Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC([O:5][C@H:6]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C@@H:21]([O:27][C:28](=[O:31])[CH2:29][Cl:30])[CH2:20][C@@:19]2([CH3:32])[C@H:12]3[CH2:13][CH:14]=[C:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1)=O.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:30][CH2:29][C:28]([O:27][C@H:21]1[CH2:20][C@@:19]2([CH3:32])[C@@H:12]([CH2:13][CH:14]=[C:15]2[C:16](=[O:18])[CH3:17])[C@H:11]2[C@H:22]1[C@:23]1([CH3:26])[C@@H:8]([CH2:9][CH2:10]2)[CH2:7][C@@H:6]([OH:5])[CH2:25][CH2:24]1)=[O:31]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OC(=O)CCl)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Yield: 67.7 %

Procedure:
3β,11β-Bischloroacetoxy-5α-pregn-16-en-20-one (1.2 g) was stirred at 100° in dioxan (20 ml) containing water (4 ml) with sodium bicarbonate (1.26 g) for 4 hours. The mixture was cooled, poured into water and the precipitate collected by filtration, dried and filtered through silica gel (20 g) in ethylacetate. The eluate was evaporated and the residue crystallised from petrol containing a little ethyl acetate to yield the title compound (684 mg), m.p. 160.5°-162°, [α]D +75.2°.
Reaction SMILES: [C:1]([Si:5]([CH3:51])([CH3:50])[O:6][CH:7]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:8][CH2:9][CH:10]([CH:25]([C:36]1[CH:41]=[CH:40][C:39](OC)=[CH:38][CH:37]=1)[NH:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)[C:11](N1C(C2C=CC=CC=2)COC1=O)=[O:12])([CH3:4])([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)[C:57](N)=[O:58])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC)(C)(C)C>C(O)(=O)C>[C:1]([Si:5]([CH3:51])([CH3:50])[O:6][CH:7]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:8][CH2:9][CH:10]1[CH:25]([C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([O:58][CH3:57])[CH:41]=2)[N:26]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[C:11]1=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Reactant: COc1ccc(C(Nc2ccc([N+](=O)[O-])cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: COc1cccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccccc3)C(=O)N2c2ccc([N+](=O)[O-])cc2)c1
Yield: 70 %

Procedure:
A mixture comprising 6.1 g (8.6 mmol) of product 3, 7.3 ml of bistrimethylsilylacetamid, 0.5 g of Tetrabutylammoniumfluorid and 100 ml of tert-butylmethylether is stirred under a argon atmosphere for 10 h at room temperature. After finishing of the reaction 5 ml of acetic acid are added slowly by cooling with ice and evaporated. The residue is separated by chromatography on silica gel (ethylacetate/heptane=1/2). 3.3 g (70%) of product 4 is obtained in form of a light yellow compound in solid form: C31H38N2O5Si (546.74) MS (ESI+) 547.3 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:34][CH2:35]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1ccccc1C(F)(F)F
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccccc1C(F)(F)F

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[2-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 473.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](Cl)(C)C.N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>ClCCl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:10]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1ccccc1
Reaction time: 3 h

Procedure:
A mixture of Example 125B (2 g, 9.2 mmol) and dichloromethane (56 mL) was treated sequentially with 1M trimethylsilyl chloride (20.4 mL, 20.4 mmol) and pyridine (3.4 mL, 41.7 mmol), stirred for 3 hours, treated with benzenesulfonyl chloride (1.4 mL, 11.1 mmol), stirred for 48 hours, diluted with dichloromethane (100 mL), acidified to pH 1 with 1M HCl and stirred for 15 minutes. The organic layer was dried (Na2SO4), filtered, and concentrated. Purification by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min provided the desired product as an off-white solid. MS (ESI(−)) m/e 354, 356 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 11.36 (br s, 1H), 7.84 (m, 3H), 7.66 (m, 4H), 7.33 (dd, 1H), 3.38 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(Cl)cc1OCc1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.07 (2H, s), 5.25 (2H, s), 5.73 (1H, d, J=1.6 Hz), 6.98-7.07 (4H, m), 7.32-7.39 (4H, m), 7.55 (1H, d, J=1.6 Hz), 8.00 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C23H16ClFN4O2, 435; Found, 435.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]1([OH:27])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:16]1([OH:27])[CH2:19][NH:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2cccc(F)c2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cccc(F)c2F)CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of tert-butyl 3-(2,3-difluorophenyl)-3-hydroxyazetidine-1-carboxylate (0.80 g, 2.80 mmol) in dichloromethane (30 ml). The reaction mixture was stirred at ambient temperature for 1 h. The solvent was evaporated and the crude product was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) to give the title compound (0.52 g). MS m/z (rel. intensity, 70 eV) 185 (M+, 1), 141 (68), 127 (bp), 114 (82), 63 (40).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:24]C)[CH:19]=1.[CH3:26]I>CO>[OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH3:26])[C:20](=[O:24])[CH:19]=1
Reactant: COc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Reactant: CI
Solvent: CO
Product: Cn1ccc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)cc1=O

Procedure:
(4S,5S)-Tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.281 g, 0.797 mmol) was refluxed in methanol (17 mL) with MeI (0.0798 ml, 1.28 mmol) for 48 hrs. Concentration and purification by silica gel chromotography (20:1 DCM/MeOH) afforded the titled compound along with recovered starting material.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])#[CH:23]>C(N(C(C)C)CC)(C)C.C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([C:23]#[C:22][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Reactant: C#Cc1ccccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ncnc(C#Cc3ccccc3C(F)(F)F)c2[N+](=O)[O-])CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
1-{6-chloro-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester (100 mg, 0.317 mmol), Pd(PPh3)2Cl2 (12 mg, 0.017 mmol) and copper(I)iodide (5 mg, 0.026 mmol) were dissolved in diisopropylethylamine and stirred for 2 min. o-ethynyl-trifluoromethylbenzene (100 ul, 0.072 mmol) was added and the mixture stirred under N2 at 70° C. for 18 hours. The yellow suspension turned black. After cooling to room temperature, the reaction mixture was diluted with chloroform (12 ml), passed through a celite plug and concentrated under vacuo. Purification by Flash Chromatography (0-30% Ethyl acetate/Hexanes) gave Compound Dl. Yield 35%. 1H NMR 400 MHz CDCl3 δ (ppm): 8.58 (s, 1H); 7.78 (d, 1H); 7.71 (d, 1H); 7.56 (m, 2H); 4.16 (m, 2H); 4.01 (d, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.26 (t, 3H). LCMS (ESI) m/z 449 (M+H+, 100%)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][N:3]1[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].IC.[H-].[Na+].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:26][C@:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][C:2](=[O:1])[N:3]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:4]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-4-carboxylate (30.05 g, 0.104 mol) in N,N′-dimethylformamide (210 mL), iodomethane 26.0 mL (59.28 g, 0.418 mol), and then sodium hydride (55%, in oil, 11.35 g, 0.260 mol) was added at room temperature in nitrogen atmosphere while stirring the mixture. When inner temperature increased to about 50° C., the reaction mixture was cooled to 30° C. by adding ice water to the outer bath. After changing the bath to a water bath at an outer temperature of 17° C., the mixture was stirred for 23 hours. The reaction mixture was poured into cold aqueous solution of citric acid (1 L of 10% citric acid and 500 g of ice), and after stirring the mixture for 30 minutes, the mixture was extracted with ethyl acetate (800 mL, 500 mL). The organic layers were combined, and washed with saturated aqueous solution of sodium chloride. After drying with anhydrous sodium sulfate, the mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by flash silica gel column chromatography (elution was started at hexane:ethyl acetate of 5:1, and after elution of the low polarity isomer, hexane:ethyl acetate was changed to 4:1) to obtain 10.63 g (33.7%) of high polarity isomer the title compound as a white solid. 14.91 g (47.3%) of low polarity isomer of tert-butyl (4R)-4-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-4-carboxylate was also obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:29]1[CH2:32][C:31](=O)[CH2:30]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:31]2[CH2:32][O:29][CH2:30]2)[CH:3]=1
Reactant: O=C1COC1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2COC2)c1
Temperature: 22 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (100 mg, 0.31 mmol) in MeOH (5 mL) was added AcOH (0.05 mL) and oxetan-3-one (22 mg, 0.31 mmol). The mixture was stirred at 22° C. for 2 h. NaBH3CN (98 mg, 1.55 mmol) was added, and the resulting mixture was stirred at 22° C. for 2 h. The reaction solution was concentrated, the residue was washed with water, extracted with EA, the organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (17 mg, Yield 14.4%). 1H NMR (CD3OD, 400 MHz): δ 7.17-6.97 (m, 6H), 6.96-6.88 (m, 1H), 6.72-6.62 (m, 1H), 5.03-4.95 (m, 2H), 4.67-4.59 (m, 1H), 4.59-4.49 (m, 2H), 4.15-4.04 (m, 1H), 3.80-3.69 (m, 2H), 3.56-3.40 (m, 2H), 2.96-2.79 (m, 4H), 2.73-2.58 (m, 2H). LCMS (m/z): 382.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([OH:34])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)C1(O)CN(c2ccc(S(C)(=O)=O)cc2)C(c2ccc(Cl)cc2)=N1

Procedure:
A mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, step 1) (1.00 g, 3.34 mmol), sodium bicarbonate (544 mg, 6.47 mmol), and ethyl bromopyruvate (1.40 g, 7.19 mmol) in 50 ml of isopropanol was stirred at reflux for 7 hours. After cooling, the mixture was evaporated. The residue was partitioned between dichloromethane and water, and the aqueous layer further extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and toluene as eluents gave the title compound as a pale yellow solid: mp (DSC) 162° C. Anal. Calc'd. for C19H19ClN2O5S (MW 422.89): C, 53.96; H, 4.53; N, 6.62. Found: C, 53.99, H, 4.49; N, 6.42.
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:19])[C:10]([C:12]1[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:26]>C(OCC)(=O)C>[Cl:26][C:1]1[NH:2][C:10]([C:12]2[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([CH3:19])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)C(C)C(=O)c1cccnc1F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)[nH]c(-c2cccnc2F)c1C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of ethyl 2-cyano-4-(2-fluoropyridin-3-yl)-3-methyl-4-oxobutanoate (19.4 g) in ethyl acetate (20 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (90 mL), and the mixture was stirred for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as yellow crystals (yield 14.3 g, 69%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Br)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]#[N:33])[CH:28]=[CH:29][CH:30]=1.[H-].[Na+]>C1COCC1.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=1)[C:32]#[N:33])=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CC#N)c1
Reactant: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)cnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(C#N)c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 3-benzyl-4-bromo-8-(trifluoromethyl)quinoline (10.0 g, 27.31 mmol) and (3-methoxyphenyl)acetonitrile (5.57 mL, 40.96 mmol) in THF (100 mL) is treated with NaH (1.64 g, 41.0 mmol, 60% dispersion in oil). After 0.5 h at ambient temperature, the reaction is heated at 50° C. for 2 h. The cooled reaction is diluted with water, extracted with ethyl acetate, and the combined extracts are dried (MgSO4) and concentrated. The residue is purified via column chromatography using 10:90 ethyl acetate:hexane as the eluent. The purified product is dissolved in a mixture of methylene chloride and hexane and concentrated until precipitation commences. After precipitation is complete, [3-benzyl-8-(trifluoromethyl)quinolin-4-yl](3-methoxyphenyl)acetonitrile is isolated as an off-white crystalline solid (5.18 g, 44%). HRMS: calcd for C26H19F3N2O+H+, 433.15222; found (ESI, [M+H]+), 433.1528.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[N:8]([CH3:18])[C:7]2=[O:19].[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>C(O)C>[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[N:8]([CH3:18])[C:7]3=[O:19])[CH2:23][CH2:22]1
Reactant: CN1C(=O)C2(CCCCBr)CCCc3cccc1c32
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)C2(CCCCN3CCC(O)(c4ccccc4)CC3)CCCc3cccc1c32
Yield: 54 %

Procedure:
A mixture of 2a-(4-bromobutyl)-1-methyl-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (322 mg, 1 mmol), 4-hydroxy-4-phenylpiperidine (210 mg, 1.2 mmol), sodium bicarbonate (102 mg, 1.2 mmol) and ethanol (15 ml) was heated under reflux for 6.3 hours on an oil bath, the reaction solution was cooled, and the thus precipitated crystals were collected by filtration to obtain 226 mg of the title compound (0.54 mmol, 54% in yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][Cl:10].[OH-].[K+].[CH2:13]([OH:16])[CH2:14][OH:15]>>[Cl:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:15][CH2:14][CH2:13][OH:16]
Reactant: OCCO
Reactant: ClCCOCCOCCCl
Agent: [K+]
Agent: [OH-]
Product: OCCOCCOCCOCCCl
Yield: 30 %

Procedure:
A solution of 1,8-dichloro-3,6-dioxaoctane (40 g) and potassium hydroxide (11.8 g) in ethylene glycol (100 ml) was stirred at 100° C. for 18 h. The mixture was then cooled, filtered and the residue washed with acetone (2×35 ml). The combined filtrate was then distilled to yield the product as a clear oil (13.5 g, 30%), b.p. 120°-122° C./0.2 mm Hg; I.r. (liquid film) 3430 cm-1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]3=[O:28])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.Cl>C(Cl)(Cl)Cl.C(OCC)C>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]3=[O:28])[CH2:16][CH2:17][C@@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3c(=O)oc4ccccc43)CC[C@H]2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CNCCN2C1

Procedure:
A solution of 3.1 g (8.01 mmol) of 3-[(7R,9aS)-2-BOC-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]-pyrazin-7-ylmethyl]-3H-benzooxazol-2-one in 40 mL of chloroform was stirred with excess HCl (g) in ethyl ether for 2 h at ambient temperature. The solvent was evaporated to give 2.3 g (100%). of the title compound dihydrochloride which was used for subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:14])[CH:8]=1)[CH3:2].[CH3:16][C:17]([CH3:24])([CH3:23])[C:18](=O)[CH2:19][C:20]#[N:21]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:20]([NH2:21])=[CH:19][C:18]([C:17]([CH3:24])([CH3:23])[CH3:16])=[N:14]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(NN)c1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 85.2 %

Procedure:
A mixture of Example Y (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (6.9 g, 55 mol) in ethanol (150 mL) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-propionic acid ethyl ester (14.3 g, 45.4 mmol) as a white solid. 1H NMR (DMSO-d6): 7.39-7.32 (m, 3H), 7.11 (d, J=6.8 Hz, 1H), 5.34 (s, 1H), 5.16 (s, 2H), 4.03 (q, J=7.2 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.19 (s, 9H), 1.15 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]2[CH:31]=[CH:32][C:33]([CH2:37][CH3:38])=[C:34]([Pb+3])[CH:35]=2)=[CH:28][CH:27]=1.C(Cl)(Cl)Cl.Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]2[CH:35]=[CH:34][C:33]([CH2:37][CH3:38])=[C:32]([CH:4]3[C:3](=[O:12])[CH:2]4[CH:6]([CH:7]5[O:10][CH:1]4[CH:9]=[CH:8]5)[C:5]3=[O:11])[CH:31]=2)=[CH:28][CH:27]=1
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 40 °C

Procedure:
To a mixture of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (1.7 g, 0.01 mol), 4-dimethylaminopyridine (5.0 g, 0.04 mol) and 4′-chloro-4-ethylbiphen-3-yllead triacetate (9.2 g, 0.015 mol) under an atmosphere of nitrogen is added dry chloroform (50 ml)). The reaction mixture is heated at 40° C. for 5 hours, then cooled to room temperature. The mixture is diluted with ethyl acetate (50 ml), acidified with 2N aqueous hydrochloric acid (50 ml), and the mixture is filtered to remove solids. The filtrate is poured into a separating funnel and extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(4′-chloro-4-ethylbiphen-3-yl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione.