Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=CC=CC=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[CH2:24](N1CCN(C2SC(C([O-])=O)=C(C)N=2)C1=O)C>>[CH2:17]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[SH:5]([CH3:24])[C:6]([C:7]([OH:9])=[O:8])=[CH:2][N:3]=2)[C:13]1=[O:23])[CH3:22]
Reactant: CCN1CCN(c2nc(C)c(C(=O)[O-])s2)C1=O
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: CCN1CCN(C2=NC=C(C(=O)O)[SH]2C)C1=O
Yield: 80 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with 2-(3-ethyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 80% yield: 1H NMR (300 MHZ, DMSO-d6) δ 3.97-3.91 (m, 2H), 3.54-3.48 (m, 2H), 3.23 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 0.98 (t, J=7.2 Hz, 3H); MS (ES+) m/z 256.3 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].CCN(CC)CC.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C)OS(C)(=O)=O
Temperature: 0 °C

Procedure:
An ice cold solution of (R)-2-butanol (888 mg) in DCM (15 ml) was treated with Et3N (1.26 ml) and followed by dropwise addition of methanesulfonyl chloride (0.52 ml). After 1 h the solution was washed with saturated sodium hydrogen carbonate solution (5 ml), water (2×5 ml), brine (5 ml), dried (MgSO4) and evaporated to give the title compound (D33)(0.9 g). 1H NMR δ (CDCl3): 4.74 (1H, m), 3.00 (3H, s), 1.67 (2H, m), 1.41 (1H, d, J=6.5 Hz), 0.99 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:21]([O:23]C)=[O:22])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)[N:4]=1.[OH-].[K+:26].O>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:21]([O-:23])=[O:22])=[N:14][C:15]([N:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)[N:6]=1.[K+:26]
Reactant: COC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(Oc2ccc(N(C)C)nc2C(=O)[O-])n1

Procedure:
9.2 g (27.5 mmol) of methyl 3-(4,6-dimethoxypyrimidin-2-yl)oxy-6-dimethylaminopicolinate was dissolved in 30 ml of methanol, and 1.55 g (27.5 mmol) of 10% potassium hydroxide was added thereto. Furthermore, 20 ml of water was added thereto, and the resultant mixture was stirred at room temperature. The reaction liquor was concentrated under reduced pressure, and acetone was added thereto to precipitate a crystal. The crystal thus obtained was separated by filtration and was washed with hexane to obtain an aimed compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]([CH3:15])[N:4]=1>[Pd].CO>[CH3:1][N:2]([CH3:16])[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]([CH3:15])[N:4]=1
Reactant: CN(C)c1nn(C)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: CN(C)c1nn(C)c2ccc(N)cc12
Yield: 87.7 %

Procedure:
An MeOH (10 ml) solution containing N,N,1-trimethyl-5-nitro-1H-indazol-3-amine (132 mg) obtained in the 2nd step was prepared and subjected to a hydrogenation reaction (70° C.; 50 bar; flow rate: 2 ml/min; 10% Pd/C) using H-Cube™. The solvent was distilled away under, reduced pressure. A red solid of N3,N3,1-trimethyl-1H-indazol-3,5-diamine (100 mg) was thus obtained.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[C:11]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: C(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a reactor was introduced 41 mL (55 mmol; 1.06 M THF solution) of benzylmagnesium chloride under a nitrogen atmosphere. The contents were cooled to 0° C. Thereafter, a solution prepared by mixing 9.11 g (50.0 mmol) of benzophenone with 18 mL of THF was gradually added dropwise thereto, and this mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was washed with 0.1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was dissolved in 46 mL of toluene, and 0.18 g of p-toluenesulfonic acid monohydrate was added thereto. Azeotropic dehydration was conducted for 2 hours with toluene refluxing. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 12.5 g (98%) of a transparent oily substance.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:10])[C@@:5]([NH2:9])([CH3:8])[CH2:6][CH3:7].C1C=CC([C@H](N)CO)=CC=1>>[ClH:1].[CH3:2][O:3][C:4](=[O:10])[C@:5]([NH2:9])([CH3:8])[CH2:6][CH3:7]
Reactant: CC[C@@](C)(N)C(=O)OC
Agent: Cl
Agent: N[C@H](CO)c1ccccc1
Product: CC[C@](C)(N)C(=O)OC

Procedure:
(S)-2-Amino-2-methyl-butyric acid methyl ester hydrochloride was prepared in analogous manner to (R)-2-amino-2-methyl-butyric acid methyl ester hydrochloride using (S)-phenylglycinol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25]([C:27]([OH:29])=O)=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:31]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][NH:38][C:27]([C:25]2[CH:24]=[CH:23][C:18]3[NH:19][C:20](=[O:22])[CH2:21][C:15]4[CH:14]=[N:13][C:12]([NH:11][C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:30][C:16]=4[C:17]=3[CH:26]=2)=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)O)ccc2NC(=O)C3)cc1OC
Reactant: NCCN1CCCC1
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)NCCN4CCCC4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic acid (I-43) and 2-(pyrrolidin-1-yl)ethanamine were converted to I-75 (6%) after purification by C-18 RP LC-MS chromatography. HRMS Calcd. for C27H30N61O4: 503.2406, Found 503.2399.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:19][CH3:20])=[C:12]([C:14](=[O:18])[C:15](O)=[O:16])[CH:13]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:19][CH3:20])=[C:12]([C:14](=[O:18])[C:15]([Cl:23])=[O:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a 20 ml volume three-necked flask, 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetic acid (8-c) (1.01 g), toluene (3.5 ml), dimethylformamide (3 drops), and thionyl chloride (624 mg) were added under a nitrogen atmosphere, and stirred at 50° C. for 3 hours. The mixture was concentrated under reduced pressure, and azeotropic-distilled with toluene 3 times to give 937 mg of 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl chloride (6-c).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[C:3](=[O:8])[NH:4][CH2:5][CH:6]=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl.O>[O:8]1[CH:6]=[CH:5][N:4]=[C:3]1[C:2]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:1]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)NCC=O
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)c1ncco1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A solution of benzyl 2-methyl-1-oxo-1-(2-oxoethylamino)propan-2-ylcarbamate (2.23 g, 8 mmol) in methylene chloride (50 mL) was added to a freshly prepared solution of PPh3 (3.15 g, 12 mmol), I2 (3.05 g, 12 mmol) and Et3N (2.43 g, 24 mmol) in methylene chloride (100 mL). The resulting mixture was stirred at room temperature until TLC showed the reaction was completed. Then water (150 mL) was added. The organic layer was washed with 5% sodium bisulfite (150 mL×2), brine (150 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a yellow oil which was purified by column chromatography (silica gel, 50 g, eluting with 25% ethyl acetate in petroleum ether) to yield the title compound (0.63 g, 30%) as colorless oil; MS: m/e 261.2 [M+H]+. 1H NMR (300 MHz, CDCl3): δ 7.57 (s, 1H), 7.37-7.33 (m, 5H), 7.05 (s, 1H), 5.06 (s, 2H), 1.74 (s, 6H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=O)[C:8]([F:23])=[CH:7][C:6]=1[Cl:24].P(Cl)(Cl)([Cl:29])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]2[Cl:29])[C:8]([F:23])=[CH:7][C:6]=1[Cl:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CON(C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.98 g of N-methoxy-N-methyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, 1.5 ml of phosphorus oxychloride and 1.2 ml of pyridine in 10 ml of toluene is stirred at 80° C. for 3.5 hours. The mixture is then treated with 50 ml of ice-water and extracted three times with 80 ml of ethyl acetate each time. The combined organic phases are washed to neutrality, dried over anhydrous sodium sulphate and treated with 200 ml of n-hexane, and the mixture is filtered through 20 g of silica gel. The mixture is then concentrated and the product is left to crystallize out. In this manner there is obtained N-methoxy-N-methyl-2-chloro-5-[2-chloro-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-4-fluorobenzamide, m.p. 183° C.;
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[OH:1][CH:21]([N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[CH2:2][CH2:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccccc2C(OCC2CO2)N1c1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCN(C(O)CCOC2c3ccccc3C(=O)N2c2ccccc2)CC1
Yield: 127.3 %

Procedure:
A solution of 3-(2,3-epoxypropoxy)-2-phenyl-isoindolin-1-one (8.4 g.) and 1-methylpiperazine (3.6 g.) in anhydrous toluene (84 cc.) is heated under reflux for 3 days. After cooling, the reaction mixture is washed with water (2 × 50 cc.) and then the organic solution is extracted with 1N hydrochloric acid (55 cc.) and water (3 × 20 cc.). The aqueous and acid solutions are combined and are rendered alkaline by addition of 1N sodium hydroxide solution (55 cc.). The oil which separates out is extracted with methylene chloride (150 cc.) and then the organic solution obtained is dried over sodium sulphate and concentrated to dryness under reduced pressure. The residual oil is dissolved in ethanol (20 cc.) and the resulting solution is added to a hot solution of fumaric acid (5.85 g.) in ethanol (80 cc.). The product which crystallises on cooling is filtered off and then washed with ethanol (30 cc.) and di-isopropyl ether (40 cc.). After drying, 3-[3-hydroxy-3-(4-methylpiperazin-1-yl)-propoxy]-2-phenyl-isoindolin-1-one acid difumarate (14.5 g.), melting at 194° C., is obtained.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:9])[CH2:5][N+:6]([O-:8])=[O:7].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CCOCC>[CH3:9][C:4]([CH2:5][N+:6]([O-:8])=[O:7])=[CH:3][CH2:2][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CC(=CCBr)C[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCOCC
Product: CC(=CCN1CCOCC1)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.1 Mol of 1-bromo-3-methyl-4-nitro-2-butene in ether at 0° C. was added 0.2 Mol of morpholine and stirred at room temperature for two days. The residue, after filtration and evaporation of the solvent, was purified by column chromatography followed by Kugelrohrdistillation at 140°-150° oven temperature and oil pump vacuum. The product obtained was a yellow oil.
Reaction SMILES: C([O:4][C@@:5]1([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[C@H:7]([CH3:8])[O:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:15][C:12]1[CH:11]=[CH:10][C:9]([C:5](=[O:4])[C@H:7]([OH:6])[CH3:8])=[CH:14][CH:13]=1
Reactant: CC(=O)O[C@]1(c2ccc(Br)cc2)O[C@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@H](O)C(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A 50 mL round bottom flask equipped with a magnetic stir bar, nitrogen gas inlet, and thermocouple was charged with (2S,3S)-2-(4-bromophenyl)-3-methyloxiran-2-yl acetate (490 mg, 1.81 mmol) and methanol (20 mL), and the reaction mixture was cooled to 0° C. in an ice/water bath. Potassium carbonate (15 mg, 0.1 mmol) was added, and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was concentrated and purified by column chromatography to give the product as an oil (208 mg, 50%): 1H NMR (CDCl3) δ 7.79 (d, 2H, J=8.4 Hz), 7.65 (d, 2H, J=8.8 Hz), 5.10 (q, 1H, J=7.0 Hz), 3.73 (bs, 1H), 1.44 (d, 3H, J=7.0Hz).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:26])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]2OC(=O)C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:44](=[O:45])[CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)OC1CS[C@@H]2C(N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 7-amino-3-acetoxycepham-4-carboxylic acid diphenylmethyl ester (4) in dichloromethane (7 parts) cooling at -30° to -10° C. are added pyridine (1.7 equivalents) and phenylacetyl chloride (1.1 equivalents). After stirring for 30 minutes, the mixture is neutralized with triethylamine (1 to 9 equivalents), stirred at 0° to 5° C. for 24 hours, and diluted with ice water. The formed organic layer is taken, washed with hydrochloric acid and water, dried, and concentrated. The residue is crystallized from a mixture of ethyl acetate and ether to give 7beta-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (6). Yield: 70.0%. mp. 170°-171° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH:4]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH2:5][OH:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CCOCC.C(=O)(O)[O-].[Na+].O.CCOC(C)=O.CCCCCC>[F:1][C:2]([F:12])([F:13])[CH2:3][CH:4]([CH2:7][C:8]([F:9])([F:10])[F:11])[CH:5]=[O:6]
Reactant: OCC(CC(F)(F)F)CC(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: O=CC(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butan-1-ol (1.5 g, 7.14 mmol) in CH2Cl2 saturated with water (30 mL) was stirred under nitrogen at 0° C. Dess-Martin periodinane reagent (6.35 g, 14.99 mmol) was added in one portion. The resulting suspension was stirred at 25° C., monitoring the progress of reaction by TLC analysis (1:2 EtOAc/hexane). As the rate of conversion of the starting material slowed, additional 2 mL portions of CH2Cl2 saturated with water were added (three portions over 15 min). After 19 h at 25° C., the reaction was complete by TLC. The solution was diluted with Et2O (50 mL) and a solution of sodium thiosulfate, Na2S2O3 (73.33 mmol, 11.6 g, 11 eq) in 80% saturated aqueous sodium bicarbonate solution (50 mL) was added. The mixture was stirred rapidly for 10 min until both phases were clear. The layers were separated and the aqueous phase was extracted with ether (30 mL). The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to 50% of its original volume to give 4,4,4-trifluoro-2-(2,2,2-trifluoro-ethyl)-butyraldehyde as a solution (20 mL). Mass Spectrum (+ESI): (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:14]=2)=[N:2]1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: COC(=O)c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-n2cc(-c3n[nH]c4ccccc34)nn2)ccc1C(=O)O
Temperature: 25 °C
Yield: 71.4 %

Procedure:
Methyl 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]-2-methoxybenzoate (363 mg; 1.04 mmol; 1.0 eq.) suspended in MeOH (8 mL) was treated with sodium hydroxide (8.3 mL, 1N; 8.3 mmol; 8.0 eq.) and stirred at RT until all solid was dissolved (3 h). MeOH was removed under reduced pressure, the resulting solution was made acidic by addition of HCl 1N and extracted with DCM (3 times). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige solid (249 mg, 71%). MS (ESI+): 336.1, MS (ESI−): 334.2.
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: [H][H]
Reactant: C=C(CCc1ccccc1)OC(C)=O
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: CON(C)[C:4](=[O:20])[CH2:5][N:6]([C@@H:14]([CH:18]=[CH2:19])[CH2:15][O:16][CH3:17])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:17][O:16][CH2:15][C@@H:14]([N:6]([CH2:5][CH:4]=[O:20])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10])[CH:18]=[CH2:19]
Reactant: C=C[C@@H](COC)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: C=C[C@@H](COC)N(CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of (S)-tert-butyl 2-(methoxy(methyl)amino)-2-oxoethyl(1-methoxybut-3-en-2-yl)carbamate (Intermediate 251, 3.35 g, 11.08 mmol) in dichloromethane (60 ml) at −78° C. under nitrogen was added diisobutylaluminum hydride (1.5 eq, 1.0M in dichloromethane) (16.62 ml, 16.62 mmol). The reaction mixture was stirred at that temperature for two hours. The reaction was quenched with slow addition of methanol at the low temperature and slowly warmed to ambient temperature. The reaction mixture was diluted with dichloromethane and washed with 10% aqueous potassium sodium tartrate twice, followed by water and brine. The organics were dried over sodium sulfate, filtered and concentrated. Silica gel chromatography (0%-50% ethyl acetate/hexanes) afforded the title compound as a clear oil (1.8 g, 68%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[N:4]=1.[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]3[CH2:27][CH2:28][CH2:29][NH:30][C:25]3=[N:24][N:23]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(O)(C)C>[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]3[CH2:27][CH2:28][CH2:29][N:30]([CH2:2][C:3]4[O:7][N:6]=[C:5]([C:8]5[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=5)[C:11]#[N:12])[N:4]=4)[C:25]3=[N:24][N:23]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1cccc(-c2noc(CCl)n2)c1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)O
Product: N#Cc1cccc(-c2noc(CN3CCCn4c(-c5ccncc5)nnc43)n2)c1
Temperature: 130 °C
Yield: 24.4 %

Procedure:
3-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile (98.2 mg, 0.447 mmol), and 3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (62.2 mg, 0.309 mmol) were suspended in acetonitrile (2 ml) and isopropanol (2.4 ml). After stirring for 45 min. potassium carbonate (88.1 mg, 0.637 mmole) was added. The mixture was heated in a microwave oven (130° C.) for 30 min. The product was filtered and then purified on prep. HPLC to give 29 mg of the title compound. 1H NMR(DMSO-d6): 8.72 (dd, 2H), 8.36 (br t, 1H), 8.30 (dt, 1H), 8.08 (dt, 1H), 7.79 (t, 1H), 7.68 (dd, 2H), 5.49 (s, 2H), 4.02(t, 2H), 3.3 (m, 1H), 2.36 (s, 3H), 1.71 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:11]=1)[N:8]=[C:7]([CH3:20])[CH:6]=[CH:5]2.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:11]=2)[N:8]=[C:7]([CH3:20])[CH:6]=[CH:5]3)=[CH:25][CH:24]=1
Reactant: CCOP(=O)(OCC)c1cc(Br)cc2ccc(C)nc12
Reactant: OCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CCNCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1cc(-c2ccc(CO)cc2)cc2ccc(C)nc12
Yield: 79.8 %

Procedure:
To a degassed solution of diethyl 6-bromo-2-methyl-8-quinolylphosphonate (429 mg, 1.2 mmol, obtained from step 1) and 4-hydroxymethylphenylboronic acid (364 mg, 2.4 mmol) in toluene (6 mL) was added Pd2(dba)3 (54.9 mg, 0.06 mmol). The mixture was degassed and Ph3P (125 mg, 0.48 mmol), Et2NH (105 mg, 1.44 mmol), n-propanaol (0.9 mL) and H2O (0.9 m-L) was added. The mixture was heated to reflux for 6 h. Aqueous NaHCO3 was added and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 369 mg (79%) of the title compound.