Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=1)[C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>CN(C)C=O.O1CCCC1>[CH2:1]([C:8]1[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=1)[CH2:12][Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)[nH]c1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]c(Cc2ccccc2)ccc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 5.9 g. of 6-benzyl-1,2-dihydro-2-oxonicotinic acid in 60 ml. of tetrahydrofuran is treated with 2.04 ml. of thionyl chloride and six drops of dimethylformamide. The mixture is stirred at room temperature for 16 hours, then evaporated at reduced pressure to give a residue of 6-benzyl-1,2-dihydro-2-oxonicotinyl chloride. This acid chloride is dissolved in 90 ml. of tetrahydrofuran, the solution is cooled to 0°-5° C. and trated with an ice-cold solution of 7.59 g. of D-N-(trimethylsilyl)-2-phenylglycine trimethylsilyl ester in 60 ml. of tetrahydrofuran, then with 2.87 ml. of N-methylmorpholine. The mixture is stirred at 0°-5° C. for 1 hour, at room temperature for 2 hours, then poured into 500 ml. of water and the pH adjusted to 8.3 with saturated aqueous sodium bicarbonate. The solution is washed with several portions of ethyl acetate and the washings discarded. The solution is adjusted to pH 2.0 with 12% hydrochloric acid and extracted with several portions of ethyl acetate. The combined acetate extract is washed with water, dried and evaporated at reduced pressure to give D-(+)-N-(6-benzyl-1,2-dihydro-2-oxonicotinyl)-2-phenylglycine; m.p. 142°-145° C. after two crystallizations from acetonitrile; [α]D25 +23.0° (1.025% in tetrahydrofuran).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:20][C:21]([N:23]2C=CN=C2)=[O:22])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[S:10][CH:11]=1.N.O1CCOCC1>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:20][C:21]([NH2:23])=[O:22])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[S:10][CH:11]=1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1nc(NC(N)=O)sc1-c1csc(C(=O)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide, prepared as in Step III of Example 36, described above (535 mg; 1.33 mmol) is added DMF (20 ml) and ammonia 0.5 M solution in dioxane (3.20 ml; 0.50 M; 1.60 mmol; 1.10 eq.). The mixture is stirred at rt overnight. Some ammonia 0.5 M solution in dioxane (1.46 ml; 0.50 M; 0.73 mmol; 0.50 eq.) is added and the mixture is stirred at rt for 5 additional hours. As the reaction is complete, solvents are evaporated. The resulting crude yellow product is purified by preparative HPLC, affording Compound (40) as white-off powder (177 mg; 26%). 1H NMR (DMSO-d6, 300 MHz) δ 2.41 (s, 3H), 3.68 (m, 6H), 4.32 (m, 2H), 6.42 (br s, 2H), 7.91 (s, 1H), 10.45 (br s, 1H). M− (ESI): 352.12; M+ (ESI): 354.11. HPLC (method A), Rt: 2.03 min (purity: 99.7%).
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>C1COCC1>[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[N:29]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:8][CH2:9][CH3:10]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCC[C@@H](C)CCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 25 °C

Procedure:
To (R)-4-methyl-heptanoic acid (19 g, 0.132 mol) and triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0° C. was added trimethylacetylchloride (20 g, 0.17 mol). After 1 hour LiCl (7.1 g, 0.17 mol) was added followed by (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone) (30 g, 0.17 mol). The mixture was warmed to room temperature and after 16 hours the filtrate was removed by filtration and the solution concentrated under reduced pressure. Flash chromatography (7:1 hexane/EtOAc) gave (4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one as an oil. 31.5 g; 79%. [α]D=+5.5 (c 1 in CHCl3). MS, m/z (relative intensity): 304 [M+H, 100%]; 1H NMR (400 MHz; CDCl3) δ 7.4–7.2 (m, 5H), 5.6 (d, J=7.32 Hz, 1H), 4.75 (m, 1H), 2.96 (m, 1H), 2.86 (m, 1H), 1.62 (m, 1H), 1.43 (m, 1H), 1.25 (m, 4H), 1.12 (m, 1H), 0.85 (m, 9H); 13C NMR (100 MHz; CDCl3) 6173.70, 153.23, 133.81, 133.59, 128.92, 128.88, 128.92, 128.88, 125.83, 79.12, 54.93, 39.24, 33.66, 32.32, 31.47, 27.18, 26.52, 20.25, 19.57, 14.75, 14.52.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[OH:11])=O)=[CH:4][CH:3]=1.[CH:19]([NH2:21])=O.P(Cl)(Cl)(Cl)=O>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:21]=[CH:19][O:11][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: Cc1ccc(C(=O)C(O)c2ccc(C)cc2)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ncoc2-c2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
4,4'-Dimethylbenzoin (25.0 g), formamide (230 ml) and phosphorus oxychloride (16.0 ml) was mixed and stirred under reflux for 5.5 hours. The reaction mixture was cooled to room temperature and poured into water, and then extracted with diethyl ether twice. The collected organic phases were washed with brine and dried over magnesium sulfate and activated carbon. The mixture was filtered and evaporated in vacuo, and then purified by column chromatography on silica. The solvent was evaporated to afford 4,5-bis(4-methylphenyl)oxazole (15.41 g) as a solid.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:15]CC)(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].N1CCCCC1>>[C:9]([O-:15])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Solvent: O=Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)CC(=O)[O-]
Reaction time: 72 h

Procedure:
The mixture of benzaldehyde (21.22 g) and ethyl acetoacetate (52.06 g) was cooled in an ice bath. Piperidine (3.3 ml) was added with stirring. The resulting mixture was kept at rt for 3 days whereupon it solidifies. The solid was recrystallised from ethanol (100 ml) to give a light yellowish solid (the bis-adduct of acetoacetate to benzaldehyde). The powdered solid was added in portions to 50% NaOH (200 ml) with stirring. The resulting yellow slurry was diluted with ethanol (70 ml) and stirred at reflux for 2 h. After addition of ice water (100 ml) and cooling in an ice bath the mixture was acidified with conc. HCl to give a white precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-phenylglutaric acid (16.4 g) was obtained as colourless crystals.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:23])[C:7](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:8](=O)[CH2:9][CH2:10][CH3:11])#[N:2].[NH2:24][C:25]([CH2:37][CH2:38][CH3:39])=[CH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CCO>[CH2:30]([O:29][C:27]([C:26]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:7]([C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:23])=[C:8]([CH2:9][CH2:10][CH3:11])[NH:24][C:25]=1[CH2:37][CH2:38][CH3:39])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCC(N)=CC(=O)OCc1ccccc1
Reactant: CCCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Solvent: CCO
Product: CCCC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(CCC)N1

Procedure:
A solution of 2-[(4-nitrophenyl)methylene]-3-oxohexanoic acid 2-cyanoethyl ester (9.80 g, 30 mmol) and benzyl 3-amino-2-hexenoate (7.24 g, 33 mmol) in 150 ml of EtOH was refluxed for 36 hrs. After the solvent was removed in vacuo, the residue was dissolved in 250 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 5-benzyloxycarbonyl-3-(2-cyanoethoxy) carbonyl-1,4-dihydro-4-(4-nitrophenyl)-2,6-dipropylpyridine was obtained as a yellow oil (15.4 g, 97%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:33][C:34]2[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:24][CH:23]4[N:25](C(OC(C)(C)C)=O)[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[N:14]=2)=[N:10][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:23]12[NH:25][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([C:15]1[N:14]=[C:13]([NH:12][C:9]3[C:8]([O:33][C:34]4[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=4)=[CH:7][C:6]([S:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][N:10]=3)[S:17][N:16]=1)[CH2:24]2
Reactant: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)ns2)c(Oc2cccnc2C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
tert-Butyl 3-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (256 mg, 0.438 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (2 mL) was added. The reaction was stirred at ambient temperature for 15 minutes. The reaction was concentrated and redissolved in CH2Cl2 and washed with saturated aqueous. NaHCO3, dried over sodium sulfate, filtered and concentrated to afford 3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (193 mg, 0.398 mmol, 91.0% yield) as a crude yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:17])[CH:14]([CH3:16])[NH2:15].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:17])[CH:14]([CH3:16])[N:15]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C(C)N
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)N=Cc1ccc(Cl)cc1
Reaction time: 20 h
Yield: 94.5 %

Procedure:
To a stirring mixture of 4-chlorobenzaldehyde (42.2 g, 0.3 mol), DL-alanine methyl ester hydrochloride (42.7 g, 0.306 mol), and 150 g of magnesium sulfate in 1 L of methylene chloride was added 30.3 g (0.3 mol) of triethylamine in 150 ml of methylene chloride in one portion and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered, the filtrate concentrated in vacuo, and the residue (solid and oil) was dissolved in 500 ml of ether. The insoluble solid (triethylamine hydrochloride) was removed by filtration and the filtrate was concentrated in vacuo to afford 64.01 g (94.6%) of N-(4-chlorophenyl)methylene-DL-alanine methyl ester as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([C:22](Cl)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:10][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:23])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 87° C. and MS: m/e=309 (M+) was prepared in accordance with the general method of example 39 from 2,2-diphenylacetamide and pentanecarboxylic acid chloride.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH3:5][N:6]1[C@@H]2[CH2:23][C:11]3[CH:12]=[CH:13][C:14]([OH:26])=[C:15]4[O:16][C@H:17]5[C:18]([O:24]C)=[CH:19][CH:20]=C2[C@:9]5([C:10]=34)[CH2:8][CH2:7]1.C(OO)(=O)C.OO>O>[CH3:5][N:6]1[C@@H:2]2[CH2:23][C:11]3=[CH:12][CH:13]=[C:14]([OH:26])[C:15]4[O:16][C@H:17]5[C:18]([CH2:19][CH2:20][C@:1]2([OH:4])[C@:9]5([C:10]=43)[CH2:8][CH2:7]1)=[O:24]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CC(=O)O
Agent: CC(=O)OO
Agent: OO
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Glacial acetic acid, HOAc, (30 mL) and water (120 mL) were added to a 250 mL flask (pH=2.6, ˜150 mL). With the stirring mechanism on, oripavine (30.00 g, assayed to be 96% wt/wt, containing oripavine 97 mmol) was charged to the flask. Heat was released and the final solution reached 25° C. from 20° C., pH=3.66. The reaction mixture was cooled to 5˜10° C., and, CH3CO3H (23.4 g, containing 33% wt/wt peroxy acetic acid and 5.34% H2O2, 97 mmol peracetic acid) was added over 10 minutes. The reaction mixture was stirred for another 30 minutes after cooling bath was removed and the final temperature reached 15° C. H2C2O4 (1.5 g) was added to the reaction mixture, and the solution was heated to 35° C. over a 30 minute period and maintained at 35° C. for 1 hour. The reaction mixture was transferred to a pressure bearing flask (350 mL) for the reduction reaction. The flask for the oxidation was washed with the 2% HOAc (v/v; 2×7.5 mL). The washes were transferred to the reduction flask. 1.0 g of 10% Pd/C was added and the flask was pump/purged first with nitrogen and then with hydrogen each 4 times. The flask was cycled under vacuum and hydrogen 4 times. The reaction mixture was stirred under hydrogen (60 PSI) at 85° C. to 90° C. (90° C. oil bath) for 4.5 hours. The reaction mixture was cooled down to 35° C. and filtered. The recovered solid was washed with a solution of 2% HOAc/H2O (v/v, 3×15 mL). Yield of oxymorphone formed in the solution was calculated by HPLC analysis: 95%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[Li]CCCC.Cl>C1COCC1>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([B:13]([OH:18])[OH:14])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(B(O)O)cc1
Temperature: 0 °C
Yield: 104.6 %

Procedure:
To a solution of 4-bromo-N-methyl-benzene sulfonamide (24.9 g, 0.1 mol) and B(OiPr)3 (28.2 g, 0.15 mol) in THF (200 mL) was added n-BuLi (100 mL, 0.25 mol) at −70° C. The mixture was slowly warmed to 0° C., then 10% HCl solution was added until pH 3˜4. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and evaporated under reduced pressure to give 4-(N-methylsulfamoyl)phenylboronic acid (22.5 g, 96%), which was used in the next step without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 8.29 (s, 2 H), 7.92 (d, J=8.1 Hz, 2 H), 7.69 (d, J=8.4 Hz, 2 H), 2.36 (d, J=5.1 Hz, 3H).
Reaction SMILES: [Na].[C:2]([C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][C:11]=1[Cl:12])([CH3:5])([CH3:4])[CH3:3].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:9]1[N:8]=[C:7]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[C:11]([Cl:12])[N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1c(Cl)nc(Cl)nc1Cl
Reactant: OCc1ccccc1
Agent: [Na]
Product: CC(C)(C)c1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred anhydrous benzyl alcohol (80 ml), was added pieces of sodium metal (1.73 g, 75 mmol). After the reaction completed, the mixture was cooled in an ice bath and 5-tert-Butyl-2,4,6-trichloro-pyrimidine (9 g, 37.5 mmol) was added. After 1 hr., the mixture was stirred at room temperature for overnight and evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:19)) to afford 13 g (90%) of a white solid. m.p. 96° C.; 1H NMR (200 MHz, CDCl3) δ 1.50 (9H, s), 5.37 (2H, s), 5.41 (2H, s), 7.34-7.46 (10H, m).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])C.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CO>[CH:30]1([NH:33][C:4]([C:6]2[S:10][C:9]([N:11]3[C:15]4[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=4[N:13]=[CH:12]3)=[N:8][C:7]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:5])[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Solvent: CO
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)NC4CC4)s3)c2cc1OC

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid cyclopropylamide was prepared from 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (24 mg, 0.06 mmol) and cyclopropylamine in methanol (4 molar) as described above in the general amide formation procedure. Product was isolated by preparative HPLC: 10 mg, 40%. 1H-NMR (DMSO-D6) 8.8 (s, 1H); 8.54 (t, 1H); 7.80-7.87 (m, 2H), 7.41-7.55 (m, 3H); 7.38 (s, 1H); 3.90 (s, 3H); 3.86 (s, 3H); 3.25 (q, 2H); 1.08 (t, 3H). MS M/z 421 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O:42][CH3:43])=[O:41])=[O:2].[O-:44]Cl=O.[Na+].NS(O)(=O)=O>CC(O)(C)C.O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O:42][CH3:43])=[O:41])([OH:44])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1Oc1cnccc1C=O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1Oc1cnccc1C(=O)O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a solution of Methyl(1RS,2SR,3RS)-3-[2-[(4-formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (128 mg, 0.24 mmol) in t-BuOH (10 mL) was added a solution of NaClO2 (34 mg, 0.28 mmol) and NH2SO3H (40 mg, 0.42 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 2 h and it was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (Mg2SO4). The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 25% ethyl acetate/hexanes containing 5% of acetic acid) to afford the title compound (90 mg, 69%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:34])([F:33])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C:7]([F:6])([F:33])[F:34])=[N:9][N:10]=4)[N:13]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)(=[O:4])=[O:3]
Reactant: OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
A solution of methanesulfonyl chloride (2.74 mL, 35.46 mmol) in DCM (40 mL) was added dropwise to a stirred solution of 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (12.04 g, 29.55 mmol) and triethylamine (8.24 mL, 59.11 mmol) in DCM (120 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes then warmed to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with DCM (100 mL), and washed with water (250 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to give 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (14.32 g, 100%) as a solid.
Reaction SMILES: CN(C)C=[CH:4][C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:16][CH2:17][CH3:18])[N:6]=1.O.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCCC1>[CH2:17]([O:16][C:7]1[N:6]=[C:5]([CH:4]=[O:22])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:18]
Reactant: CCOc1nc(C=CN(C)C)c([N+](=O)[O-])cc1C#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1nc(C=O)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a stirred solution of the compound prepared in Example 445 (1.07 g) in tetrahydrofuran (20 mL) at ambient temperature was added water (20 mL), and to the resulting mixture was added sodium periodate (2.62 g). The resulting mixture was stirred at ambient temperature for 18 hours. There was a significant amount of precipitate present in the reaction mixture, and it was collected by filtration and washed with 50% aqueous tetrahydrofuran. The combined filtrate and wash were concentrated to remove most of the tetrahydrofuran, and the residue was extracted with chloroform. The organic layers were combined and dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 1/1 hexanes/ethyl acetate, to provide the title compound (0.61 g) with the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](Cl)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:26][NH2:27])=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)NN)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
20 g of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carbonyl chloride in 100 ml of ethanol are placed under nitrogen and the mixture is heated at reflux for 2 hours. It is allowed to return to a temperature of 20-25° C., then 50 g of hydrazine hydrate are added and the mixture is again heated at reflux for 3 and a half hours. The reaction medium is filtered while hot and then the ethanol is evaporated. The reaction medium is concentrated, then taken up in 150 ml of DCM and separated by settling. The aqueous phase is discarded, the organic phase is washed twice with 100 ml of water and then the DCM is evaporated. After drying under vacuum, 16.9 g of the expected compound are obtained.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][C:20]=12.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22]([N:8]3[C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11][O:10][C:9]3=[O:12])=[N:21][C:20]=12
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: Clc1ccn2ncc(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
To a solution of (S)-4-phenyloxazolidin-2-one (0.737 g, 4.517 mmol) in DMF was added sodium hydride (0.189 g, 4.73 mmol) and the reaction stirred at ambient temperature for 45 minutes. 3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (1.00 g, 4.302 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction mixture was poured into water and the water layer extracted with ether. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using 2% EtOAc/DCM as the eluent to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (1.233 g, 3.433 mmol, 79.80% yield).