Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C@H:13]3[CH2:16][C@H:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([CH:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1
Reactant: CO[C@H]1C[C@H](n2c([C@H](C)N)nc3ccc(F)cc32)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC1CC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccc(F)cc32)C1
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a solution of (S)-1-[6-fluoro-1-(trans-3-methoxycyclobutyl)-1Hbenzoimidazol-2-yl]ethylamine (79 mg, 0.3 mmol) in IPA (1 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (72 mg, 0.3 mmol) and DIPEA (0.26 mL, 1.5 mmol) and the reaction mixture heated at 90° C. for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford 397 as a white solid (37 mg, 32%). 1H NMR δ (DMSO-d6): 12.82 (1H, s), 8.25 (1H, s), 8.14 (1H, s), 7.92 (1H, s), 7.67-7.57 (2H, m), 7.05 (1H, td, J=9.30, 2.38 Hz), 5.86 (1H, s), 5.44-5.33 (1H, m), 4.17 (1H, t, J=6.72 Hz), 3.12 (3H, s), 3.07-2.96 (1H, m), 2.88-2.86 (1H, m), 2.56-2.45 (1H, m), 2.27-2.18 (1H, m), 1.65 (3H, d, J=6.69 Hz)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:54]1[CH:59]=[CH:58][N:57]2[C:60]([C:63]([NH:65][C:66]3[CH:74]=[CH:73][CH:72]=[C:71]4[C:67]=3[C:68]([CH2:83][CH3:84])=[N:69][N:70]4[CH2:75][C:76]3[CH:81]=[CH:80][CH:79]=[C:78]([CH3:82])[N:77]=3)=[O:64])=[CH:61][N:62]=[C:56]2[CH:55]=1.[CH3:85][N:86]([CH2:88][B-](F)(F)F)[CH3:87].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:85][N:86]([CH2:88][C:54]1[CH:59]=[CH:58][N:57]2[C:60]([C:63]([NH:65][C:66]3[CH:74]=[CH:73][CH:72]=[C:71]4[C:67]=3[C:68]([CH2:83][CH3:84])=[N:69][N:70]4[CH2:75][C:76]3[CH:81]=[CH:80][CH:79]=[C:78]([CH3:82])[N:77]=3)=[O:64])=[CH:61][N:62]=[C:56]2[CH:55]=1)[CH3:87]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Reactant: CN(C)C[B-](F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CN(C)C)ccn34)c12
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A round bottom flask equipped with a reflux condenser and a nitrogen line was charged with palladium acetate (3.4 mg, 0.015 mmol), cesium carbonate (300 mg, 0.92 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.030 mmol), 7-bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 127, Step A; 150 mg, 0.307 mmol), and potassium (dimethylaminomethyl)trifluoroborate (Frontier Scientific; 101 mg, 0.613 mmol). To the reaction flask was added a 1,4-dioxane:water mixture (10:1; 1.1 mL) and the reaction flask was immediately evacuated and refilled with nitrogen three times. The reaction mixture was heated at reflux for 16 hours under nitrogen. After cooling to ambient temperature, the reaction mixture was diluted with water, and extracted multiple times with dichloromethane. The combined dichloromethane extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, 2% 7N ammonia-MeOH:8% MeOH:DCM) to afford the product (84.8 mg) as a white solid. 1H NMR (CDCl3) δ 9.5 (d, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.84 (d, 1H), 7.62 (m, 1H), 7.40 (t, 1H), 7.32 (t, 1H), 7.12 (m, 2H), 7.01 (d, 1H), 6.48 (d, 1H), 5.65 (s, 2H), 3.52 (s, 2H), 3.23 (q, 2H), 2.29 (s, 6H), 1.51 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[CH:23]2[CH2:28][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26](O)[CH:25]([CH3:38])[CH2:24]2)=[O:15])[N:13]=1.CCN(S(F)(F)[F:45])CC>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[CH:23]2[CH2:28][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH:26]([F:45])[CH:25]([CH3:38])[CH2:24]2)=[O:15])[N:13]=1
Reactant: CC1CC(c2ccncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)CC(NC(=O)OC(C)(C)C)C1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC1CC(c2ccncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)CC(NC(=O)OC(C)(C)C)C1F
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of (+/−)-2-(tert-butoxycarbonylamino)-4-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-6-methylcyclohexyl acetate in MeOH (0.03 M) was added potassium carbonate (3.0 equiv.) and the reaction was stirred at room temperature for 3 h. Upon completion, the reaction was partitioned between water and ethyl acetate. The aqueous phase was further extracted 3 more times with ethyl acetate. The organics were combined, dried with brine and sodium sulfate, filtered, and concentrated. Isolated tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate was obtained as an off-white solid in 87% yield. LC/MS=545.2 (M+H), Rt=0.75 min. To a solution of tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in DCM (0.07M) at 0° C. was added DAST (1.0 equiv.) under a nitrogen atmosphere. The reaction was stirred for 1 h, upon which time, 2 more equivalents of DAST were added. After 30 min, the consumption of the starting material was complete. The reaction was quenched by the addition of water, the organic phase was dried with sodium sulfate, and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to afford tert-butyl(+/−)-5-(3-(2-(2,6-difluorophenyl)thiazole-4-carboxamido)pyridin-4-yl)-2-fluoro-3-methylcyclohexylcarbamate as a clear oil in 60% yield. LC/MS=547.3 (M+H), Rt=0.92 min. The Boc group was removed by treating with 25% TFA in dichloromethane for 2 hours. Upon concentration under vacuo, the crude was purified via semi-prep HPLC. The pure fractions were lyophilized to yield N-(4-((+/−)-3-amino-4-fluoro-5-methylcyclohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as the desired product as the TFA salt in 74% yield. LC/MS=447.0 (M+H), Rt=0.56 min.
Reaction SMILES: [CH3:1]C(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.[Cl:36][C:37]1[C:60]([Cl:61])=[CH:59][CH:58]=[CH:57][C:38]=1[CH2:39][C:40]1[C:41]([OH:56])=[N:42][NH:43][C:44]=1[N:45]1[C:53](=[O:54])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]1=[O:55]>C1COCC1.C(Cl)Cl>[Cl:36][C:37]1[C:60]([Cl:61])=[CH:59][CH:58]=[CH:57][C:38]=1[CH2:39][C:40]1[C:41]([O:56][CH3:1])=[N:42][NH:43][C:44]=1[N:45]1[C:46](=[O:55])[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:53]1=[O:54]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: O=C1c2ccccc2C(=O)N1c1[nH]nc(O)c1Cc1cccc(Cl)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1n[nH]c(N2C(=O)c3ccccc3C2=O)c1Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A mixture of DIAD (1.14 g, 5.67 mmol), PPh3 (1.49 g, 5.67 mmol) and methanol (0.18 g, 5.67 mmol) in THF (30 mL) was stirred at 0° C. for 1 h. Then, the mixture was added dropwise to a solution of 2-(4-(2,3-dichlorobenzyl)-3-hydroxy-1H-pyrazol-5-yl)isoindoline-1,3-dione (2 g, 5.15 mmol) in THF (500 mL) and DCM (500 mL), and the mixture was stirred at room temperature for 2 h. It was quenched with water (50 mL), and the solvent was evaporated in vacuo to dryness. The residue was purified by silica gel chromatography eluted with EA:PE=1:1 to give the titled compound (620 mg, 30%) as a white solid. LC/MS: MS (ES+) m/e 402 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.74 (s, 2H), 3.84 (s, 3H), 7.08 (d, J=4.8 Hz, 2H), 7.27-7.31 (m, 1H), 7.94 (s, 5H), 12.27 (s, 1H).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[S:11]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]12.[OH-].[Na+]>ClCCl.ClC>[CH:4]([C:16]1[N:13]2[C:12]([S:11][CH:15]=[CH:14]2)=[CH:18][N:17]=1)=[O:5]
Reactant: CN(C)C=O
Reactant: c1cn2cncc2s1
Agent: CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ncc2sccn12

Procedure:
To the mixture of 15.48 ml of DMF and 80 ml of dichloromethane was added dropwise a solution of 18.32 ml of phosphorus oxychloride in 80 ml of dichloromethane under ice-cooling. The mixture was reacted at room temperature for 30 minutes, and a solution of imidazo[5,1-b]thiazole in 40 ml of chloromethane was added dropwise. After heating under reflux for 2.5 hours, the reaction mixture was poured onto ice, adjusted to pH 9.8 with a 5 N aqueous sodium hydroxide solution, extracted five times with 200 ml of dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=5:1-ethyl acetate alone—dichloromethane:methanol=10:1). As a low polar component, 5-formylimidazo[5,1-b]thiazole was obtained in a yield of 495 mg.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17][N:16]2[C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[F:31][C:28]([F:29])([F:30])[C:27]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:15]1[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)=[O:32]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(O)cc1
Yield: 88.4 %

Procedure:
1-[1-(4-Benzyloxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone (26.97 g, 61.1 mmol) was hydrogenated using 10% Pd/C (1.000 g) in EtOH (300 ml) at an initial pressure of 44 psi (˜300,000 Pa) at rt for 6 hr. The reaction mixture was filtered through a pad of Celite to remove the catalyst and the filtrate was evaporated in vacuo to give 18.98 g (88% yield) of white solid.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[N:7]2[C:8]=1[C:9]([O:11]CC=C)=[O:10])=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[K+:50].C(OCC)(=O)C>C(OCC)C.C(Cl)Cl.C(OCC)(=O)C>[N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10])=[N+:2]=[N-:3].[K+:50]
Reactant: C=CCOC(=O)C1=C(N=[N+]=[N-])C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(N=[N+]=[N-])C[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of allyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (42 mg, 0.15 mmol) and triphenylphosphine (12 mg, 0.045 mmol) in 1:1 methylene chloride-ethyl acetate (2.7 ml) is treated with 0.5M potassium 2-ethylhexanoate in ethyl acetate (0.3 ml, 0.15 mmol) and tetrakis(triphenylphoshine)palladium (O) (13.8 mg, 0.012 mmol). The mixture is stirred 15 minutes at ambient temperature under a nitrogen atmosphere, diluted with diethyl ether, and centrifuged. The insoluble pellet is washed with ether and dried under vacuum to afford potassium (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.
Reaction SMILES: [K].CC(C)([O-])C.[N+:7]([C:10]1[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].Cl[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C)C=O>[N+:7]([C:10]1[CH:11]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:14][C:15]=1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
2.6 g of potassium-tert.butoxide are placed in 45 ml of dimethylformamide and at an internal temperature of −5° C. 1.3 ml of 3-nitro-trifluorotoluene and 1.5 ml of tert.butyl chloroacetate in 1 ml of dimethylformamide are added dropwise. The mixture is stirred for another 5 minutes and the solution is then poured onto ice water and the precipitate formed is suction filtered.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].[Br-].[Li+].O>CN(C)C=O>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](=[CH:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: CCCC1(Br)Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC=C1Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O

Procedure:
A stirred solution of 4,5-dimethyl-6-oxo-7-bromo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid (0.8 g., 0.0022 mole) and anhydrous lithium bromide (0.49 g., 0.0056 mole) in dimethylformamide (10 ml.) is heated at 95° in an inert atomosphere for one hour then poured into water (100 ml.) affording 4,5-dimethyl-6-oxo-7-propylidene-7,8-dihydro-6H-indeno-[5,4-b]furan-2-carboxylic acid which melts at 301°C after recrystallization from ethanol.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[S:11])[NH:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>>[CH:1]1([NH:7][C:8](=[S:11])[NH:9][N:10]=[CH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccccn1
Reactant: NNC(=S)NC1CCCCC1
Product: S=C(NN=Cc1ccccn1)NC1CCCCC1

Procedure:
The title compound was prepared from a mixture of 4-cyclohexyl-3-thiosemicarbazide (100 mg, 0.577 mmol) and 2-pyridinecarboxaldehyde (55 μL, 0.577 mmol) similar to Example 3 and isolated as a white solid (40 mg, 26%). 1H NMR (CDCl3): 9.16 (s, 1H), 8.65-8.63 (m, 1H), 7.87-7.85 (m, 2H), 7.78-7.73 (m, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.34-7.27 (m, 1H), 4.344.27 (m, 1H), 2.18-2.12 (m, 2H), 1.82-1.75 (m, 2H), 1.50-1.22 (m, 6H).
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:22])=[O:21].CC(C)([O-])C.[K+]>CS(C)=O.O>[C:2]1([C:1]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:27][CH2:26][CH2:25][CH2:24][CH2:23][C:20]([OH:22])=[O:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccc2ccccc2n1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCCCC=C(c1ccccc1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a solution of 2-benzoylquinoline (4.0 g) and (5-carboxy-l-pentyl)triphenylphosphonium bromide (11.8 g) in DMSO (50 ml) was added potassium t-butoxide (5.8 g) gradually and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was poured in iced water and washed with toluene. The aqueous layer was neutralized with 3N HCl and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried and the solvent was distilled off. The crude residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to give 0.90 g of 7-phenyl-7-(2-quinolyl)-6-heptenoic acid as a mixture of its (E) and (Z) forms. This mixture (0.90 g) and 5% palladium-on-carbon (0.90 g) were suspended in methanol (10 ml) and stirred in a hydrogen atmosphere at room temperature for 3 hours. The catalyst was then filtered off and the filtrate was concentrated to provide the title compound (1.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[C:3]=1[F:12]>[Fe].C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Br:11])[C:3]=1[F:12])[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)c(F)c(Br)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(Br)c(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.4 %

Procedure:
A 250 ml round bottom flask was charged with iron powder (325 mesh) (2.6 g, 46.6 mmol), 1,3-dibromo-2-fluoro-5-nitrobenzene (2.0 g, 4.01 mmol) and acetic acid (50 ml). The flask was evacuated and back-filled with nitrogen twice, then stirred at room temperature for 1 hour. The reaction mixture turned into a very thick slurry. Acetic acid (50 ml) was added and the mixture stirred for an additional hour. The reaction mixture was poured into EtOAc. The EtOAc solution was washed with water (2×), NaHCO3+Na2CO3 solution until CO2 evolution stopped, then once with brine, then dried over MgSO4, filtered and evaporated to dryness to give 1.6 g crude 3,5-dibromo-4-fluoroaniline (1.6 g). The product was used without further purification in the next experiment.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of (5R)-5-(azidomethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (2.22 g, INTERMEDIATE 9) and triphenylphosphine (3.44 g) was heated to 65° C. for 6 h in 444 ml of tetrahydrofuran and 56 ml of water. The sample was then cooled to room temperature, and concentrated in vacuo. The residue was purified via column chromatography on a Biotage Horizon 40M column eluting with 100% ethyl acetate (5 column volumes) to remove excess triphenylphosphine and triphenylphosphine oxide, followed by 100% methanol (5 column volumes), to provide the title compound (1.74 g, 87%). Mass spectrum (ESI) 228.1 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5](=O)[CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][C@@H:2]1[CH2:6][CH:5]([N:24]2[CH2:25][CH2:26][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)[CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: C[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: c1ccc(C2CCNCC2)cc1
Product: C[C@@H]1CC(N2CCC(c3ccccc3)CC2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from (R)-tert-butyl 2-methyl-4-oxopyrrolidine-1-carboxylate and 4-phenylpiperidine according to the general procedure E.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:11]([C:14]#[N:15])[C:12]#[N:13])[CH3:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:11]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:14]#[N:15])[C:12]#[N:13])[CH3:10])=[CH:7][CH:8]=1
Reactant: FC(F)(F)CCBr
Reactant: CC(c1ccc(C(F)(F)F)cc1)C(C#N)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccc(C(F)(F)F)cc1)C(C#N)(C#N)CCC(F)(F)F
Yield: 39 %

Procedure:
Using 0.48 g of 2-(1-(4-(trifluoromethyl)phenyl)ethyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.26 g of 2-(1-(4-(trifluoromethyl)phenyl)ethyl-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (57)).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH2:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[O:27]C.[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=2)[CH2:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[OH:27]
Reactant: COc1cc(CN(CCCS(C)(=O)=O)c2ccc(S(C)(=O)=O)cc2)ccc1F
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CS(=O)(=O)CCCN(Cc1ccc(F)c(O)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
To 694 mg (1.67 mmol) of (4-fluoro-3-methoxy-benzyl)-(4-methanesulfonyl-phenyl)-(3-methanesulfonyl-propyl)-amine, prepared following the method of Example 5 but replacing 3-pyridinecarboxaldehyde with 4-fluoro-3-methoxybenxaldehyde, dissolved in 3 mL of 2,4,6-collidine was added 402 mg (3.01 mmol) lithium iodide. The mixture was heated to 150 degrees for 3 hrs, cooled to room temperature, and partitioned between ethyl acetate and 1 N HCl. Upon drying over magnesium sulfate and concentration, column chromatography, eluting with acetone/dichloromethane, provided 169 mg of 2-fluoro-5-{[(4-methanesulfonyl-phenyl)-(3-methanesulfonyl-propyl)-amino]-methyl}-phenol; (m+H)+=401.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21]>O.C(O)(=O)C>[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH:14]([C:2]([NH2:3])=[O:1])[CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21]
Reactant: N#C[O-]
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC1C2=C3C(=CN1OC)OCCC3CC(C(N)=O)C2
Reaction time: 6 h

Procedure:
A solution of sodium cyanate (2.0 g) in water (20 ml) is added dropwise to a solution of 1,2,3a,4,5,6-hexahydro-7,8-dimethoxypyrano[2,3,4-de]isoquinoline (2.0 g), described in Example 56, (2.0 g) in acetic acid (8.0 ml) and water (12.0 ml). The mixture is left at room temperature for 6 hr. and the precipitate is then collected, washed with water, and crystallized from methanol to give the title compound, m.p. 224° - 226° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][C:14]#[N:15])[C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:21]=1[CH:22]=O.N1CCCCC1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([C:14]#[N:15])=[CH:22][C:21]2[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[CH:27][C:20]=2[O:19][CH3:18])[C:3]=1[C:16]#[N:17]
Reactant: COc1cccc(OC)c1C=O
Reactant: N#CCc1nn(-c2ccccc2)c(N)c1C#N
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C=C(C#N)c1nn(-c2ccccc2)c(N)c1C#N
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
1 g (4.48 mmol) of 5-amino-4-cyano-1-phenyl-3-pyrazoleacetonitrile is suspended in 15 mL of toluene, in a round-bottomed flask, under an argon atmosphere, surmonted by a Dean and Stark apparatus. 0.744 g (1 eq.) of 2,6-dimethoxybenzaldehyde and 0.030 mL of piperidine are added to the mixture. The reaction medium is refluxed overnight, and is then allowed to return to ambient temperature. A whitish precipitate forms and is filtered off and washed with toluene. The filtrate is concentrated to dryness and the residue is taken up in ethanol with agitation for 15 minutes. The suspension is filtered and the filtrate is concentrated to dryness. The residue is combined with the precipitate previously obtained, and purified on silica gel (eluent: 98/2 dichloromethane/methanol). 619 mg of product are thus obtained with a yield of 37%.