Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:35])([CH3:34])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH:56]1[O:61][CH2:62][CH2:63]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:30]([Si:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:16][CH2:15][C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:63][CH2:62][O:61][CH:56]3[CH2:57][CH2:58][CH2:59][CH2:60][O:55]3)[CH:8]=2)[N:5]=1)([CH3:35])[CH3:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(O)c2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
A mixture of Intermediate 153d (0.53 g, 1.09 mmol) in dry THF (8 mL) was treated with triphenylphosphine (0.57 g, 2.18 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.22 mL, 1.64 mmol). The mixture was cooled to 0° C. then diisopropylazodicarboxylate (0.43 mL, 2.18 mmol) was added dropwise. After stirring at ambient temperature for 20 h the mixture was treated with water (0.1 mL) and concentrated in vacuo to a yellow oil. The oil was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound as an orange oil (0.41 g, 61%). LCMS (Method 3): Rt 5.25 min, m/z 614.6 [MH+].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][N:17]=1.[NH2:25][C:26]1[S:27][CH:28]=[C:29]([CH3:31])[N:30]=1>>[CH3:14][O:15][C:16]1[N:17]=[CH:18][C:19]([C:5]2[CH:4]=[N:3][C:2]([NH:25][C:26]3[S:27][CH:28]=[C:29]([CH3:31])[N:30]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:20][CH:21]=1
Reactant: Cc1csc(N)n1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: COc1ccc(-c2cnc(Nc3nc(C)cs3)c3nc(C)ccc23)cn1

Procedure:
The title compound, MS: m/e=364.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 2-methoxypyridine-5-boronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[I:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN=C=N
Reactant: O=C(O)c1cc(I)ccc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
5-Iodosalicylic acid (528 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-iodosalicylate (457 mg, yield 78%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].ClC1C=CC=C2C=1C1C(=O)NC(NC(=O)C(C)(C)C)=[N:26][C:20]=1[NH:21]2.O.[OH-].[NH4+]>CS(C)(=O)=O>[NH2:21][C:20]1[NH:26][C:7](=[O:8])[C:6]2[C:5]3[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: CS(C)(=O)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Temperature: 150 °C
Yield: 59.7 %

Procedure:
To a 50 mL flask was added 4 (225 mg, 1 mmol), 9 (452 mg, 4 mmol) in DMSO2 (500 mg) was heated at 150° C. for 2 h. The mixture was cooled to room temperature. 15 mL water was added and ammonium hydroxide was used to neutralize the suspension. The brown solid was obtained by filtration, Washed with water and dried. The solid was dissolved in methanol and silica gel was added A dry silica gel plug obtained after evaporation. The plug was then loaded on the column and washed with 5% methanol in chloroform. The fractions containing the desired product (TLC) were pooled and evaporated to afford 132 mg (60%) of 10 as a white solid: 1H NMR (DMSO-d6) δ 1.71 (m, 4H), 2.60 (m, 2H), 2.72 (m, 2H), 6.38 (s, 2H), 10.72 (s, 1H). Anal. calcd for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99: O, 7.23; S, 14.49. Found: C, 53.45; H, 5.06; N, 18.26; S, 14.02.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[C:19]([C:20]([O-:22])=O)=[C:18]([N:23]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:17]=[C:16]([S:41][CH3:42])[N:15]=1.O>O1CCCC1>[Cl:13][C:14]1[C:19]2[C:20](=[O:22])[CH:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34][CH2:33][N:23]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:18]=2[N:17]=[C:16]([S:41][CH3:42])[N:15]=1
Reactant: CCOC(=O)CCCN(Cc1ccc(OC)cc1)c1nc(SC)nc(Cl)c1C(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCOC(=O)C1CCN(Cc2ccc(OC)cc2)c2nc(SC)nc(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
To an ice-cooled solution of diisopropylamine (28.16 mL, 198.96 mmol) in tetrahydrofuran (400 mL) was added n-BuLi (15% in hexane, 82.5 mL, 192.93 mmol) dropwise and the mixture was then stirred at the 0° C. for 45 min. The reaction mixture was cooled to -78° C. and 4-chloro-6-((4-ethoxy-4-oxobutyl)(4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (29.0 g, 60.17 mmol) in tetrahydrofuran (300 mL) was added to the mixture dropwise over 45 min. and the reaction mixture was stirred at −78° C. for 15 min and ice cooled water (1 L) was added to the reaction mixture at same temperature. The reaction mixture was then warmed to room temperature and extracted with EtOAc (500 mL×2). The combined organic layer was washed with water (1 L), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford ethyl 4-chloro-9-(4-methoxybenzyl)-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepine-6-carboxylate (23.5 g); which was used in the next step without any purification. 1HNMR (400 MHz, CDCl3): δ 7.19 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.17 (d, J=14.8 Hz, 2H), 4.23-4.16 (d, J=14.8 Hz, 2H), 4.12-4.06 (m, 1H), 3.85-3.83 (m, 1H), 3.80 (s, 3H), 3.45-3.33 (m, 2H), 2.72-2.64 (m, 1H), 2.47 (s, 3H), 2.29-2.22 (m, 1H), 1.17 (t, J=7.2 Hz, 3H). LCMS [M+H]: 436
Reaction SMILES: [H-].[Na+].[CH2:3]([N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]([Cl:25])=[N:11][C:10]=2[N:9]=[C:8]1[N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)[C:4]#[C:5][CH3:6].[CH3:39][OH:40]>O>[ClH:25].[CH2:3]([N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:12]([O:40][CH3:39])=[N:11][C:10]=2[N:9]=[C:8]1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:4]#[C:5][CH3:6]
Reactant: CO
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(CCc3ccccc3)c(=O)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC#CCn1c(N2CCNCC2)nc2nc(OC)n(CCc3ccccc3)c(=O)c21
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
10 mg of sodium hydride (60%; oily) was added to a mixture consisting of 7 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-phenylethyl)-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 0.5 ml of methanol. The mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and concentrated. 0.5 ml of trifluoroacetic acid was added to the residue. The mixture was stirred at room temperature for 30 minutes, and then concentrated. The residue was purified by reverse-phase column chromatography using 20 to 80% methanol/water (containing 0.1% concentrated hydrochloric acid) to give 4.3 mg of the title compound.
Reaction SMILES: [Li][CH3:2].[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C:5](=[O:11])[CH2:4]2.O>C(OCC)C>[CH3:2][C:5]1([OH:11])[CH:6]2[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]2)[CH2:4]1
Reactant: [Li]C
Reactant: O=C1CN2CCC1CC2
Solvent: O
Solvent: CCOCC
Product: CC1(O)CN2CCC1CC2
Temperature: -78 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a well-stirred solution of MeLi [3.0M/diethyl ether] (67.0 mL, 201 mmol) in anhydrous diethyl ether (150 mL) at −78° C. was added, dropwise, a solution of quinuclidin-3-one (12.5 g, 100 mmol) in diethyl ether (100 mL). The resulting solution was maintained at −78° C. for 1 hour, then at room temperature for 18 hours. Water (60 mL) was added dropwise at 0° C. and the mixture was concentrated in vacuo to give a residue, which was purified by neutral aluminum oxide column chromatography (0-20% MeOH in CHCl3) to give 3-methylquinuclidin-3-ol (10.0 g, 71%) as a light yellow solid. To stirred acetonitrile (250 mL) at 0° C. was slowly added concentrated sulfuric acid (100 mL). The resulting solution was added dropwise to a mixture of 3-methylquinuclidin-3-of (9.10 g, 64.5 mmol) in acetonitrile (250 mL) at 0° C. The reaction mixture was stirred at room temperature for 60 hours, then cooled with an ice bath and basified with aqueous sodium hydroxide solution to pH 10. The mixture was extracted with 5:1 (v/v) CHCl3/i-PrOH. The organic layer was concentrated to afford a residue which was diluted with 2N aq. HCl and washed with 5:1 (v/v) CHCl3/i-PrOH. The remaining aqueous layer was then basified with 2N NaOH and extracted with 5:1 (v/v) CHCl3/i-PrOH. The combined organic layers were washed with water, dried (Na2SO4) and concentrated to give 9.5 g (82%) of the desired compound as a light yellow oil. The 2 enantiomers of the above intermediate are separated from each other by using chiral column on supercritical fluid chromatography (SFC) system.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.OS(O)(=O)=O.N([O-])=O.[Na+].[I-:29].[Na+]>COCCOC.O.CCOC(C)=O>[I:29][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([O:3][C:2]([F:19])([F:18])[F:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Oc2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
In a 300 mL round bottom flask, 6.92 g (25.63 mmol) 4-(4-(trifluoromethoxy)phenoxy)aniline was dissolved in 40 mL DME and cooled to 0° C. in a brine/ice bath. Using a dropping funnel, 10 equivalents aqueous H2SO4 (10N aqueous) were slowly added to the DME solution, immediately creating a salt suspension. The suspension was stirred at 0° C. for 10 minutes. Then, a solution of 1.5 equivalents sodium nitrite (2.65 g, 38.45 mmol) in 20 mL water was dropped slowly into the suspension while keeping the temperature below 5° C. After adding the sodium nitrite, the mixture was stirred at 0° C. for 30 minutes. Then, an aqueous solution of 3 equivalents sodium iodide was dropped slowly into the mixture. LC/MS showed the reaction was complete. The reaction mixture was diluted with 400 mL EtOAc and washed with 700 mL water and then 700 mL 1M sodium bisulfate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was then chromatographed by combiflash using a 330 gram silica column and a gradient of EtOAc (15% max) in hexane to provide 6.53 g of 1-iodo-4-(4-(trifluoromethoxy)-phenoxy)benzene (67%, white solid). m/z 380, 1H NMR (CHCl3): 7.67-7.61 (m, 2H), 7.23-7.16 (m, 2H), 7.04-6.97 (m, 2H), 6.81-6.75 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1Cc2ccccc2N1
Solvent: CC#N
Product: O=C1Cc2cc(Br)ccc2N1
Yield: 91.8 %

Procedure:
2-Oxindole (1.3 g) in 20 mL acetonitrile was cooled to −10° C. and 2.0 g N-bromosuccinimide was slowly added with stirring. The reaction was stirred for 1 hour at −10° C. and 2 hours at 0° C. The precipitate was collected, washed with water and dried to give 1.9 g (90% yield) of the title compound.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1CCCCC1.ClC(Cl)(Cl)C(=N)O[C:34]([CH3:37])([CH3:36])[CH3:35].B(F)(F)F.CCOCC>ClCCl>[C:1]([NH:11][C@H:12]([C:21]([O:23][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](CCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](CCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
At room temperature, to a solution of (N-carbobenzyloxy)-(L)-homophenylalanine (0.476 g, 1.52 mmol) in anhydrous dichloromethane (3.5 mL) was added anhydrous cyclohexane (7 mL). To this clear solution was added with vigourous stirring tert-butyl 2,2,2-trichloroacetimidate (0.30 mL, 1.67 mmol) followed by dropwise addition of boron trifluoride diethyl etherate (30 mL). After stirring at room temperature for 2 hr, additional tert-butyl 2,2,2-trichloroacetimidate (0.45 mL, 2.50 mmol) and boron trifluoride diethyl etherate (45 mL) were added to the reaction mixture and stirring was continued overnight at room temperature. The reaction mixture was filtered through a pad of celite, and the residue was washed with ether. The solvent was removed from the filtrate by rotoevaporation and the crude product was purified by flash column chromatography on silica gel eluted with 2-6% ethyl acetate in hexane to afford the title compound (211 mg, 38% yield), homogeneous by TLC (4/1 hexane/ethyl acetate).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][CH:6]([C:11]([O:13]C)=O)[C:7](OC)=[O:8].C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].Cl>CO>[OH:13][C:11]1[C:6]([O:5][CH3:4])=[C:7]([OH:8])[N:21]=[CH:19][N:20]=1
Reactant: N=CN
Reactant: COC(=O)C(OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(O)ncnc1O
Temperature: 0 °C

Procedure:
A modified procedure of Bretschneider, Richter, and Klotzer, Monatsh. Chem. 96(6), 1661-76 (1965), was used. Absolute methanol (1.0 l) was added with ice bath cooling to sodium methoxide (175 g, 3.24 mole) in a 3 L round bottom flask. When the mixture had cooled to less than 20° C., dimethyl methoxymalonate (162.14 g, 1.00 mole) was added, and then solid formamidine acetate (104.11 g, 1.00 mole) was added. The mixture was stirred in the ice bath for 30 minutes, and then refluxed for 1 hour. The mixture was cooled in a cold water bath and then concentrated HCl (about 350 mL) was added until the mixture was strongly acidic on pH test paper. The precipitate was filtered, suspended in cold water (about 400 ml), and then filtered again. The white powder was dried in vacuo (125.84 g, 88.7%), and carried on without further purification.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[C:18]([CH:20]([OH:34])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>N1C=CC=CC=1>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:34][CH:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1

Procedure:
A method for the preparation of the compound (-)-α-cyano-m-phenoxybenzyl (+)-α-isopropyl-4-difluorophenylacetate comprising: reacting (+)-α-isopropyl-4-difluoromethoxyphenylacetyl chloride with α-cyano-m-phenoxybenzyl alcohol in the presence of pyridine and isolating from the thus-obtained mixture of (+)-α-cyano-m-phenoxybenzyl (+)-α-isopropyl-4-difluoromethoxyphenylacetate said (-)-α-cyano-m-phenoxybenzyl (+)-α-isopropyl-4-difluoromethoxyphenylacetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]2=[N:8][CH:9]=1
Reactant: CCOC(=O)C1CCc2cc([N+](=O)[O-])cnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(N)cnc21

Procedure:
A mixture of ethyl 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (4.2 g, 17.8 mmol) and Pd/C (0.5 g, 10%) in 80 mL of ethanol was stirred at room temperature under 50 psi of hydrogen for 2 hours then filtered. The filtrate was concentrated to afford the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[N:14][C:15]([NH:16][C@@H:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18]O)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl>C(Cl)Cl>[C:1]1([N:7]2[C:11]3[N:12]=[CH:13][N:14]4[CH2:18][C@H:17]([CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:16]=[C:15]4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H](Cc1ccccc1)Nc1ncnc2c1cnn2-c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C1=Nc2c(cnn2-c2ccccc2)C2=N[C@@H](Cc3ccccc3)CN12

Procedure:
Next, 300 mg of the above product (S)-β-[(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol was dissolved in 15 ml CH2Cl2 followed by addition of 0.44 ml SOCl2. The reaction was heated to reflux for 3.5 hours. The solvent was then removed under a stream of nitrogen. The white solid was recrystallized from about 30% isopropyl alcohol/hexane followed by a second recrystallization from about 5% MeOH/butanone to yield 45 mg of (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine after drying under vacuum at 39° C. for 5 days (m.p. 255° C.).
Reaction SMILES: C[OH:2].[NH2:3][OH:4].C1C=NC2C3N=CC=CC=3C=CC=2C=1.[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([C:29]([F:32])([F:31])[F:30])[C:21]=1[C:22]#[N:23]>[Fe](Cl)Cl.CC#N.O>[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([C:29]([F:32])([F:30])[F:31])[C:21]=1[C:22](=[N:3][OH:4])[NH2:23].[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([C:29]([F:32])([F:30])[F:31])[C:21]=1[C:22]([NH2:23])=[O:2]
Reactant: NO
Reactant: N#Cc1c(C(F)(F)F)ccc(F)c1F
Reactant: CO
Agent: Cl[Fe]Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CC#N
Solvent: O
Product: NC(=NO)c1c(C(F)(F)F)ccc(F)c1F
Product: NC(=O)c1c(C(F)(F)F)ccc(F)c1F
Reaction time: 6 h

Procedure:
In a colorless, transparent glass reaction vessel was placed a mixed solvent of 150 ml of methanol-distilled water (volume ratio 1:2) into which were dissolved beforehand 9.91 g (150 mmol) of 50% hydroxylamine aqueous solution, 99 mg (0.50 mmol) of o-phenanthroline and on purpose 86 μg (0.00068 mmol) of iron(II) chloride. Into the mixed solvent was added 10.36 g (50.0 mmol) of 2,3-difluoro-6-trifluoromethylbenzonitrile (I″). The reaction temperature stood at 60° C. for 6 hours and was returned to room temperature. When the reaction solution was analyzed with HPLC [column: Inertsil ODS—34.6 mm ø×250 mm (GL Sciences Inc.), mobile phase; CH3CN—H2O—10% H3PO4 500:500:10 (v/v/v), flow rate; 1.0 ml/min, detection wavelength; 225 nm, and the same conditions for Example 2 and after], it was shown that (I″) (tR 16.0 min) disappeared, 2,3-difluoro-6-trifluoromethylbenzamidoxime (II′) was mainly produced (yield 76.9%, tR 3.6 min) and 2,3-difluoro6-trifluoromethylbenzamide (III′) was produced as a byproduct (yield 8.4%, tR 4.8 min).
Reaction SMILES: [C:1]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)#[N:2].[SH2:12].C(Cl)Cl>N1C=CC=CC=1>[CH3:10][C:8]1[CH:7]=[C:6]([CH3:11])[N:5]=[C:4]([NH:3][C:1]([NH2:2])=[S:12])[N:9]=1
Reactant: S
Reactant: Cc1cc(C)nc(NC#N)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)nc(NC(N)=S)n1
Reaction time: 1 h

Procedure:
A suspension of 10 g of 2-cyanoamino-4,6-dimethylpyrimidine in 50 ml of pyridine was saturated with hydrogen sulfide and stored for 1 hour at 25°. The H2S treatment was repeated twice more, and the mixture was allowed to stir at 25° for 16 hours. Methylene chloride was added, and the product was filtered and washed with methylene chloride to afford 8 g of 4,6-dimethylpyrimidin-2-yl thiourea, m.p. >260°. IR (Nujol) 3280, 3180, 3120, 1610 cm-1.
Reaction SMILES: C(OCC)(=O)C.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[O:19][C:18]([CH3:21])([CH3:20])[N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:16]2[CH2:29][F:30])=[CH:11][CH:10]=1)#[CH:8].Cl/[C:32](=[N:38]/[OH:39])/[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:25]([O:24][C:22]([N:17]1[C@H:16]([CH2:29][F:30])[C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]3[O:39][N:38]=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:8]=3)=[CH:14][CH:13]=2)[O:19][C:18]1([CH3:21])[CH3:20])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#Cc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To an ethyl acetate (20 ml) solution of (4S,5R)-tert-butyl 5-(4-ethynylphenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.35 g, 4.0 mmol) is added a dimethylformamide solution of (E)-ethyl 2-chloro-2-(hydroxyimino)-acetate (12.5 ml, 1.5 g, 2.5 equiv). Sodium hydrogen carbonate (3.5 g) is added to the solution and it is allowed to stir overnight at room temperature. The mixture is filtered and diluted with ethyl acetate (100 ml). After washing with water (4×25 ml) the organic phase is concentrated to give the crude product, which is purified on silica gel using a gradient of ethyl acetate in hexanes (0% to 20% ethyl acetate) to give the title compound (567 mg): 1H NMR (400 MHz, CDCl3) 1.43-1.56 (m, 14H) 1.62 (s, 3H) 1.74 (br. s., 3H) 4.50 (q, J=7.24 Hz, 3H) 5.20 (d, J=7.33 Hz, 1H) 6.96 (s, 1H) 7.60 (d, J=8.34 Hz, 2H) 7.86 (d, J=8.59 Hz, 2H), m/z (Cl) 449 ([M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1)=O.Cl.[NH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][C:13](=[N:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1
Reactant: Cc1cccc(C(=O)Cc2ccnc3ccc(Br)cc23)n1
Reactant: NN1CCCC1=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(C(Cc2ccnc3ccc(Br)cc23)=NN2CCCC2=O)n1
Yield: 69.6 %

Procedure:
Stir a mixture of 2-(6-bromo-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone (38.5 g, 113 mmol) and 1-aminopyrrolidinone hydrochloride (20 g, 147 mmol) in 115 mL pyridine at ambient temperature for 10 hours. Add about 50 g of 4 Å unactivated sieves. Continue stirring an additional 13 h and add 10-15 g silica and filter the mixture through a 50 g silica plug. Elute the silica plug with 3 L ethyl acetate. Combine the filtrates and concentrate in vacuo. Collect the hydrazone precipitate by filtration and suction dry to yield 33.3 g (69.7%) of the desired subtitled intermediate as an off-white solid. MS ES+=423 (M+1).