Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:14][C:15]([C@@H:17]([N:25]1[CH2:33][C:29]2[CH:30]=[CH:31][S:32][C:28]=2[CH2:27][CH2:26]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[Cl:24])=O.Cl>C(OCC)C.C(OCC)(=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:17]([N:25]1[CH2:26][CH2:27][C:28]2[S:32][CH:31]=[CH:30][C:29]=2[CH2:33]1)[CH2:15][OH:14]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: OCC(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of clopidogrel hydrosulfate (10 g, 23.8 mmol) in deionized water (300 mL) was added sodium bicarbonate (4 g, 47.6 mmol) in small portions. After mixing, t-butyl methyl ether (200 mL) was added and the solution was stirred for one hour. The layers were separated and the aqueous layer was extracted again with t-butyl methyl ether (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining brown oil was dried under high vacuum to a constant weight to afford clopidogrel free base (8.24 g, 106% yield which includes a trace of MTBE). While under a nitrogen atmosphere, a solution of lithium aluminum hydride (0.46 g, 12 mmol) in anhydrous diethyl ether (8 mL) was added drop wise to a solution of clopidogrel free base (3.22 g, 10 mmol) in anhydrous diethyl ether (4 mL). The lithium aluminum hydride was added at a rate to keep the ether refluxing gently. The addition was completed and the mixture was stirred at reflux temperature for an additional 30 minutes. After 30 minutes, the solution was cooled to 0° C. in an ice/water bath. The excess LiAlH4 was decomposed with ethyl acetate (2 mL, added slowly), followed by 6N HCl solution (20 mL added slowly with vigorous stirring). The mixture was transferred to a separatory funnel. The aqueous fraction was separated and extracted with ether (30 mL, which was discarded). The aqueous fraction was adjusted to pH=7 with 6 N NaOH solution (20 mL) and extracted with ether (4×15 mL). The combined ether extracts were washed with brine (20 mL), dried over MgSO4, and concentrated under vacuum to yield 2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl)ethanol (Compound Is, 2.12 g, 75.4% yield) as a white solid. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.45-7.40 (m, 2H), 7.23 (m, 2H), 7.04 (d, 1H, J=5.1 Hz), 6.70 (d, 1H, J=5.1 Hz), 4.47 (dd, 1H, J=6.9, 5.8 Hz), 3.97-3.91 (m, 1H), 3.81-3.74 (m, 2H), 3.62 (d, 1H, J=14.4 Hz), 3.01-2.95 (m, 1H), 2.84 (m, 2H) 2.76-2.68 (m, 1H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 135.31, 134.92, 133.81, 133.26, 130.03, 129.35, 128.85, 126.72, 125.34, 122.82, 64.53, 61.55, 50.20, 47.67, 26.15. MS (FIR, DIP-CI): Calculated for C15H17ClNOS (MH)+: 294.0714. found 294.0715
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].[F-].[K+].O>CN(C=O)C>[CH:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[O:11][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:16]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: O=Cc1cccc(O)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)n1
Yield: 97.9 %

Procedure:
2-Chloro-6-methylnicotinonitrile (0.50 g, 3.3 mmol), 3-hydroxybenzaldehyde (0.40 g, 3.3 mmol) and potassium fluoride (0.57 g, 9.8 mmol) were heated with stirring in dry DMF (5 mL) at 120° C. for 7 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (4×), water (4×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-phenoxy)-6-methyl-nicotinonitrile (0.77 g, 97%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[BH4-].[Na+].C1(C)C=CC=CC=1.O>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][OH:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2CO)C(C)=C1C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (2.26 g, 10.0 mmol) in ethanol (29.0 mL) was added sodium borohydride (0.42 g, 11.0 mmol) at room temperature and the mixture was stirred for 3 hrs. To the reaction mixture solution were added toluene (20.0 mL) and deionized water (20.0 mL) to separate an organic layer and an aqueous layer. The organic layer was dried over sodium sulfate and the solvent was then distilled off to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzylalcohol (2.23 g, yield 96.0%) as a pale oily substance.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)N=C(O[Si](C)(C)C)C.C1C(=O)N([Br:35])C(=O)C1.O>CN(C=O)C>[Br:35][C:8]1[C:9]2[C:10](=[O:15])[NH:11][CH:12]=[CH:13][C:14]=2[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]ccc2c1ccn2C1CCCC1
Agent: CC(=N[Si](C)(C)C)O[Si](C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2c1c(Br)cn2C1CCCC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 1-cyclopentyl-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (3.40 g) in DMF (42.0 mL) was added trimethylsilyl N-(trimethylsilyl)ethanimidate (7.52 g) at room temperature, and the mixture was stirred at 40° C. for 3 hr. The reaction mixture was allowed to be cooled to room temperature, and NBS (3.59 g) was added thereto at room temperature. The reaction mixture was stirred overnight at room temperature, water was added thereto, and the mixture was stirred at room temperature for 2 hr. The white precipitate was collected by filtration, and dried under reduced pressure to give the title compound (3.28 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+]>C(O)C.O>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: CSc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1ccccc1CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.00 g (6.57 mmol) of 2-methylsulfanylbenzaldehyde in 10 mL of ethanol at 0° C. was added 250 mg of NaBH4. The reaction was stirred at 0° C. for 10 min, then diluted with 50 mL of water. The aqueous suspension was extracted with diethyl ether (3×15 mL), then the combined ether layers were back extracted with brine (1×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to 1.01 g (100%) of the titled compound as an oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:13])[CH2:5]1)[CH:2]=C.[O:14]=[O+][O-]>CO.ClCCl>[Cl:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH:4]([CH2:1][CH2:2][OH:14])[CH2:5]2
Reactant: O=[O+][O-]
Reactant: C=CCC1Cc2cccc(Cl)c2C1
Solvent: ClCCl
Solvent: CO
Product: OCCC1Cc2cccc(Cl)c2C1
Reaction time: 16 h

Procedure:
Amalgamated zinc (prepared from zinc powder (6 g), mercuric chloride (0.6 g)) was heated under reflux for 7 hours with 2-allyl-4-chloro-indan-1-one (3 g), toluene (20 ml), conc. hydrochloric acid (20 ml), water (8 ml) and acetic acid (2 ml). Upon cooling conventional work-up gave a crude product which was purified by chromatography (silica/hexane) to give a 2-allyl-4-chloroindane (1.8 g). 2-Allyl-4-chloroindane (0.8 g) in dry methanol (10 ml) and dry dichloromethane (2 ml) was reacted at -35° with ozone until the blue colour persisted. After purging with nitrogen the solution was stirred 16 hours with dimethyl sulphide (2.58 g). The volatiles were removed and the residue taken up in tetrahydrofuran (10 ml) and heated under reflux with 4-toluenesulphonic acid (30 mg) and water (circa 0.5 ml) for 2 hours. After conventional work up the product, 2-(4-chloro-2-indanyl) ethanol, was obtained as a yellow oil (0.8 g).
Reaction SMILES: C1C([CH2:4][N:5]2[C:15](=[O:16])[N:14]([CH2:17]C3CC3)[C:12](=[O:13])[C:7]3[N:8]=[C:9](N)[NH:10][C:6]2=3)C1.C[O:22][C:23]1C=CC(C2CNC(=O)NC2)=C[C:28]=1[O:29][C@@H:30]1[C@@H:35]2C[C@@H](CC2)C1.N1(C(=O)C2NC=NC=2N(C)C1=O)C.CC(CN1C(=O)N(C)C(=O)C2N=CNC1=2)C.CCCOC1C=C([C@@]2(C)OC(=O)NC2)C=CC=1OC.COC1C=C(C2C=CC(=O)NN=2)C=CC=1OC(F)F.CC[C@]12C=C(C(OCC)=O)N3C4=C(CCN([C@@H]14)CCC2)C1C=CC=CC=13.COC1C=CC(C2CNC(=O)C2)=CC=1OC1CCCC1.CCCN1C(=O)N(C2C=CC(Cl)=CC=2)C2NC=NC=2C1=O.C1C(C(NC2C(Cl)=CN=CC=2Cl)=O)=CC(OCC2CC2)=C(OC(F)F)C=1.CCOC1C=C2[C@H]3CN(C)CC[C@H]3N=C(C3C=CC(C(N(C(C)C)C(C)C)=O)=CC=3)C2=CC=1OC>>[CH3:4][N:5]1[C:15](=[O:16])[N:14]([CH3:17])[C:12](=[O:13])[C:7]2[N:8]([CH2:35][CH:30]3[O:22][CH2:23][CH2:28][O:29]3)[CH:9]=[N:10][C:6]1=2
Reactant: COc1ccc(C2CNC(=O)NC2)cc1O[C@H]1C[C@@H]2CC[C@H]1C2
Reactant: Nc1nc2c(=O)n(CC3CC3)c(=O)n(CC3CC3)c2[nH]1
Agent: CC(C)Cn1c(=O)n(C)c(=O)c2nc[nH]c21
Agent: CCCOc1cc([C@]2(C)CNC(=O)O2)ccc1OC
Agent: CCCn1c(=O)c2nc[nH]c2n(-c2ccc(Cl)cc2)c1=O
Product: Cn1c(=O)c2c(ncn2CC2OCCO2)n(C)c1=O

Procedure:
Cipamfylline (HEP-688); atizoram (CP-80633); theophylline; isobutylmethylxanthine; Mesopram (ZK-117137); Zardaverine; vinpocetine; Rolipram (ZK-62711); Arofylline (LAS-31025); roflumilast (BY-217); Pumafentrin (BY-343);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].BrC1C2[C:62](=[N:63]C=C([N+]([O-])=O)C=2)[N:61](COCC[Si](C)(C)C)[N:60]=1>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]>[NH:61]1[C:62]2=[N:63][CH:4]=[CH:5][CH:6]=[C:7]2[C:2]([NH2:1])=[N:60]1
Reactant: Nc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(Br)c2cc([N+](=O)[O-])cnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Nc1n[nH]c2ncccc12
Temperature: 25 °C

Procedure:
Aniline (0.035 mL, 0.386 mmol), Pd2 dba3 (0.024 g, 0.0257 mmol), Xantphos (0.030 g, 0.0714 mmol), K3PO4 (0.120 g, 0.566 mmol) was added to a suspension of 3-bromo-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.096 g, 0.257 mmol) in toluene (10 mL), and the mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate. The combined filtrate was concentrated to give the crude product 5-nitro-N-phenyl-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-amine. This material was used without purification in the next step.
Reaction SMILES: [CH3:1][Mg]Br.[Cl-].[Li+].[CH3:6][C:7]1[N:8]([C:13]2[N:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:30]4[N:35]=[CH:34][C:33]([C:36]5[N:41]=[N:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)([CH3:29])[CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[CH:15][N:14]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH3:6][C:7]1[N:8]([C:13]2[N:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([C:30]4[N:35]=[CH:34][C:33]([C:36]5[N:41]=[N:40][C:39]([C:42]([OH:44])([CH3:1])[CH3:43])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)([CH3:29])[CH:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=3)=[CH:15][N:14]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: CC(=O)c1ccc(-c2ccc(C(C)(c3ccc(-c4cnc(-n5c(C)ccc5C)nc4)cc3)C(C)C)nc2)nn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ncc(-c2ccc(C(C)(c3ccc(-c4ccc(C(C)(C)O)nn4)cn3)C(C)C)cc2)cn1
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (32.4 mL of a 1.4 M solution in THF:toluene (25:75)) was added to a stirred solution of lithium chloride (1.93 g, 45.4 mmol) and 4z (11.7 g, 22.7 mmol) in THF (70 mL) at 0° C. After approximately 1 h at 0° C., the reaction was quenched by the dropwise addition of 1.0 M hydrochloric acid, and the resulting mixture stirred for 15 min. The resulting mixture was poured slowly into saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 35%-75% EtOAc/hexanes as eluent) to furnish the title compound 4e. m/z (ES) 533 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.23 (d, 1H, J=2.1 Hz), 8.95 (s, 2H), 8.39 (dd, 1H, J=2.3, 8.5 Hz), 7.89 (d, 1H, J=9.0 Hz), 7.79 (d, 1H, J=8.9 Hz), 7.57 (m, 4H), 7.46 (d, 1H, J=8.5 Hz), 5.92 (s, 2H), 4.20 (s, 1H), 3.22 (m, 1H), 2.38 (s, 6H), 1.81 (s, 3H), 1.70 (s, 6H), 0.93 (d, 3H, J=6.4 Hz), 0.88 (d, 3H, J=6.6 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]1[C:21]2[CH2:29][N:28]([C:30]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:31]=3[C:32]#[N:33])[CH2:27][CH2:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[OH:8][CH2:9][C@@H:10]([NH:19][C:20]1[C:21]2[CH2:29][N:28]([C:30]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:31]=3[C:32]#[N:33])[CH2:27][CH2:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C:11]1[CH:16]=[N:15][C:14]([O:17][CH3:18])=[N:13][CH:12]=1
Reactant: COc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ncc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-(4-(2-(tert-butyldimethylsilyloxy)-1-(methoxypyrimidin5-yl)ethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (740 mg, 1.39 mmol) in THF (10 mL) was added 1M TBAF in THF (5 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then treated with water and EtOAc. The organic layer was washed with aq. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was purified by semi-preparative HPLC to yield a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:12]3[N:11]=[C:10]([CH3:23])[C:9]=2[CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3]1.[C:31](OC(=O)C)([CH3:34])([CH3:33])[CH3:32].C(Cl)Cl.Cl(O)(=O)(=O)=O>CCOC(C)=O>[C:31]([O:29][CH:24]([C:9]1[C:10]([CH3:23])=[N:11][C:12]2[N:13]([N:14]=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)[C:8]=1[N:5]1[CH2:4][CH2:3][C:2]([CH3:30])([CH3:1])[CH2:7][CH2:6]1)[C:25]([O:27][CH3:28])=[O:26])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of methyl 2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (56 mg, 0.137 mmol) in t-butylacetate (2 ml, 0.137 mmol) was added anhydrous DCM (Volume: 2 ml) followed by perchloric acid (0.012 ml, 0.205 mmol). The resulting mixture was stirred at r.t for 1 h. Diluted with EtOAc, washed with sat'd NaHCO3. The organic phase was dried and evaporated to an oil, which was purified by Pre-HPLC to afford methyl 2-tert-butoxy-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (25 mg, 0.053 mmol, 38.5% yield). 1H-NMR (400 MHz, CDCl3) δ 1.16 (6H, s), 1.26 (9H, s), 1.58-1.60 (2H, m), 1.69-1.73 (2H, m), 2.69 (3H, s), 3.77 (3 H, s), 5.87 (1 H, s), 7.49-7.53 (3 H, m), 8.35-8.37 (2 H, m).
Reaction SMILES: N1CCC[CH:2]1C(O)=O.[C:9]([O:13][C:14]([N:16]1[CH2:20][C:19](=[N:21][O:22][CH3:23])[CH2:18][C@H:17]1[C:24]([OH:26])=[O:25])=[O:15])([CH3:12])([CH3:11])[CH3:10].CO.C[Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[CH3:23][O:22][N:21]=[C:19]1[CH2:20][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[C@H:17]([C:24]([O:26][CH3:2])=[O:25])[CH2:18]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C1CCCN1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1

Procedure:
A solution of the oximether- and/or olefin-type 2-pyrrolidinecarboxylic acid intermediate, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (0.648 g, 2.5 mmol), in a 1:1 mixture of methanol and toluene (35 ml) was made. Trimethylsilyl diazomethane (3.8 ml of a 2M solution in hexanes, 7.5 mmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluting with ethyl acetate. Removal of solvent from the filtrate gave the methylester product, e.g. 1-tert-butyl 2-methyl(2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate, as a yellow oil (0.646 g, 95% yield).
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.C[Si]([C:15]#[N:16])(C)C.[CH:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:15]([C@H:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:16]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccccc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: N#C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of L(+)-tartaric acid derivative shown in Table 1 (2 mmol) in a solvent shown in Table 1 (20 ml), a tetraalkyl titanate shown in Table 1 (2 mmol) was dropwise added and stirred for 30 minutes at room temperature. After evaporating volatile components off in the same manner as in Example 1, a solvent shown in Table 1 (20 ml) was added to the residue and stirred at room temperature to obtain a homogeneous solution. To the resulting solution, trimethylsilylcyanide (218 mg) and then benzaldehyde (212 mg) were added and stirred for 14 hours at room temperature. After the reaction, the reaction mixture was treated in the same manner as in Example 1. The product was analyzed by HPLC. The results are shown in Table 1.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:26][CH2:25][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:27]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:32][C:27]1([CH2:1][S:2]([N:5]2[CH2:6][CH2:7][C:8]3([C:12](=[O:13])[N:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=4)[CH2:10][CH2:9]3)[CH2:25][CH2:26]2)(=[O:4])=[O:3])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Reactant: O=C1CCCC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC1(O)CCCC1)CC2

Procedure:
The title compound was prepared in analogy to example 208 step B from 8-methanesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 208, step A) and cyclopentanone. White solid. MS (ESI): 477.2 (MH+).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=1>C1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:1]([O:5][CH2:6][CH3:7])=[O:8])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Yield: 89.2 %

Procedure:
Under argon flow, 10.85 g of diethyl carbonate was dissolved in 60 ml of benzene, and 2.75 g of 60% sodium hydride was added and the mixture was heated to reflux. A solution of 5.58 g of ethyl 4-bromophenylacetate/20 ml of benzene was added dropwise to the solution over 1 hour, and the mixture was heated to reflux for 1 hour. After cooling, ice-cold water was added dropwise to the reaction solution slowly. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1) to provide 6.45 g of the objective compound as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:16]([CH3:15])=[CH:25][C:24]([N+:26]([O-:28])=[O:27])=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (4.2 g), methyl 3-methyl-5-nitrosalicylate (1.8 g) and triphenylphosphine (6.8 g) in dichloromethane (100 ml) was added diethyl azodicarboxylate (4.1 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (3.1 g, yield 91%) as a rose oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27](COCC[Si](C)(C)C)[C:26](=[O:39])[CH:25]=[CH:24]4)=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26](=[O:39])[CH:25]=[CH:24]4)=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:10])[F:11]
Reactant: C[Si](C)(C)CCOCn1c(=O)ccc2cc(CCc3cnc(Nc4ccc(OC(F)F)c(Cl)c4)nc3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2cc(CCc3cnc(Nc4ccc(OC(F)F)c(Cl)c4)nc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-(2-(2-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (0.05 g, 0.087 mmol) in DCM (5 mL) was added TFA (0.067 mL, 0.872 mmol) and stirred at room temperature for 12 h. The reaction mixture was concentrated and purified by preparative HPLC on a Symmetry C8 column (19×250 mm, 7 μm) using 0-100% mobile phase B (ACN) in mobile phase A (10 mM ammonium acetate) to give 6-(2-(2-((3-chloro-4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)ethyl)quinolin-2(1H)-one as an off white solid (0.017 g, 44% yield). 1HNMR 400 MHz, DMSO-d6: δ 2.83 (t, J=14.80 Hz, 2H), 2.93 (t, J=14.80 Hz, 2H), 6.46-6.49 (m, 1H), 6.95-7.39 (m, 4H), 7.48 (s, 1H), 7.65-7.68 (m, 1H), 7.84 (d, J=9.60 Hz, 1H), 8.09 (d, J=2.40 Hz, 1H), 8.37 (s, 2H), 9.78 (s, 1H), 11.68 (s, 1H). LCMS (ES-API), RT: 2.95 min, m/z 441.0 (M−H)−.