 mmol) in dichloromethane (4.750 mL) and the resulting yellow solution stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue taken up in methanol (2 mL) and dichloromethane (1 mL) and passed through an SCX cartridge and the product eluted with 2M ammonia in methanol and concentrated in vacuo. The filtrate was purified further by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were collected and lypholised to give the product as a yellow solid (96.4 mg, 69% yield); 1H NMR (400.0 MHz, DMSO) d 1.18 (d, 6H), 2.61 (s, 3H), 2.62 (m, 3H), 3.48 (m, 1H), 4.20 (m, 2H), 7.24 (br s, 2H), 7.48-7.52 (m, 2H), 7.63 (s, 1H), 7.84 (m, 1H), 7.93 (m, 2H), 8.37 (m, 2H), 8.81 (br s, 2H) and 8.97 (s, 1H) ppm; MS (ES+) 478.3
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: C(O)(C)C.Cl[C:6]1[C:7]2[C:14]3[CH2:15][CH2:16][C:17]4([CH2:22][C:13]=3[S:12][C:8]=2[N:9]=[CH:10][N:11]=1)[O:21][CH2:20][CH2:19][O:18]4.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1)[NH2:27].Cl>O1CCOCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:6]2[C:7]3[C:14]4[CH2:15][CH2:16][C:17]5([CH2:22][C:13]=4[S:12][C:8]=3[N:9]=[CH:10][N:11]=2)[O:21][CH2:20][CH2:19][O:18]5)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1
Reactant: Clc1ncnc2sc3c(c12)CCC1(C3)OCCO1
Reactant: Cc1cccc(COc2ccc(N)cc2Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCC3(C5)OCCO3)cc2Cl)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To isopropanol (80 mL) was sequentially added 4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane] (5.5 g, 19.4 mmol), 3-chloro-4-[(6-methylpyridin-2-yl)methoxy]aniline (4.61 g, 18.5 mmol), and 4N HCl in dioxane (0.8 mL). The suspension was stirred with heating to 80° C., upon which time the contents turn brown and homogeneous. After 8 h, the heterogeneous mixture was removed from heating, and allowed to cool to rt. The resultant precipitate was collected by filtration as a light-brown solid (5.67 g, 81%), which was used without further purification. 1H-NMR (DMSO-d6) δ 8.35 (s, 1H), 8.16 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.51 (dd, 1H), 7.34 (d, 1H), 7.21 (m, 1H), 7.19 (d, 1H), 5.21 (s, 2H), 3.97 (s, 4H), 3.26 (t, 2H), 3.01 (s, 2H), 2.48 (s, 3H), 1.95 (t, 2H); LCMS RT=2.78 min; [M+H]+=495.2.