Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].CO.[Li+].[BH4-].CO.[F:9][C:10]1[C:11]2[O:36][N:35]=[C:34]([C:37](OCC)=[O:38])[C:12]=2[CH:13]=[C:14]2[C:27]=1[N:26]1[CH2:28][C@@H:29]([CH3:33])[O:30][C@@H:31]([CH3:32])[C@@H:25]1[C:16]1([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18][C:17]1=[O:24])[CH2:15]2>C1COCC1.O>[F:9][C:10]1[C:11]2[O:36][N:35]=[C:34]([CH2:37][OH:38])[C:12]=2[CH:13]=[C:14]2[C:27]=1[N:26]1[CH2:28][C@@H:29]([CH3:33])[O:30][C@@H:31]([CH3:32])[C@@H:25]1[C:16]1([C:17](=[O:24])[NH:18][C:19](=[O:23])[NH:20][C:21]1=[O:22])[CH2:15]2
Reactant: CCOC(=O)c1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN2c3c(cc4c(CO)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Lithium borohydride (0.434 ml, 0.87 mmol) was added to an ice cooled solution of methanol (0.035 ml, 0.87 mmol) in THF (10 ml). The solution was warmed to room temperature and stirred for 1 hour. 1.5 ml of the LiBH4/MeOH solution was added to a solution of (2R,4S,4aS)-rel-ethyl 11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-2,2′,3′,4,4a,4′,6,6′-octahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-8-carboxylate (Example 134, 30 mg, 0.07 mmol) in 5 ml of THF. The reaction was stirred at room temperature of 1 hour. The reaction was diluted with water and extracted with ethyl acetate 2×. The organic layers were washed twice with brine, dried over MgSO4 and concentrated. The residue was purified by HPLC (Acetonitrile (5 to 50%)/Water with a TFA modifier over 10 minutes). Freeze dried for 48 hours to give the title compound (22 mg, 0.053 mmol, 81%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:30]=[CH:29][C:19]2[S:20][C:21]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:22][C:18]=2[CH:17]=1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:30]=[CH:29][C:19]2[S:20][C:21]([C:23]3[CH2:24][CH2:25][N:26]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH:28]=3)=[CH:22][C:18]=2[CH:17]=1
Reactant: Clc1ccc2sc(C3=CCNCC3)cc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2cc3cc(Cl)ccc3s2)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.075 g, 0.042 mmol), and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.100 g, 0.042 mmol) using ethanol as reaction solvent. Yield 0.103 g (58%) of an orange oil. FDMS m/e=438 (M+ of free base). α[D]589 =+7.3 (c=0.95, dimethylsulfoxide)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)(=[O:11])=[O:10].Cl.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[CH:32]([CH3:35])[CH2:33][NH2:34].ClC1C=C(Cl)C=CC=1CC#N>>[Cl:22][C:20]1[CH:19]=[CH:18][C:14]([C:15]([NH:34][CH2:33][CH:32]([C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[Cl:24])[CH3:35])=[O:17])=[C:13]([NH:12][S:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:10])=[O:11])[CH:21]=1
Reactant: CC(CN)c1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F
Agent: Cl
Agent: N#CCc1ccc(Cl)cc1Cl
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 2-(2,6-difluoro-benzenesulfonylamino)-4-chloro-benzoic acid and 2-(2,4-dichloro-phenyl)-propylamine hydrochloride (prepared as in EXAMPLE 5, substituting 2,4-dichlorophenyl-acetonitrile in Part A) as in Example 1, Part C. HPLC: RT=11.20 min. MS (ESI−): mass calcd. for C22H17Cl3F2N2O3S, 533.8; m/z found, 533 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.62 (s, 1H), 7.73 (d, J=1.9, 1H), 7.52-7.45 (m, 1H), 7.40 (d, J=1.8, 1H), 7.28-7.25 (m, 2H), 7.18 (d, J=8.5, 1H), 7.01-6.96 (m, 3H), 6.05 (br m, 1H), 3.76-3.70 (m, 1H), 3.68-3.57 (m, 1H), 3.57-3.49 (m, 1H), 1.32 (d, J=6.8, 3H).
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[OH:4][CH2:5][CH:6]([CH2:8][OH:9])O>O>[OH:9][CH2:8][CH2:6][CH:5]=[O:4].[CH:1](=[O:3])[CH3:2].[CH2:1]=[O:3]
Reactant: OCC(O)CO
Agent: CC=O
Solvent: O
Product: C=O
Product: O=CCCO

Procedure:
It is known that acetaldehyde is obtained with a yield of 26% in the dehydration of glycerol in supercritical water at 500° C. and 34.5 MPa and with a residence time of 90 s [Ant1985]. A free radical mechanism by dehydration of the glycerol to 3-hydroxy-propionaldehyde and homolytic cleavage of this intermediate to give acetaldehyde and formaldehyde is assumed for the stated conditions. An alternative mechanism via homolytic cleavage of acetol can be ruled out. The selectivity with respect to acetaldehyde is lower under near-critical water conditions at 360° C. and the same conditions. Addition of sodium hydrogen sulphate as acidic catalyst merely leads to an increase in the yield of acrolein, which presumably results from the acid-catalysed dehydration of 3-hydroxypropionaldehyde.
Reaction SMILES: C[O:2][C:3]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[C:4]=1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(O)(=O)C.Br>[OH:2][C:3]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[C:4]=1[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1c(CC(=O)O)cc2ccoc2c1C(=O)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cc2ccoc2c(C(=O)c2ccccc2)c1O
Reaction time: 1 h

Procedure:
6-Methoxy-7-benzoylbenzofuran-5-ylacetic acid (5.0 g) was heated at reflux in a mixture of acetic acid (50 ml) and 48% hydrobromic acid (50 ml). After the reaction was completed, approximately 1 hour, the cooled solution was added to 400 ml of water which was then extracted with ethyl acetate. The combined organic extracts were washed four times with water, dried with sodium sulfate and evaporated to give 6-hydroxy-7-benzoylbenzofuran-5-ylacetic acid.
Reaction SMILES: ON1[C:6](=[O:7])[C:5](N2C(=O)CCC2=O)=[C:4]([CH2:15][C:16]2(NC(=O)CCCCC)CCCC[C:17]2([NH:30]C(=O)CCCCC)NC(=O)CCCCC)C1=O.CN(C)C=[O:50]>>[NH2:30][CH2:17][CH2:16][CH2:15][CH2:4][CH2:5][C:6]([OH:7])=[O:50]
Reactant: CN(C)C=O
Reactant: CCCCCC(=O)NC1(CC2=C(N3C(=O)CCC3=O)C(=O)N(O)C2=O)CCCCC1(NC(=O)CCCCC)NC(=O)CCCCC
Product: NCCCCCC(=O)O

Procedure:
An N-hydroxysuccinimidyltricaproamidocyclohexylmethylmaleimide, a compound having the structure of FIG. 14 of the attached drawings where Z has the structure of FIG. 3, Z' has the structure of FIG. 11, n is 3, and C6H10 is 1,4-cyclohexyl, was then produced from a solution of 100 mg N-hydroxysuceinimidyldicaproamidocyclohexylmethylmaleimide in 2 ml dry dimethylformamide, 23.4 mg 6-aminocaproic acid and 40.5 mg dicyelohexylearbodiimide. A nitrogen atmosphere was established in a flask above the N-hydroxysuccinimidyldicaproamidocyclohexylmethylmaleimide solution, and the 6-aminocaproie acid was added to the flask. The reaction mixture was then stirred under nitrogen at room temperature of about 22° for 16 hours, after which time the dieyclohexylcarbodiimide was added to the flask. Stirring at room temperature was continued for an additional 6 hours, after which time dicyclohexylurea which had precipitated was removed from the reaction mixture by filtration, and the dimethylformamide was evaporated under reduced pressure from the filtrate. A tacky solid which remained was purified by flash chromatography on silica gel (10v/v methanol in chloroform), yielding 60 mg of the N-hydroxysuccinimidyltricaproamidocyclohexylmethylmaleimide, a white solid which has the indicated formula.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[NH:13][C@H:12]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)(C)(C)C.C1COCC1>Cl.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[NH:13][C@H:12]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The crude, wet product of Example 3a was slurried in 1N HCl (192 mL) and the slurry was heated to 70° C. with stirring. After 1 hour, THF (100 mL) was added and stirring at 65° C. was continued for 4 hours. The mixture was then allowed to cool to 20–25° C. and was stirred overnight at 20–25° C. The THF was removed by evaporation under vacuum and the resulting aqueous solution was cooled to about 5° C., causing some precipitation to occur. The aqueous mixture was adjusted to pH 7 by addition of 50% aqueous sodium hydroxide (about 18.3 g). The resulting mixture was extracted with ethyl acetate (2×100 mL) at about 15° C. The combined organic extracts were washed with 100 mL of brine and the organic layer was separated and stirred with sodium sulfate (5 g) and Darco G-60 (3 g). This mixture was warmed on a hot plate for 1 hour at 45° C. The hot mixture was then filtered through a bed of diatomaceous earth and the filter pad was washed with ethyl acetate (100 mL). The filtrate was evaporated under vacuum to provide an oil. The oil was redissolved in methylene chloride (300 mL) and the solvent was evaporated under vacuum. The resulting oil was dried at room temperature under vacuum to provide the desired product (18.4 g) as a glassy syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:18][CH2:19][C:20]1[N:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1)(=[O:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:15]([O:18][CH2:19][C:20]1[N:25]=[CH:24][C:23]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:22][CH:21]=1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CC(=O)OCc1ccc(O)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cn1
Yield: 86.2 %

Procedure:
A sample of (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (1.64 g, 8.18 mmol, prepared as in Example 15a above) and 1.05 g (6.29 mmol) of 6-acetyloxymethyl-3-hydroxypyridine, prepared as described by Deady and Dayhe, Aust. J. Chem., 2565:36 (1983), were reacted with triphenylphosphine and DEAD (8.18 mmol each) in 25 mL of THF according to the procedure of Example 14a. Workup gave 1.90 g of title compound. MS (DCI/NH3) m/e: 309 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32-8.28 (m, 1H), 7.33-7.25 (m,.2H), 5.15 (s, 2H), 4.30-3.90 (m, 2H), 3.65-3.25 (m, 3H), 2.13 (s, 3H), 2.10-1.80 (m, 3H), 1.49 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N[C:13]1C=CC(Cl)=NC=1>>[CH3:13][NH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: Nc1cncc(C(F)(F)F)c1
Product: CNc1cncc(C(F)(F)F)c1

Procedure:
The reaction procedure of Reference Example 24 was repeated except that 3-amino-5-trifluoromethylpyridine was used in lieu of 5-amino-2-chloropyridine to obtain the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32](Cl)=[O:33])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32](=[O:33])[NH:15][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:14]=[CH:13][N:12]=2)[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1-c1cc(N)ncn1
Reactant: O=C(Cl)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1-c1cc(NC(=O)[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (5.80 g, 28.5 mmol) in 60 ml of dichloromethane was added 4-dimethylaminopyridine (4.16 g, 34.2 mmol) followed by dropwise addition of (R)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXIX) (8.00 g, 28.5 mmol) at room temperature. The reaction mixture was stirred for 2 hours and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated. The obtained crude residue was passed through a pad of silica gel eluting with 25% ethyl acetate in hexane to provide (R)-3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXX) (8.5 g, 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>>[CH:12](=[C:5]1[C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc2c(n1)CCCC2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2c(n1)C(=Cc1ccccc1)CCC2
Temperature: 25 °C

Procedure:
A solution of Intermediate 200A1 (27.5 g, 187 mmol), benzaldehyde (18.4 mL, 181 mmol) and acetic anhydride (32.5 mL, 290 mmol) was heated at 155° C. for 4 h. The mixture was cooled to room temperature, mixed with crushed ice, basified with 2M NaOH to pH>8. The aqueous layer was extracted with hexane/ethyl acetate. The pooled organic layers were dried over MgSO4, filtered, evaporated and purified by chromatography on SiO2 to give 8-benzylidene-2-methyl-5,6,7,8-tetrahydro-quinoline (Intermediate 200A2) as the major product. This material was carried onto the next step. Note: 2-styryl-5,6,7,8-tetrahydro-quinoline (removed by chromatography on SiO2 with 1.5% acetone in hexanes) and 8-benzylidene-2-styryl-5,6,7,8-tetrahydro-quinoline were also produced as side products.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:28][N:29]([CH3:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.C(O)(=O)C>CN(C=O)C>[CH2:17]([NH:16][C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([N:29]([CH3:28])[CH3:39])=[CH:38][CH:37]=3)[CH:20]=[CH:19][C:9]=2[N:10]=1)=[O:15])[CH3:18]
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)c3ccc(N(C)C)cc3)cc2s1
Yield: 25 %

Procedure:
Similar to the synthesis of Example 248, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 4-dimethylaminobenzoyl chloride in DMF was reacted to give the desired compound 0.025 g (25%) as an acetic acid salt. LC/MS 440.1 (M+1); LC retention time 2.86 min.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (R)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 75.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.89 min, m/z=459.1-460.1 [M+H]+, m/z=458.2-457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.61 (m, 1H) 1.79-1.88 (m, 1H) 2.17-2.26 (m, 1H) 2.93-3.00 (m, 1H) 3.10-3.37 (m, 5H) 4.60 (t, J=5.14 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.48 (dd, J=7.82, 4.89 Hz, 1H) 7.79-7.83 (m, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.20 Hz, 1H) 8.57 (dd, J=4.89, 1.47 Hz, 1H) 8.64 (d, J=2.20 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>CO>[OH:1][CH:2]([CH2:15][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)N
Solvent: CO
Product: COC(=O)c1ccc(OCC(O)CNC(C)(C)C)cc1
Yield: 65 %

Procedure:
A mixture of methyl 4-(2,3-epoxypropoxy)benzoate (prepared as described in Example I) (2.1 g, 0.01 mole), 10 mL of t-butylamine and 10 mL of methanol was heated to reflux for three hours. The reaction medium was then evaporated under reduced pressure to provide the amine as an oil. The free amine was crystallized from hexane-ethyl acetate in 65% yield: m.p. 88°-89° C. The NMR spectrum and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][OH:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].I([O-])(=O)(=O)=[O:22].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([C:15]([OH:22])=[O:16])=[CH:13][C:12]([C:17]([F:19])([F:20])[F:18])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2CO)ccc1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)ccc1F
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 1-(3-cyano-4-fluoro-phenyl)-3-trifluoromethyl-5-hydroxymethylpyrazole (0.45 g, 1.58 mmol) in acetonitrile (10 mL) was added catalytic amount of ruthenium chloride at 0° C. followed by addition of a solution of sodium periodate (0.71 g, 3.32 mmol) in water. The reaction was stirred at 0° C. to room temperature overnight. The next day the acetonitrile was evaporated and the residue was partitioned between ethyl acetate and water, washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(3-cyano-4-fluoro-phenyl)-3-trifluoromethyl-5-hydroxycarbonylpyrazole (0.27 g, 57% yield) as pure compound: MS (ES−): 298 (M—H)− (40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH2:9][C:10]([NH2:11])=[O:14])=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The crude 3-(4-chloro-phenyl)-3-oxo-propionitrile obtained above was stirred with 100 mL of sulfuric acid at room temperature for 4 hours. The mixture was poured into 500 mL of ice-water and stirred for 30 minutes. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 5.73 g of 3-(4-chloro-phenyl)-3-oxo-propionamide as a brown solid which was used in next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:12][CH2:13][CH2:14][C:10]=2[CH:9]=[C:5]2[O:6][CH2:7][CH2:8][C:4]=12)=[O:2].[OH-:15].[Na+]>[Ag-]=O>[O:6]1[CH2:7][CH2:8][C:4]2=[C:3]([C:1]([OH:15])=[O:2])[C:11]3[O:12][CH2:13][CH2:14][C:10]=3[CH:9]=[C:5]12
Reactant: O=Cc1c2c(cc3c1OCC3)OCC2
Reactant: [OH-]
Agent: O=[Ag-]
Agent: [Na+]
Product: O=C(O)c1c2c(cc3c1OCC3)OCC2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
4-Formyl-2,3,6,7-tetrahydro-benzo[1,2-b; 4,5-b′]difuran (0.25 mmol; Lit.: A. P. Monte, D. Marona-Lewicka, M. A. Parker, D. B. Wainscott, D. L. Nelson, D. E. Nichols J. Med. Chem., 1996, 39, 2953-2961) is added to a stirred suspension of silver(I) oxide (0.375 mmol) in an aq. NaOH solution (5%, 0.20 mL). The mixture is stirred for 5 h, filtered and washed with water (2.0 mL). The filtrate is cooled to 0° C. and made acidic by dropwise addition of hydrochloric acid (25%). The obtained suspension is filtered off and washed with ice-cold water and heptane. The residue is dried in vacuo to give the desired acid as a grey powder which is used without further purification. LC-MS (basic): tR=0.20 min; [M−H]−=205.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([NH2:21])[N:10]([CH3:22])[N:9]=1.[ClH:23].[N:24]([O-])=O.[Na+]>O>[Cl:23][C:13]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:24][N:21]=[C:11]2[N:10]([CH3:22])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:12]=12
Reactant: Cn1nc(-c2ccccc2Cl)c(C#Cc2ccccc2)c1N
Reactant: Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
To a cooled (cooling bath −15° C.) stirred suspension of 3-(2-chlorophenyl)-1-methyl-4-(phenylethynyl)-1H-pyrazol-5-amine (136 mg, 0.44 mmol) in cone. HCl (3.7 mL) was added a solution of sodium nitrite (34 mg, 0.49 mmol) in water (0.3 mL). After 5 min, the cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction was cooled again (0° C.) and poured onto a sat. NaHCO3 solution. Ethyl acetate was added and pH was adjusted to 7-8 with sat. NaHCO3. The aqueous phase was extracted with ethyl acetate and the organic phases combined, dried over MgSO4, filtered and evaporated. Crude material was purified by column chromatography (silica gel, gradient 0 to 4% ethyl acetate/CH2Cl2) yielding Compound 37 as a solid (47 mg).
Reaction SMILES: [O-:1][P:2]([O:5][P:6]([O:9]P([O-])([O-])=O)([O-:8])=[O:7])(=[O:4])[O-:3].[Na+].[Na+].[Na+].[Na+].[Na+]>O>[P:2]([O-:5])([O-:4])([O-:3])=[O:1].[O-:3][P:2]([O:5][P:6]([O-:9])([O-:8])=[O:7])(=[O:1])[O-:4]
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: O=P([O-])([O-])[O-]
Yield: 8 %
Yield: 15 %

Procedure:
The industrially important pentasodium triphosphate, Na5P3O10 (sodium tripolyphosphate), is a nonhygroscopic, white, water-soluble salt which is anhydrous or crystallizes with 6H2O and has the general formula NaO—[P(O)(ONa)—O]n—Na where n=3. About 17 g of the anhydrous salt dissolve in 100 g of water at room temperature, about 20 g dissolve at 60°, and about 32 g dissolve at 100°; after heating the solution for two hours at 100°, about 8% orthophosphate and 15% diphosphate are produced by hydrolysis. In the case of the preparation of pentasodium triphosphate, phosphoric acid is reacted with soda solution or sodium hydroxide solution in the stoichiometric ratio and the solution is dewatered by spraying. Similarly to Graham's salt and sodium diphosphate, pentasodium triphosphate dissolves many insoluble metal compounds (including lime soaps, etc.). Pentapotassium triphosphate, K5P3O10 (potassium tripolyphosphate), is commercially available, for example, in the form of a 50% strength by weight solution (>23% P2O5, 25% K2O). The potassium polyphosphates are widely used in the detergents and cleaners industry. There also exist sodium potassium tripolyphosphates, which can likewise be used within the scope of the present invention. These form, for example, when sodium trimetaphosphate is hydrolyzed with KOH: (NaPO3)3+2KOH→Na3K2P3O10+H2O.