Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].C1(O[CH2:9][C:10]2[CH:17]=[C:16]([C@:18]3([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]3[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=2[C:12]#[N:13])C=CC=CC=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:1][CH2:9][C:10]1[CH:17]=[C:16]([C@:18]2([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]2[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C#N)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A 33% solution of hydrobromic acid in acetic acid (15 mL) is added to a solution of 2-phenyloxymethyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile (0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 ml). The resulting solution is stirred at 55° C. for 6 h and then cooled in an ice-bath. The reaction mixture is neutralized with chilled aqueous potassium carbonate solution, and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate/cyclohexane (1:5), and the precipitate is separated by filtration and dried at 50° C. to give the product.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[N:12]=1)=[C:9]=[O:10]>C(Cl)Cl>[CH3:18][O:17][C:15]1[CH:14]=[C:13]([C:19]([F:20])([F:22])[F:21])[N:12]=[C:11]([NH:8][C:9]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[N:16]=1
Reactant: Oc1ccccc1
Reactant: COc1cc(C(F)(F)F)nc(N=C=O)n1
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)nc(NC(=O)Oc2ccccc2)n1
Reaction time: 16 h
Yield: 86.6 %

Procedure:
4.2 g of phenol (45 mmol) were added at 25° C. to a solution of 9.9 g of 2-isocyanato-4-methoxy-6-trifluoromethylpyrimidine (45 mmol) in 50 ml of methylene chloride. Stirring was carried out for 16 hours at 25° C., the methylene chloride was distilled off under reduced pressure and the residue was stirred vigorously with 100 ml of a diisopropyl ether/hexane mixture (v/v 1:20), whereupon crystallization occurred. The product was filtered off with suction and dried under reduced pressure from a water pump at 50° C. The title compound (12.2 g; 87% of theory) was obtained as colorless crystals of melting point 85°-88° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[C:13]1[C:14]([C:28]2([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:15][C:16]2[N:17]([C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)[N:18]=1>CN(C)C=O>[CH3:33][C:28]1([C:14]2[C:13]([O:1][CH2:2][C:3]3[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:18][N:17]3[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[N:20][N:21]=[C:16]3[CH:15]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC1(c2cc3nnc(-c4ccccc4)n3nc2Cl)CCCC1
Reactant: Cc1cccnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1nn2c(-c3ccccc3)nnc2cc1C1(C)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Hydroxymethyl-3-methylpyridine (43 mg) was dissolved in dimethylformamide (2 ml) under N2. Sodium hydride (60% w/w in oil, 14 mg) was added followed after 5-10 minutes by 6-chloro-7-(1-methylcyclopentyl)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg). Reaction was stirred at room temperature for 18 hours, partitioned between ethyl acetate and water, organic phase separated, dried (MgSO4) and evaporated to dryness. Recrystled from ethyl acetate to give pure product. 1H NMR (360 MHz, CDCl3) δ1.30 (3 H, s), 1.77 (6 H, m), 1.93 (2 H, m), 2.44 (3 H, s), 5.62 (2 H, s), 7.25 (1 H, m), 7.50 (3 H, m), 7.58 (1 H, d, J=7.8 Hz), 7.92 (1 H, s), 8.42 (2 H, d, J=6.4 Hz), 8.50 (1 H, m), ms (ES+) m/e 400 [MH]+.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH:17]1([S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:2]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:21]=3[F:20])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:19][CH2:18]1
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)C2CC2)cc1
Product: CCOC(=O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 150 °C

Procedure:
Ethyl 2-bromo-2-(4-cyclopropylsulfonylphenyl)acetate (0.8 g, 2.30 mmol) [obtained as described in WO2009/047798 A2; Example A1] and 2,4-difluoroaniline (3.0 mL) mixed together and heated at 150° C. in a seal tube for 12 hrs. Reaction mixture was cooled to rt and purified by column chromatography using 20% ethyl acetate in hexane as eluent to provide ethyl 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetate (0.65 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:3][CH:4]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCNc2cnc(C(N)=O)cn2)CC1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
A mixture of 1.12 g (7.15 mmol) of 5-chloropyrazine-2-carboxamide, 1.95 g (8.58 mmol) of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate and 1.18 g (8.58 mmol) of potassium carbonate in 1.4 ml of dimethyl sulphoxide is heated during 5 hours at 100° C. under an argon atmosphere and with stirring. After cooling to ambient temperature, 25 ml of ethyl acetate and 25 ml of water are added. The organic phase is separated by settling and washed 3 times with 25 ml of water and then 25 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, elution being carried out with a 97:3, then 95:5 and 93:7 mixture of dichloromethane and methanol, in order to obtain 1.99 g (5.69 mmol) of product in the form of a light-yellow paste.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11](OC)(OC)OC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:27]=[C:28]([NH2:31])[S:29][CH:30]=2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[C:6](=[CH:11][NH:31][C:28]2[S:29][CH:30]=[C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[CH:27]=2)[C:4](=[O:5])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1cccc(-c2csc(N)c2)c1
Reactant: COC(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(-c2csc(NC=C3C(=O)OC(C)(C)OC3=O)c2)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 47.2 %

Procedure:
Meldrum's acid (1.58 g, 10.96 mmol) was dissolved in trimethyl orthoformate (24.23 mL, 219 mmol) and the mixture was heated at 110° C. for 1 h. After cooling to RT, 4-[3-(methyloxy)phenyl]-2-thiophenamine (Description 40) (1.5 g, 7.31 mmol) was added to the mixture and reheated at 90° C. for 15 h. After cooling to RT, the mixture was evaporated in vacuo. The residue was dissolved in DCM and treated with potassium carbonate (3.03 g, 21.92 mmol). After stirring for 30 min, the mixture was filtered and the filtrate was evaporated in vacuo, to give the title compound (1.24 g). LCMS (A) m/z: 360 [M+1]+, Rt 1.19 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9]S(C)=O)=[C:4]([NH:14][CH3:15])[CH:3]=1>C(O)(=O)C.C(O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH3:9])=[C:4]([NH:14][CH3:15])[CH:3]=1
Reactant: CNc1cc(Cl)ccc1C(=O)CS(C)=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1cc(Cl)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-[4-chloro-2-(methylamino)phenyl-2-methylsulphinylethanone (17 g) in a mixture of glacial acetic acid (35 ml) and absolute ethanol (35 ml) was added dropwise over 20 minutes to a stirred suspension of zinc dust (22.5 g) in acetic acid (20 ml) and absolute ethanol (35 ml) under nitrogen at ambient temperature. After stirring at ambient temperature for 24 hours, the reaction mixture was filtered through diatomaceous earth (sold under the trade name CELITE) and the filter bed was washed with glacial acetic acid (200 ml). Water (600 ml) was added to the combined filtrate and washing and the mixture was extracted with dichloromethane (3×200 ml). The combined extracts were dried over magnesium sulphate and the solvent was removed by distillation to give the novel compound 4'-chloro-2'-(methylamino)acetophenone, m.p. 65°-66°.
Reaction SMILES: Br[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][NH:5][CH:6]=1.[Li]CCCC.[CH3:18][S:19]SC>C1COCC1>[CH3:18][S:19][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][NH:5][CH:6]=1
Reactant: CSSC
Reactant: Brc1c[nH]nc1-c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1c[nH]nc1-c1cccnc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of anhydrous THF (150 ml) containing compound 20A (3.0 g, 13.4 mmol, prepared accordingly to Bioorganic & Medicinal Chemistry, 4, 1996, 227-237) was added 2.1 eq n-BuLi (11.2 ml, 2.5 M in hexane) dropwise at −78° C. under N2. After the addition, the resulting solution was stirred for 2 hours at −78° C. At this temperature 1.1 eq methyldisulfanyl methane (1.33 ml) was added and the resulting solution was stirred for 1 hour at −78° C. and subsequently allowed to warm to ambient temperature overnight. Then the mixture was quenched with a saturated NH4Cl solution at 0° C. and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with 5% NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (ethyl acetate) afforded compound 21A (oil, 1.71 g, 67%). 1H-NMR (200 MHz, CDCl3): δ 9.18 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.28 (dt, J=8 Hz, 2 Hz, 1H), 7.70 (s, 1H), 7.42-7.33 (m, 1H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[NH:5][C:4]2=[N:15][CH:16]=[CH:17][C:3]=12.[I:18]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:11])[CH3:12])[NH:5][C:4]2=[N:15][CH:16]=[C:17]([I:18])[C:3]=12
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2ccnc-2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)cnc-2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
4-Chloro-2-trimethylacetamido-pyrrolo[2,3-d]pyrimidine (9a, 10.9 g, 43.24 mmol) was dissolved in anhydrous THF (120 mL) under nitrogen. After the addition of N-iodosuccinimide (10.7 g, 47.56 mmol), the mixture was stirred at RT for 1 h. The solvent was then removed in vacuo. The residue dissolved in EtOAc (100 mL) and washed with 1 M sodium thiosulfate (3×100 mL). Column chromatography purification (2% MeOH in DCM, isocratic) yielded 9b (12.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C(C(C)=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]Cl>C(OCC)(=O)C>[CH3:26][O:25][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:20]([CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[CH:7][CH:6]=2)=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[CH:17][CH:16]=3)=[CH:13][CH:12]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(c1ccc(OCCN(C)C)cc1)c1c-2ccc2ccccc12
Temperature: 25 °C

Procedure:
A 3.4 g portion of the compound of Example 1 was combined with 75 ml of methyl ethyl ketone, 6.1 g of potassium carbonate, and 2.45 g of dimethyl-(2-chloroethyl)amine hydrochloride. The mixture was stirred under reflux for 24 hours. After cooling to 25° C., 50 g of ice and 100 ml of ethyl acetate were added. The organic layer was separated, washed with brine, and concentrated to provide the crude product which was then purified on a silica gel column (120 mm high and 70 mm in diameter). The elution started with 500 ml of toluene, and proceeded through 300 ml increments of toluene containing from 1 to 10% triethylamine, in 1% increments. The product-containing fractions were combined and concentrated to dryness under vacuum to obtain 3.1 g of partially purified product, which was chromatographed again on a similar column, beginning with 100 ml of toluene. The gradient solvent was then changed in 100 ml increments from toluene containing 10% of 5:3 ethyl acetate:acetonitrile, to 10% of toluene in the ethyl acetate:acetonitrile mixture. Then a second gradient solvent was used, again in 100 ml increments, starting with the 5:3 ethyl acetate:acetonitrile mixture, going to the same solvent containing 10% of triethylamine. The product-containing fractions were then evaporated under vacuum to obtain 2.9 g of purified desired product, m.p. 159°-160° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH:17]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](O[C:29](=[O:31])[CH3:30])OC(=O)C)(=O)C.[Na+].F[C:34](F)(F)[C:35]([O-])=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][NH:8][CH2:9][C:10]1[O:31][C:29]2[CH:30]=[CH:35][CH:34]=[CH:13][C:12]=2[CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)C[C@@H]2CCCC[C@@H]21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CNCc2cc3ccccc3o2)C[C@@H]2CCCC[C@@H]21
Reaction time: 3 h

Procedure:
To a solution of 31 mg (0.12 mmol) of (2S,3aS,7aS)-2-formyl-octahydro-indole-1-carboxylic acid tert-butyl ester in 1 mL dichloromethane, 18 mg (0.12 mmol) of c-benzofuran-2-yl-methylamine 40 mg (0.18 mmol) of sodium triacetoxyborohydride were added and the mixture was stirred for 3 hours, then diluted with 5 mL dichloromethane and quenched with 3 mL of aqueous sodium bicarbonate. The aqueous layer was extracted once with dichloromethane and the combined organic layers were dried with anhydrous magnesium sulfate, evaporated in vacuum and purified using reverse phase HPLC, mobile phase with a gradient 15-80% acetonitrile in 50 min. Fractions containing pure product were evaporated in vacuum to yield, 53 mg of white solid as the trifluoroacetate. LC-MSD, m/z for C23H32N2O3 [M+H]+: 385.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[N:22]1([CH:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=4[N:11]=3)=[CH:6][CH:5]=2)[CH3:2])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1)N1CCCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 34A (0.1 g, 0.4 mmol) and pyrrolidine (0.13 mL, 1.6 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (0.05 g, 0.8 mmol) and acetic acid (0.2 mL) and the mixture stirred overnight at 70° C. The residue was concentrated and purified by flash chromatography on silica gel using 0-10% dichloromethane/methanol/0.1% ammonium hydroxide to provide the title compound, which was dissolved in methanol (1 mL), treated with a solution of 1M hydrochloric acid in ether (2 mL) and stirred at ambient temperature for 2 hours. The precipitate was filtered to give the title compound as the hydrochloride salt. 1H NMR (DMSO-d6) δ 11.26 (s, 1H), 8.34 (d, J=8.4 Hz, 2H), 7.85-7.91 (m, 3H), 7.79 (d, J=7.2 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 4.51 (qd, J=7.4, 7.2 Hz, 1H), 3.70 (dd, J=11.4, 4.5 Hz, 1H), 3.12-3.20 (m, 1 Hz), 2.95-3.02 (m, 1H), 2.89 (dq, J=11.2, 8.1 Hz, 1H), 1.91-2.00 (m, 2H), 1.79-1.88 (m, 1H), 1.69 (d, J=6.9 Hz, 3H).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C:20]([CH2:24][S:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)([OH:23])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)#[N:8].C(=O)([O-])[O-:37].[K+].[K+].C(OCC)(=O)C>CO.O>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][C:20]([CH2:24][S:25]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=3)=[O:37])([OH:23])[CH2:21][CH2:22]2)=[CH:13][CH:14]=1)#[N:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(SCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)CC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium metaperiodate (235 mg) was added to a solution of the compound (411 mg) obtained in Example 42 in a mixture of methanol (10 mL) and water (2 mL) under cooling with ice-water, followed by stirring at room temperature for one hour. Another portion of sodium metaperiodate (64 mg) was added, followed by stirring at room temperature for two hours. The reaction mixture was mixed with 10% aqueous potassium carbonate solution (10 mL) and ethyl acetate (20 mL), was stirred, and insoluble matter was removed by filtration. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine and was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography [Chromatorex NH™] (eluent; hexane:ethyl acetate=3:1 to ethyl acetate) to yield the titled compound (180 mg) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[N+:14]([O-])([OH:16])=[O:15].C(O)(=O)C>C(OC(=O)C)(=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:14]([O-:16])=[O:15])[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)CCCC2=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)CCC2
Yield: 24 %

Procedure:
6-Methoxy-1-tetralone (12.0 g, 68.1 mmol) was dissolved in acetic anhydride (60 ml), a fuming nitric acid (4.8 ml)-acetic acid (4.2 ml) mixed solvent was slowly added dropwise under ice-cooling with stirring, and thereafter the mixture was stirred at the same temperature for 2 hr. The reaction mixture was diluted with ether, and the precipitated solid was collected by filtration and dried under reduced pressure. The obtained solid was recrystallized from benzene (100 ml), and the precipitated solid was filtered, dried under reduced pressure to give the title compound (3.62 g, yield 24%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 70 °C
Yield: 45 %

Procedure:
A solution of the racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (4.4 g) and (1R)-10-camphorsulfonic acid (2 g) in toluene (40 ml) containing glacial acetic acid (0.6 ml) was warmed up to approximately 70° C., then allowed to cool slowly to 20° C., seeded with the pure enantiomeric salt whereupon the pure enantiomeric salt start to crystallize out. After ca. 2 hrs at this temperature the solid was collected, washed with cold toluene and dried. The crystals were taken with a solvent mixture of methylenechloride/water and after addition of aqueous saturated sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated and the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 2 g (45% yield, 99% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][O:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:43][CH:42]([CH:44]([CH3:46])[CH3:45])[C:41]([O:40][CH3:39])=[O:47])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]
Reactant: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid (1.0 equiv.) was dissolved in 25 ml of DMF, N,N′-dicyclocarbodiimide (1.2 equiv.) and 1-hydroxybenzotriazole (1.0 equiv.) was added and stirred at room temperature for 10 min. L-valine methyl ester hydrochloride (1.5 equiv.) was neutralized with triethylamine (1.5 equiv.) in 10 ml of DMF and was added to the above mixture and the resulting reaction mixture was stirred at room temperature for 48 hours. DMF was evaporated and then diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in a chloroform and methanol mixture, adsorbed on silica (100-200 mesh) and purified by flash chromatography on silica gel, and then eluted with 0-2% methanol in chloroform to obtain a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[CH:17]=2)=[CH:5][CH:4]=1.[CH3:18][I:19]>C(#N)C>[I-:19].[CH3:18][N+:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:17][N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: CI
Reactant: COc1ccc(-c2cn3ccccc3n2)cc1
Solvent: CC#N
Product: COc1ccc(-c2cn3ccccc3[n+]2C)cc1
Product: [I-]
Reaction time: 1 h

Procedure:
To 2.23 g. of 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine in 50 ml. of acetonitrile is added 2.84 g. of methyl iodide, and the resulting reaction mixture refluxed for 3 hrs. Additional methyl iodide (2 ml.) is added and reflux continued for one hour. The solids which precipitate on cooling are filtered and partially dissolved in boiling isopropanol and filtered. The isopropanol filtrate is cooled and treated with diethyl ether. The crystallized product is filtered and dried to give 1.03 g., m.p. 194°-196° C.