Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[O:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:32])[C@@H:14]([N:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C-]#N.[Na+].[CH3:37][N:38](C)C=O>CO.O>[OH:32][C@@H:13]1[C@@H:14]([N:24]2[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]2)[CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:33])[CH2:2][C:37]#[N:38])[CH2:12]1
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CC#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1

Procedure:
A stirred mixture of (2β,3α,5α)-21-chloro-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (500 mg), sodium cyanide (500 mg), N,N-dimethylformamide (1.25 ml) in methanol (10 ml) and water (0.25 ml) was heated under reflux for 16 h. The resulting solution was cooled and poured into water (50 ml). The mixture was extracted with dichloromethane and the organic layer was washed with water to pH 7. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure and the residue (430 mg) was chromatographed on silica gel. The purified product (208 mg) was crystallised from dichloromethane-methanol to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-11,20-dioxopregnane-21-carbonitrile (96 mg). δ (CDCl3) 0.62 (s, 3H), 1.06 (s,3H), 1.22 (s,3H), 1.26 (s,3H) and 3.38 (s,2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:3]=1)#[N:6]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Cc1ccc(C#N)cc1N
Agent: Br
Product: Cc1ccc(C#N)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 54.3 %

Procedure:
3-amino-4-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-cyano-2-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (50 mg, 53%) as a white solid. Mass Spectrum: M+H+ 461. NMR Spectrum (DMSOd6): 1.62 (d, 3H), 2.30 (s, 3H), 2.69 (bs, 3H), 2.93 (bs, 3H), 3.51-3.64 (m, 4H), 3.70-3.80 (m, 4H), 5.00-5.08 (m, 1H), 5.56 (d, 1H), 5.61 (s, 1H), 5.96 (dd, 1H), 6.24 (ddd, 1H), 6.96 (dd, 1H), 7.58 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30]O)[CH2:26][CH2:25]2)[O:21][N:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][O:17][C:14]3[CH:15]=[CH:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:12][CH:13]=3)[CH2:28][CH2:29]2)[O:21][N:20]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: Cc1noc(N2CCC(CO)CC2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1noc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)cc3)CC2)n1
Yield: 21 %

Procedure:
The title compound (43 mg, 21%) was prepared as a white solid from 4′-(methylsulfonyl)-4-biphenylol (prepared as in Example 1, Step 1, 120 mg, 0.48 mmol), [1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-piperidinyl]methanol (143 mg, 0.73 mmol) and Ph3P (191 mg, 0.73 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.144 mL, 0.73 mmol) in a manner similar to Example 1, Step 2, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.6 Hz), 7.72 (d, 2H, J=8.4 Hz), 7.55 (d, 2H, J=8.8 Hz), 6.99 (d, 2H, J=8.8 Hz), 4.25-4.15 (m, 2H), 3.89 (d, 2H, J=6.4 Hz), 3.22-3.08 (m, 2H), 3.08 (s, 3 H), 2.24 (s, 3H), 2.04-1.94 (m, 2H), 1.55-1.42 (m, 3H); LRMS (ESI), m/z 428 (M+H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Cl>C(OC)(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Yield: 93.3 %

Procedure:
Ethyl trifluoroacetate (23.52 g, 166 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in methyl tert-butyl ether (75 mL). To the stirred solution was added 25 weight % sodium methoxide (40 mL, 177 mmol) via an addition funnel over a 2 minute period. Next 4'-chloroacetophenone (23.21 g, 150 mmol) was dissolved in methyl tert-butyl ether (20 mL), and Added to the reaction dropwise over 5 minutes. After stirring overnight (15.75 hours), 3N HCl (70 mL) was added. The organic layer was collected, washed with brine (75 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a 35.09 g of yellow-orange solid. The solid was recrystallized from iso-octane to give 31.96 g, 85% of the dione, mp 66°-67° C.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C[O-].[Na+].[C@:9]12([C:22](OCC)=O)[CH2:14][C@H:13]1[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2>CC1CCCO1>[CH3:2][C:1]1[N:3]=[C:22]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[O:5][N:4]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)[C@]12C[C@H]1CN(C(=O)OC(C)(C)C)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: Cc1noc([C@]23C[C@H]2CN(C(=O)OC(C)(C)C)C3)n1
Yield: 56.5 %

Procedure:
2-Methyl-tetrahydrofuran (40 mL), acetamide oxime (0.93 g, 0.0125 mol) and sodium methoxide (1.1 g, 0.020 mol) were added to (1R,5R)-3-tert-butyl 1-ethyl 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (142) (1.27 g, 0.0050 mol) and the mixture was heated to reflux for 3 hours. Upon cooling the suspension was partitioned between ethyl acetate (100 mL) and water (25 mL). The organic layer was washed with water (25 mL), saturated sodium chloride (25 mL) and dried over Na2SO4. The mixture was concentrated and the residue was chromatographed over 25 g of silica gel with 15-25% ethyl acetate/hexanes, to obtain 0.75 g of clear colorless oil. MS (ESI) m/z 304 [M+K]+. 1H NMR (CDCl3) δ 1.16-1.17 (m, 1H), 1.46 (s, 9H), 1.60 (s, 1H), 1.72-1.75 (m, 1H), 2.36 (s, 3H), 3.49-3.51 (m, 1H), 3.65-3.79 (dd, 1H), 3.91-4.00 (m, 2H).
Reaction SMILES: F[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:28][O-:29].[Na+]>>[F:27][C:24]1[CH:23]=[CH:22][C:21](/[CH:20]=[CH:19]/[C:16]2[CH:17]=[CH:18][C:13]([S:10]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[O:29][CH3:28])(=[O:11])=[O:12])=[CH:14][CH:15]=2)=[CH:26][CH:25]=1
Reactant: COc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1OC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-1-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)-3-methoxybenzene (Example 192, 45 mg, 0.116 mmol) and sodium methoxide (0.5M in methanol, 1 mL) was heated to 150° C. for 10 minutes in a microwave reactor. A further 0.5 mL sodium methoxide was added and heating continued at 150° C. for 30 minutes. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20% ethyl acetate/isohexane, to give the title compound. δH (500 MHz, d6 DMSO): 7.91 (2H, d, J=8.5 Hz), 7.76 (2H, d, J=8.4 Hz), 7.67 (2H, dd, J=5.7, 8.7 Hz), 7.52 (1H, dd, J=2.2, 8.5 Hz), 7.39 (2H, d, J=2.3 Hz), 7.28 (1H, s), 7.25–7.19 (2H, m), 7.14 (1H, d, J=8.6 Hz), 3.82 (3H, s), 3.80 (3H, s).
Reaction SMILES: [CH3:1][S:2](=[O:19])([CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[CH3:8])=[N:3][C:4]([NH2:6])=[S:5].Br[CH:21]([CH3:25])[C:22](=O)[CH3:23]>CCO>[CH3:25][C:21]1[N:6]=[C:4]([N:3]=[S:2]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=2)[CH3:8])([CH3:1])=[O:19])[S:5][C:22]=1[CH3:23]
Reactant: CC(=O)C(C)Br
Reactant: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=NC(N)=S
Solvent: CCO
Product: Cc1nc(N=S(C)(=O)C(C)c2ccc(C(F)(F)F)nc2)sc1C
Temperature: 85 °C

Procedure:
In a microwave crimp tube, N-(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)thiourea (J) (200 mg, 0.642 mmol) was suspended in EtOH (3 mL) and 3-bromobutan-2-one (151 mg, 69 μL, 0.642 mmol) was added via syringe, while stirring. The reaction was sealed and heated to 85° C. for 15 min in the microwave. The solvent was subsequently removed on the rotary evaporator and the remaining residue purified by preparative reverse phase chromatography (water/acetonitrile). 5-{1-[(4,5-dimethyl-1,3-thiazol-2-yl)(methyl)sulfonimidoyl]ethyl}-2-(trifluoromethyl)pyridine (67) was obtained in form of a slightly yellow oil as a 1:1 mixture of diastereomers (67 mg, 0.185 mmol, 29%). 1H-NMR (CDCl3, 400 MHz): δ=1.89 (d, J=7.2 Hz, 1.5H, CHCH3, diastereomer 1); 1.93 (d, J=7.2 Hz, 1.5H, CHCH3, diastereomer 2); 2.15 (s, 1.5H, thiazole-CH3, one diastereomer); 2.17 (s, 1.5H, thiazole-CH3, one diastereomer); 2.18 (s, 1.5H, thiazole-CH3, one diastereomer); 2.20 (s, 1.5H, thiazole-CH3, one diastereomer); 3.04 (s, 1.5H, S—CH3, diastereomer 1); 3.15 (s, 1.5H, S—CH3, diastereomer 2); 5.11 (q, J=7.2 Hz, 0.5H, CHCH3, diastereomer 1); 5.22 (q, J=7.2 Hz, 0.5H, CHCH3, diastereomer 2); 7.71 (d, J=8.1 Hz, 0.5H pyr-C3-H, diastereomer 1), 7.73 (d, J=8.1 Hz, 0.5H, pyr-C3-H, diastereomer 2); 8.08 (dd, 3J=8.1 Hz, 4J=2.0 Hz, 0.5H, pyr-C4-H, diastereomer 1); 8.10 (dd, 3J=8.1 Hz, 4J=2.0 Hz, 0.5H, pyr-C4-H, diastereomer 2); 8.72 (d, 4J=2.0 Hz, 0.5H, pyr-C6-H, diastereomer 1); 8.78 (d, 4J=2.0 Hz, 0.5H, pyr-C6-H, diastereomer 2). 13C-NMR (CDCl3, 100 MHz): δ=10.9, 11.0 (thiazole-CH3, two diastereomers); 13.8, 14.4 (CHCH3, two diastereomers); 14.4 (double peak, thiazole-CH3, two diastereomers); 36.3, 36.5 (S—CH3, two diastereomers); 60.5, 61.2 (CHCH3, two diastereomers); 117.9, 118.0 (Ar, two diastereomers); 119.4, 119.5 (pyr-C, 2 diastereomers); 131.4, 132.1 (Ar, two diastereomers), 137.1, 137.4 (pyr-C, 2-diastereomers); 141.7, 141.9 (Ar, two diastereomers) 149.3, 149.4 (pyr-C, 2-diastereomers); 161.4, 161.7 (thiazole, two diastereomers); CF3, not detected. HPLC-MS (ESI+): mass calc'd for C14H17F3N3OS2 (M+H+): 364.1. Found 364.5, HPLC-MS (ESI−) mass calc'd for C14H15F3N3OS2 (M−H+): 362.1. Found 361.8.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[NH:11][C:10](=[O:12])[C:5]3=[CH:6][CH:7]=[CH:8][C:9]=1[N:4]23.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C=O)C>[C:22]1(=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]2[C:3]3=[CH:2][N:1]=[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([N:4]34)[C:10]2=[O:12])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: O=c1[nH]c2cnc3cccc1n32
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCn1c(=O)c2cccc3ncc1n32
Yield: 20.9 %

Procedure:
To a suspension of 81 mg (0.51 mmol) of 3,4-dihydro-1,3,7b-triazacyclopent[cd]inden-4-one in 1 ml of DMF was added, while stirring under ice-cooling, 25 mg (0.63 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 151 mg (0.51 mmol) of N-(5-bromopentyl)phthalimide in 1 ml of DMF. The mixture was stirred for two hours at 110° C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with an aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to afford 40 mg of the desired compound (20.9%, a colorless solid).
Reaction SMILES: [CH3:1]I.[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[NH:14][C:15](=[O:23])[N:16]([C@H:17]4[CH2:20][C@@H:19]([O:21][CH3:22])[CH2:18]4)[C:7]=3[C:6]=2[CH:5]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[N:14]([CH3:1])[C:15](=[O:23])[N:16]([C@H:17]4[CH2:18][C@@H:19]([O:21][CH3:22])[CH2:20]4)[C:7]=3[C:6]=2[CH:5]=1
Reactant: CI
Reactant: CO[C@H]1C[C@@H](n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl iodide (11.49 mL, 183.81 mmol) was added to a mixture of 8-bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one (32 g, 91.90 mmol), sodium hydroxide (5.51 g, 137.85 mmol) and tetrabutylammonium bromide (2.94 g, 9.19 mmol) in DCM (400 mL) and water (300 mL) and the resulting mixture stirred at r.t. for 2 h. The DCM was removed in vacuo and the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum to afford the desired material (25.00 g, 75%) as a pale yellow solid. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.72-2.86 (2H, m), 2.9-3.08 (2H, m), 3.22 (3H, s), 3.49 (3H, s), 3.85-3.89 (1H, m), 4.88-5.06 (1H, m), 7.74 (1H, dd), 7.98 (1H, d), 8.50 (1H, d), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=362, 364.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[OH-].[K+].Cl[CH2:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(CCl)cc1
Reactant: COCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOCc1ccc(C(=O)c2ccccc2)cc1
Yield: 86 %

Procedure:
To 25 milliliters of 2-methoxyethanol was added, with magnetic stirring, 5.0 grams (0.75 mole) of 85% potassium hydroxide pellets dissolved in 5 milliliters water. The amount of 5.0 grams (0.0216 mole) of 4-(chloromethyl)benzophenone was added, the mixture was refluxed for three hours, filtered with suction, and concentrated. Water was added and the oil which separated was isolated by extraction with ether to provide 5.0 grams (86% yield) of 4-(2-methoxyethoxymethyl)benzophenone as an orange colored liquid. Infrared analysis revealed the presence of a carbonyl band at 1660 cm-1. Ultraviolet analysis revealed λ max (ε) at 256 nanometers (18,380).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[N:13][NH:12][C:11]=1[NH2:24].O.NN>C(O)C.[Ni]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[C:11]([NH2:24])[NH:12][N:13]=2)=[CH:20][CH:19]=1
Reactant: Nc1[nH]nc(-c2ccc([N+](=O)[O-])cc2)c1-c1nc2ccccc2s1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2n[nH]c(N)c2-c2nc3ccccc3s2)cc1
Reaction time: 2 h
Yield: 24.9 %

Procedure:
An aqueous solution of Raney Ni (1 mL) was added to a suspension of 4-benzothiazol-2-yl-5-(4-nitrophenyl)-2H-pyrazol-3-ylamine (115 mg, 0.34 mmol) in ethanol (20 mL). To the vigorously stirring solution was added hydrazine hydrate dropwise in 3 portions (3×50 mg, 3 mmol in total), and the resulting mixture was then stirred for 2 hrs. The solids were removed by filtration and the mother liquor was evaporated to afford the crude material. The residue was purified by flash column chromatography eluting with CH2Cl2:MeOH=9:1 to yield 26 mg (25%) of the title compound as a cream coloured solid. MS (m/z, ES+): 308.1 (M+1, 100%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C([C:38](C2C=CC(NC3C=CC(OC)=CC=3)=CC=2Cl)=[O:39])C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:39][CH3:38])=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: COc1ccc(Nc2ccc(C(=O)c3cc(N)ccc3C)c(Cl)c2)cc1
Product: COc1ccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)cc1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 447 (0.08 mmol). The crude product was used without any further purification.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Reactant: COc1ccc(OB(O)O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCc1nn2c(-c3ccc(OC)cc3Cl)cccc2c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
After dissolving 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (100 mg) in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2-chloro-4-methoxyphenylboric acid (138 mg), tetrakis(triphenylphosphine)palladium (0) complex (86 mg) and barium hydroxide octahydrate (233 mg) were added and the mixture was heated and stirred at 80° C. for 3 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine, in that order. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as yellow crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH2:28][CH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>CN(C=O)C>[C:37]([O:36][C:34]([C:33]1[CH:41]=[CH:42][C:30]([CH2:29][CH2:28][C:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=2)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Reactant: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC(C)(C)C)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
0.6 g (14.92 mmol) of sodium hydride is added in portions to a solution of 4.13 g (12.43 mmol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate in 40 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 1 hour. The reaction solution is then cooled again to 0° C., 3.9 g (13.68 mmol) of tert-butyl 4-(2-bromoethyl)benzoate in 10 ml of DMF are added, and the mixture is stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. The reaction mixture is added to ice-water and extracted three times with ethyl acetate, and the combined organic phases are washed with saturated brine and dried over sodium sulphate. After filtration, the solvent is evaporated to dryness in vacuo, and the resulting crude product is purified by preparative HPLC. 933 mg (1.7 mmol, 14% yield) of a colourless solid are obtained.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl[CH:7](Cl)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[NH:27][NH2:28]>O.C(OCC)C>[Cl:22][C:20]1[C:19]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:18][C:17]([NH:27][N:28]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:16]([F:15])[CH:21]=1
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Reactant: O=C(C(Cl)Cl)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 5.3 g of sodium acetate dissolved in 100 ml of water was added 4.4 g of 1,1-dichloro-3,3,3-trifluoroacetone under ice cooling, and the reaction was allowed to proceed at 90° C. for 30 minutes. The reaction solution was left cooling to room temperature, to which a solution of 5.8 g of 2-fluoro-4-chloro-5-isopropoxyphenyl-hydrazine dissolved in 20 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed once with 10 ml of saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and evaporated to remove the diethyl ether to give 6.5 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone), compound 3-3.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH:17][C:18]([C:20]1[C:21](Cl)=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])[CH2:14]2.[CH:28]1([SH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH:9]12[CH2:10][CH:11]3[CH2:12][CH:13]([CH2:14][CH:7]([CH2:16]3)[CH:8]1[NH:17][C:18]([C:20]1[C:21]([S:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])[CH2:15]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1SC1CCCCC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Anhydrous sodium carbonate (2.201 mL, 52.58 mmol) was added in one portion to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (5.7 g, 17.53 mmol) and cyclohexyl mercaptan (2.14 mL, 17.53 mmol) in DMF (50 mL) under nitrogen. The resulting suspension was stirred at 60° C. for 6 hours.