Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].O.[C:8]([NH:11][C@@H:12]1[C@@H:17]([CH2:18][CH:19]([OH:22])CO)[CH2:16][C:15]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])=[CH:14][C@H:13]1[O:32][CH:33]([CH3:35])[CH3:34])(=[O:10])[CH3:9]>CO>[C:8]([NH:11][C@@H:12]1[C@@H:17]([CH2:18][CH:19]=[O:22])[CH2:16][C:15]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])=[CH:14][C@H:13]1[O:32][CH:33]([CH3:35])[CH3:34])(=[O:10])[CH3:9]
Reactant: CC(=O)N[C@@H]1[C@@H](CC(O)CO)CC(C(=O)OCC[Si](C)(C)C)=C[C@H]1OC(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: CC(=O)N[C@@H]1[C@@H](CC=O)CC(C(=O)OCC[Si](C)(C)C)=C[C@H]1OC(C)C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Sodium periodate (54 mg, 0.252 mmol) and water (1.5 mL) were added to a room temperature solution of Example 10B (70 mg, 0.168 mmol) in methanol (15 mL). After stirring for 3 hours, the reaction mixture was filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using ethyl acetate to afford 57 mg (92%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][N:24]4[CH:27]=[C:28]([CH2:30][C:31]([O:33]CC)=[O:32])[N:29]=[C:23]4[CH:22]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[OH-].[Na+].[ClH:40].Cl.CCOC(C)=O>C1COCC1.CCOC(C)=O>[ClH:40].[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][N:24]4[CH:27]=[C:28]([CH2:30][C:31]([OH:33])=[O:32])[N:29]=[C:23]4[CH:22]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14]
Reactant: CCOC(=O)Cc1cn2ccc(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Oc1ccc(-c2nc(-c3ccn4cc(CC(=O)O)nc4c3)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (7-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridin-2-yl)acetate (230 mg) in THF (2.0 ml) was added a 1M aqueous NaOH solution (1.0 ml), followed by stirring at 80° C. for 2 hours. After cooling to room temperature, a 1 M HCl aqueous solution (1.0 ml) was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=10:1 to 5:1) to obtain colorless powders. To a solution of this colorless powder in EtOAc was added a 4M HCl/EtOAc solution, followed by concentration. The resulting colorless powder was powdered/washed with IPE to obtain (7-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridin-2-yl)acetic acid hydrochloride (180.4 mg) as colorless powders.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH2:38]([C@H:35]1[CH2:36][CH2:37][C@H:32]([C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[CH2:33][CH2:34]1)[CH:39]=[CH:2][CH2:3][CH3:4]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 5.1 g of propyl-triphenylphosphonium bromide in 80 ml of t-butyl methyl ether was treated within 5 minutes with 1.48 g of potassium t-butylate while gassing with argon at -10° C. and the mixture was stirred at room temperature for a further 60 minutes. Thereafter, the mixture was treated within 5 minutes at 0° C. with a solution of 2.0 g of [trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde in 25 ml of t-butyl methyl ether and the resulting mixture was stirred for a further 45 minutes at room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The residue was dissolved in 20 ml of ethyl acetate and the solution was treated with 250 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the yellowish, oily residue (3.33 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 2.1 g of p-[trans-4-(2-pentenyl)cyclohexyl]benzonitrile as a colourless oil containing 92.7% of p-[trans-2-(2Z-pentenyl)cyclohexyl]benzonitrile and 6.6% of p-[trans-4-(2E-pentenyl)cyclohexyl]benzonitrile. The material was reacted further without additional purification. If desired, however, this mixture of isomers can be separated by chromatography on silica gel coated with silver nitrate (as illustrated in paragraph d).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=O)[NH:6][CH:7]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[Cl:20][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c[nH]c(=O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Clc1ccccc1
Product: Cc1cnc(Cl)c([N+](=O)[O-])c1
Yield: 75.3 %

Procedure:
A solution of 5-methyl-3-nitro-1H-pyridone (3.1 g, 20 mmol) in 50 mL chlorobenzene was treated with pyridine (0.47 g, 6.0 mmol) and phosphorus oxychloride (4.7 g, 30.8 mmol). The mixture was refluxed for 1 h. Upon cooling it was treated with sodium carbonate aq. followed by extraction with CH2Cl2. The organic phase was dried over Mg2SO4 and filtered. The solvent was evaporated in vacuo to give 2.6 g of the titled compound which was further purified by flash chromatography on silica gel (PE:EtOAc, 8:2, v/v). 1H-NMR (CDCl3) δ: 2.45 (s, 3H, CH3), 8.44 (d, 1H, J=2.0 Hz, Py-H), 8.58 (d, 1H, J=2.0 Hz, Py-H); MS (ESI+) m/z 173.0209 [M+H]+, C6H5ClN2O2 requires 172.0040.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:12][CH2:13][CH2:14][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: ClCCCl
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Yield: 83.9 %

Procedure:
A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloroethane (260.0 g, 2.65 mol), potassium carbonate (35.0 g, 0.252 mol) and 2-butanone (750 ml) was refluxed for 24 hours. The mixture was cooled, filtered and the solids were washed with ethyl acetate. The filtrate was concentrated to an oily residue that was dissolved in ethyl acetate (500 ml). The organic layer was washed sequentially with 1N sodium hydroxide (250 ml), water (500 ml) and brine (2×500 ml) and then dried over anhydrous magnesium sulfate. Concentration of the filtered solution and trituration of the residue with hexanes afforded 37.8 g (84.6%) of product as an orange solid: mp 71-73° C.; MS EI m/e 216 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:27])=[N:25][OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].O>C(OCC)(=O)C>[CH2:20]([O:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]3[NH:27][C:34](=[O:35])[O:26][N:25]=3)[CH:16]=2)[C:11](=[O:28])[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=1[CH2:8][NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=NO)cc12
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3noc(=O)[nH]3)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl[6-[amino(hydroxyimino)methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.78 g, 1.7 mmol) in ethyl acetate (10 ml) tetrahydrofuran (10 ml) was added 1,1′-carbonyldiimidazole (0.83 g, 5.1 mmol) and the mixture was stirred at 80° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give tert-butyl [4-butoxy-2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.54 g, 65.9%) as crystals.
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([OH:20])[CH:18]=[CH2:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:24][C:25]1([CH3:35])[CH:27]([CH:28]=[C:29]([Cl:31])[Cl:30])[CH:26]1[C:32](Cl)=[O:33]>C1C=CC=CC=1>[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([O:20][C:32]([CH:26]1[CH:27]([CH:28]=[C:29]([Cl:30])[Cl:31])[C:25]1([CH3:35])[CH3:24])=[O:33])[CH:18]=[CH2:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=CC(OC(=O)C1C(C=C(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g of pyridine in 10 ml of benzene is added dropwise at 5° C. to a solution of 8 g of 3-phenoxy-α-vinyl-benzyl alcohol in 30 ml of benzene, and at 10° C. is subsequently added 8 g of 2,2-dimethyl-3-(dichlorovinyl)-cyclopropanecarboxylic acid chloride. The reaction mixture is stirred for two hours at room temperature and is then allowed to stand for 12 hours. In further processing, the reaction mixture is diluted with ice water, the organic phase is extracted 3 times with 100 ml of 3% HCl solution each time and 3 times with 100 ml of 3% sodium bicarbonate solution each time; it is dried over sodium sulfate, and the benzene is distilled off. There is obtained the compound of the formula ##STR7## as colourless oil have a refractive index of nD40 =1.5710. (isomeric mixture 40% cis and 60% trans compound)
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:12][O:10][C:1](=[O:11])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@H](O)c1ccccc1

Procedure:
Into methanol (20 ml) were added (R)-mandelic acid (5.0 g) and p-toluenesulfonic acid (0.1 g), and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled, then neutralized, and concentrated. Ethyl acetate and water were added to the resulting residue, and the organic layer was collected by layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off from the filtrate to obtain a colorless oily compound mentioned above (5.35 g, 97.9%).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].C[O:12][C:13](=N)N.C[NH+]([CH2:19][C:20](CN(C)C)=[CH:21][NH+](C)C)C.C(OC(C)C)(=O)C.C(=O)(O)[O-].[K+]>O>[CH3:6][O:7][C:8]1[N:9]=[CH:21][C:20]([CH:13]=[O:12])=[CH:19][N:10]=1
Reactant: CN(C)CC(=C[NH+](C)C)C[NH+](C)C
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: COc1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred slurry of O-methylisourea hemisulfate (1.08 g, 4.13 mmol), vinamidinium salt (3.00 g, 8.26 mmol), 1-methylethyl acetate (16.0 mL, 137 mmol) was added a solution of potassium bicarbonate (1.17 g, 11.6 mmol) in water (5.0 mL) over a 10 minutes period. After completion of the addition the resulting reaction mixture was stirred at room temperature for 40 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][CH:4]=2)=[O:7])[CH2:13][CH2:12]1
Reactant: CN1CCN(C(=O)c2ccc(O)cc2)CC1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN1CCN(C(=O)c2ccc(OC(=O)N(C)c3ccccc3)cc2)CC1

Procedure:
The title product was prepared from 1-(4-hydroxybenzoyl)-4-methyl-piperazine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (22%, colorless oil). HPLC-MS: m/z=354.1 (M+1); Rt: 2.07 min.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)=[O:2].[C:20]([C:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1)#[CH:21]>CCCCCCC.C(Cl)Cl>[C:22]1([C:20]#[C:21][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Reactant: C#CC1=CCCCC1
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=Cc1ccc(C#CC2=CCCCC2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-formyl-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/DCM 1:1; yield (71 mg, 68%); 1H NMR δ (CDCl3): 9.99 (s, 1H), 8.02 (d, J=8.51 Hz, 2H), 7.52 (d, J=8.60 Hz, 2H), 6.31-6.27 (m, 1H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 210.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8]OS(C)(=O)=O)=[C:5]([CH3:14])[N:4]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:3]=1.[CH3:25][O:26][C:27](=[O:41])/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([C@@H:36]2[CH2:40][CH2:39][CH2:38][NH:37]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C(=O)C>[CH3:25][O:26][C:27](=[O:41])/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([C@@H:36]2[CH2:40][CH2:39][CH2:38][N:37]2[CH2:8][CH2:7][C:6]2[C:2]([CH3:1])=[N:3][N:4]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[C:5]=2[CH3:14])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c(CCOS(C)(=O)=O)c2C)cc1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)nn(S(=O)(=O)c3ccc(C)cc3)c2C)cc1
Yield: 60.8 %

Procedure:
To a mixture of methanesulfonic acid 2-[3,5-dimethyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-ethyl ester (600 mg, 1.61 mmol) and (E)-3-((S)-4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (317 mg, 1.37 mmol) in 10 mL acetonitrile-N,N-dimethylacetamide (3:1 v/v) was added potassium carbonate (334 mg, 2.42 mmol). The mixture was subjected to microwave irradiation for 15 minutes and the crude mixture was filtered through a plug of Celite, which was washed with dichloromethane. The combined filtrates were partially concentrated and partitioned between ethyl acetate and aqueous ammonium chloride solution. The organic layer was washed three times with the same salt solution, which was back extracted once. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give a yellow oil, which was purified via silica gel column chromatography (0-50% ethyl acetate in heptane) to give ((E)-3-[4-((S)-1-{2-[3,5-dimethyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-ethyl}-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (423 mg, 0.833 mmol, 52% yield) as a colorless solid.
Reaction SMILES: C([O:4][C:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:6])(=O)C.[H][H].C(OC(CCC1C=CC=CC=1)C)(=O)C.C(Cl)(Cl)Cl>C1COCC1.F[B-](F)(F)F.C1([Rh+]C2CCCCC=CC=2)CCCCC=CC=1>[C:9]1([CH2:8][CH2:7][CH:5]([OH:4])[CH3:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(CCc1ccccc1)OC(C)=O
Reactant: [H][H]
Agent: C1=CCCCCC([Rh+]C2=CC=CCCCC2)=C1
Agent: CC(=O)OC(C)CCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(O)CCc1ccccc1

Procedure:
This reaction was performed as in Example 1 with bis(cyclooctadienyl)rhodium tetrafluoroborate (20 mg; 0.05 mmol; 0.02 equiv), R,R-1,2-bis(2,5-dimethylphospholano)benzene (6, R"=CH3 ; 18 mg; 0.06 mmol; 0.024 equiv) and 4-phenylbut-1-en-2-yl acetate (476 mg; 2.5 mmol) in 20 mL of degassed THF until hydrogen uptake ceased (1.5 h) to afford 0.51 g of crude product. 1H NMR analysis indicated 4-phenyl-2-butyl acetate as the sole product, and chiral GC analysis and comparison to racemate indicated 77% ee for 4-phenyl-2-butyl acetate. Base hydrolysis afforded 4-phenyl-2-butanol, [α]D25 -12.0° (c 2.115, CHCl3), which indicates the (R) configuration when compared with the known rotation ([α]D +13.5° (c 2.1, CHCl3)) for the (S) enantiomer.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[CH2:14]([CH2:16][NH2:17])[OH:15]>C(Cl)(Cl)Cl>[OH:15][CH2:14][CH2:16][NH:17][C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: CC1CCC(C(C)C)C(C(=O)NCCO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of p-menth-3-oyl chloride prepared as in Example 1 (4.0 g., 0.020 moles) in chloroform (30 ml.) was added dropwise to a stirred solution of ethanolamine (3 g., 0.043 moles) in chloroform (50 ml.). The reaction mixture becomes warm, goes cloudy and finally a yellow oil starts to separate out. After stirring for 2 hours at room temperature the mixture was poured into water. The organic layer was separated, washed with dilute H2SO4, and dried (MgSO4). Removal of the solvent left a viscous oil (3.8 g.). This was distilled under vacuum to yield N-(2-hydroxyethyl)-p-menthane-3-carboxamide as a colourless very viscous oil, b.p. 160°/01. mm.
Reaction SMILES: [Cu][C:2]#[N:3].[NH2:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8](Br)=[CH:7][CH:6]=1.[C-]#N.[Na+]>CN(C)C=O.O>[NH2:4][C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:2]#[N:3])=[CH:7][CH:6]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N)ccc1C#N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Copper(I) cyanide (12 mmol) is added to 10 mmol of 6-amino-3-bromo-2-methylpyridine dissolved in dimethylformamide. The mixture is refluxed for 10 hours, then cooled to 80° C. and poured into a solution of sodium cyanide (40 mmol) in water. After stirring for 1 hour at ambient temperature, the mixture is extracted with ethyl acetate. The organic phase is washed and then dried and evaporated to yield the expected product in the form of an ochre solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:8])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].Cl.[CH2:10](N(CC)CC)C.CCOCC>CO>[NH2:1][C@@H:2]([CH3:8])[CH:3]([OH:7])[C:4]([O:6][CH3:10])=[O:5]
Reactant: CCN(CC)CC
Reactant: C[C@H](N)C(O)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(O)[C@H](C)N
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Into a suspension of (3S)-3-amino-2-hydroxybutanoic acid (1.0 g, 8.4 mmol) in methanol (25 ml) was bubbled anhydrous hydrogen chloride gas until a solution resulted. After a solution resulted, the reaction was cooled in an ice bath and saturated with hydrogen chloride. The cooling bath was removed and the reaction stirred at room temperature for 3.5 hours. The solvent was removed on a rotary evaporator at ambient temperature and the resultant residue dissolved in methanol (25 ml), cooled in an ice bath and saturated with hydrogen chloride gas. Warming of the reaction solution to room temperature and removal of the solvent on a rotary evaporator gave an oil. To this oil was added triethylamine (15 ml) followed by the minimum amount of methanol (about 15 ml) needed to dissolve the initial gummy solid. The solution was cooled in an ice bath and ether (75 ml) added in portions with stirring. The precipitated triethylamine hydrochloride was filtered and the filtrate evaporated to give methyl (3S)-3-amino-2-hydroxybutanoate.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])=[O:12])[C:4]=2[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>CCO>[N:36]1([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:32])([F:33])[F:34])=[O:24])[CH:9]=[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=4[CH3:21])=[O:12])[C:4]=3[N:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: C1CNC1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(N3CCC3)nc12
Yield: 32.4 %

Procedure:
A solution of 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (80 mg, Example 135), azetidine hydrochloride (60 mg) and N,N-diisopropylethylamine (208 μL) in EtOH (1.8 mL) was reacted at 120° C. for 20 minutes in a microwave reactor (Biotage, Initiator). The reaction mixture was concentrated under reduced pressure, and the residue was purified on column chromatography to obtain 2-(azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (27 mg). This was dissolved in MeOH (1 mL), 2N hydrogen chloride/MeOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (21 mg) as white powder.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:36]=1[CH2:37]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:35]=3[F:34])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Reactant: Fc1cc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(OCc2ccc(C(F)(F)F)cc2F)c(Cl)c1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To 20 ml of N,N-dimethylformamide are added 3-(2-chloro-6-fluorophenyl) 5-[3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (0.90 g) and potassium carbonate (0.40 g) and 2-fluoro-4-trifluoromethylbenzyl chloride (0.50 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 5 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.60 g of desired compound (melting point: 109.0°-111.0° C.).