Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:17][C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
Under a nitrogen atmosphere, a solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide (5.0 g, 28 mmol) (i.e. the product of Example 12, Step A) in tetrahydrofuran (50 mL) was cooled to −78° C. and then treated with n-butyllithium (2 M solution in cyclohexane, 15.0 mL, 30 mmol) dropwise. The reaction mixture formed a thick precipitate, and stirring was continued for 30 minutes after the addition. To the stirred suspension, a solution of hexachloroethane (7.1 g, 30 mmol) in tetrahydrofuran (20 mL) was added dropwise. After 30 minutes the resulting clear solution was warmed to ambient temperature and quenched with the addition of water (70 mL). The reaction mixture was extracted with dichloromethane and dried over MgSO4. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (50% hexanes in dichloromethane as eluant) to give 1.71 g of 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide. The 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide was heated to 110° C. for 12 h with a catalytic amount of pyrazole to isomerize to the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[N:11]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]=2)[CH:6]=[CH:5][N:4]=1>CO.C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[N:11]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(N)cc23)ccn1

Procedure:
To the stirred suspension of 3-(2-Methoxy-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole 4BV (5.125 g, 10.0 mmole) in MeOH/toluene (50 mL/50 mL) was added 10% Pd/C (Degussa type, 0.5 g) at r.t. under dry N2 gas. The mixture was degassed and was stirred under a balloon inflated with H2 gas overnight. The catalyst was filtered through microfiber filter and was washed with MeOH and CH2Cl2. The filtrate was evaporated to dryness and a brown solid 5BV was obtained (5.0 g).
Reaction SMILES: N#N.[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[O:10])[CH3:9].COC([O:16][CH3:17])OC.[C:18]([O-])(O)=O.[Na+]>C(O)CO>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1([CH3:9])[O:16][CH2:17][CH2:18][O:10]1
Reactant: COC(OC)OC
Reactant: O=C([O-])O
Reactant: CC(=O)c1ccco1
Agent: N#N
Agent: [Na+]
Solvent: OCCO
Product: CC1(c2ccco2)OCCO1
Temperature: 92 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-furan-2-yl-ethanone (50.00 g, 454.0 mmol) in ethylene glycol (500.0 mL) was treated with trimethylorthoformate (100.0 mL, 908.0 mmol) followed by LiBF4 (7.00 g, 75 mmol). The reaction mixture was heated at 92° C. overnight. Sat. aq. NaHCO3 (500 mL) was added and the mixture was extracted with EA (500 mL). The org. extracts were washed with brine (2×250 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by distillation (11 mbar, 71-73° C.) gave the title compound as colorless oil. LC-MS-conditions 02: tR=0.50 min.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[K+].[S:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=O)=[CH:22][CH:21]=1)([OH:19])(=[O:18])=[O:17].C(N=C=NCCCN(C)C)C.Cl>O>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:24]([C:23]3[CH:22]=[CH:21][C:20]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:28][CH:27]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C([O-])c1ccc(S(=O)(=O)O)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Reaction time: 18 h
Yield: 67.6 %

Procedure:
A mixture of 5,6-diamino-1,3-diethyl-2,4(1H,3H)-pyrimidinedione (41.2 g, 0.208 moles), 4-sulfobenzoic acid monopotassium salt (50.0 g, 0.208 moles), and water (250 ml) is prepared, and the pH adjusted to 6.0. Ethyl-3-(3-dimethylaminopropyl)carbodiimide (39.9 g, 0.208 moles) is added in one portion, and the pH of the resulting solution maintained at 5.5±0.5 with the dropwise addition of 4 N hydrochloric acid. When the pH of the solution ceases to rise, the mixture is concentrated on a rotary evaporator, and the residue taken up in 400 ml 10% potassium hydroxide and stirred for 18 hours. At the end of this time, the solution is boiled under reflux for one hour, cooled, filtered, and made acidic with the portionwise addition of 12 N hydrochloric acid. The resulting suspension is cooled and filtered; the solids are triturated with ethanol, filtered, and dried to yield 51.2 grams of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)-benzenesulfonic acid; mp greater than 360° C.
Reaction SMILES: Cl.NC1C2C(=CC(CC(NC(=O)CNS(C3C(C)=C(C)C4OC(C)(C)CCC=4C=3C)(=O)=O)C(=O)N3CCCCC3)=CC=2)C=CN=1.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][C:53]([CH2:57][CH:58]([NH:67]C(=O)OC(C)(C)C)[C:59](=[O:66])[N:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1.[CH3:75][C:76]([O:79][C:80](=[O:97])[CH2:81][C@H:82]([NH:86][S:87]([CH2:90][C:91]1[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1)(=[O:89])=[O:88])[C:83](O)=[O:84])([CH3:78])[CH3:77].N[C@H](C(O)=O)CC(=O)OC(C)(C)C.C1(CS([Cl:121])(=O)=O)C=CC=CC=1>>[ClH:121].[CH3:78][C:76]([O:79][C:80](=[O:97])[CH2:81][C@H:82]([NH:86][S:87]([CH2:90][C:91]1[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1)(=[O:89])=[O:88])[C:83]([NH:67][CH:58]([CH2:57][C:53]1[CH:52]=[C:51]2[C:56](=[CH:55][CH:54]=1)[C:47]([NH2:46])=[N:48][CH:49]=[CH:50]2)[C:59](=[O:66])[N:60]1[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]1)=[O:84])([CH3:75])[CH3:77]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Reactant: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Product: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1

Procedure:
The procedure described for 5c was used. Deprotection of 100 mg of 5a and coupling with 95 mg of (2S)-[[(phenylmethyl)sulfonyl]amino]butanedioic acid 4-(1,1-dimethylethyl)ester (prepared from Asp(OtBu)-OH and phenylmethylsulfonylchloride using the procedure described for 5b) yielded the title compound (133 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 0.83-1.69 (6H, m), 1.41 and 1.42 (9H, 2× s), 2.42-2.63 (2H, m), 3.09-3.61 (6H, m), 4.01-4.38 (3H, m), 5.22-5.31 (1H, m), 7.13-7.80 (9H, m), 8.25-8.30 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>>[ClH:1].[ClH:1].[NH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)[CH2:26][CH2:25]1
Reactant: Clc1nc(Nc2ccccc2)c2ncn(C3CCOC3)c2n1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: NC1CCC(Nc2nc(Nc3ccccc3)c3ncn(C4CCOC4)c3n2)CC1
Yield: 115.6 %

Procedure:
The operation is carried out as in Stage 3 of Example 2 starting from 198 mg of the product obtained in Stage 1 above and 716 mg of trans-1,4-diaminocyclohexane. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2 and salification with 1.4 N hydrochloric acid in ethanol, 169 mg of expected product is obtained in the form of pink beige crystals
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:42])[CH2:21][C:22]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>CN1C(=O)CCC1>[C:15]([O:19][C:20](=[O:42])[CH2:21][C:22]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([O:33][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc(O)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h
Yield: 51.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added to a mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(5-hydroxy-2-methylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (290 mg), pyridine (1 mL), and NMP (3 mL) at 50 C, and the obtained mixture was stirred at 50 C for 20 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred at 50 C for 20 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred at 50 C for 3 hours. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred overnight at 50 C. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) and then further fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (210 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:32]1[C:42]2=[C:43]3[C:38](=[CH:39][CH:40]=[CH:41]2)[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[C:34]3[CH2:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:33]1[C:34]2=[C:43]3[C:38](=[CH:37][CH:36]=[CH:35]2)[C:39]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:3]=2)=[CH:40][CH:41]=[C:42]3[CH2:32]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: CC1(C)OB(c2ccc3c4c(cccc24)CC3)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc2c3c(cccc13)CC2
Yield: 36.1 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2-(1,2-dihydroacenaphthylen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.105 g; 0.375 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.040 g (36%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1([CH3:14])[CH2:13][O:12]1.B(F)(F)F>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH:11]([CH3:14])[CH:13]=[O:12]
Reactant: CC1(c2cc([N+](=O)[O-])ccc2F)CO1
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C=O)c1cc([N+](=O)[O-])ccc1F
Reaction time: 1 h

Procedure:
2-(2-fluoro-5-nitrophenyl)-2-methyloxirane (1 eq) was dissolved in ethyl ether (1 mL) under nitrogen. BF3-etherate (0.87 eq) was added dropwise at room temperature and after complete addition solution was allowed to stir for 1 h. Solution was then quenched with water, extracted with ethyl ether. Organics washed with brine, dried with sodium sulfate and concentrated. Crude product was purified using flash chromatography (85% Hex: 15% EtOAc) on silica to afford 2-(2-fluoro-5-nitrophenyl) propanal.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].[ClH:31]>CCOCC.CCOC(C)=O.O>[ClH:31].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)nsc2c1
Reactant: CCOC(=O)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN1CCN(c2nsc3cc(F)ccc23)CC1
Yield: 6.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1,2-benzisothiazole (6.0 g, 25 mmol), ethyl 3-bromopropionate (4.5 g, 25 mmol), K2CO3 (3.5 g) CH3CN (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into H2O, and after extractive workup with EtOAc, 6.0 g of am orange oil was realized. The oil was dissolved in Et2O and ethereal HCl was added to precipitate 6.3 g of a white hydrochloride salt. The salt was recrystallized from CH3CN to yield 6.0 g (6.4%) of the desired compound. An analytical sample was obtained by recrystallization of a 1.0 g sample from EtOH-Et2O to yield 0.8 g of a white solid, m.p.=197-199° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:21])C=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:9])=[O:21])=[CH:4][CH:3]=1
Reactant: CSc1ccc(Br)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1ccc(Br)cc1
Reaction time: 4 h

Procedure:
4.06 g (20 mmol) of 4-bromothioanisole and 75 ml of dichloromethane were introduced into a round-bottomed flask and 6.3 g (20 mmol) of meta-chloroperbenzoic acid were added. Stirring was carried out at room temperature for four hours and the reaction mixture was poured into water. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (70/30). After evaporating the solvents, 1.22 g (28%) of the expected sulfoxide, with a melting point of 80°-81° C., was recovered.
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[NH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:16]>CCO.O>[N+:13]([C:12]1[C:7]2[NH:6][C:3](=[S:5])[O:16][C:8]=2[CH:9]=[CH:10][CH:11]=1)([O-:15])=[O:14]
Reactant: S=C=S
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc2oc(=S)[nH]c12
Yield: 78.6 %

Procedure:
A solution of KOH (3.31 g, 59.0 mmol) in EtOH and water was treated with carbon disulfide (10.4 g, 136.3 mmol) followed by 2-amino-3-nitrophenol (7.00 g, 45.4 mmol). The mixture was heated at reflux temperature overnight, cooled, concentrated, acidified with 1M HCl and filtered. The filtercake was washed with water and dried in vacuo to provide the title compound (7.0 g, 79%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:18]#[N:19])(C)C.C(Cl)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:18]#[N:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: N#Cc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-phenylpyridine N-oxide (5 g) in DCM (50 mL) was added at RT trimethylsilylcyanide (11 mL), followed by acetyl chloride (3.1 mL) over 10 min. The reaction mixture was stirred overnight at RT. A solution of aq. 10% Na2CO3 was added and the mixture was extracted with EA. The combined org. phases were washed with brine, dried (Na2SO4) and evaporated off. Filtration over a plug of silica gel (Hept/EA 1/1) gave the desired compound (450 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
A mechanically stirred mixture of 6-bromonaphth-2-ol (10.00 g, 0.04483 mol), benzyl bromide (6.97 g, 0.0408 mol), potassium carbonate (11.26 g, 0.08147 mol) and butan-2-one (350 ml) was heated under reflux for 24 hrs. (GLC and TLC analyses revealed a complete reaction). The potassium carbonate was filtered off and the filtrate was washed with water before being dried (MgSO4). The drying agent was filtered off and the solvent was removed in vacuo to give a pale orange solid. The crude product was crystallized twice from ethanol and was dried in vacuo (P2O5, CaCl2, paraffin wax, 48 h) to afford white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.CO[CH2:19][CH2:20]OCCOC.[Li+].[Cl-].C(C([Sn])=C(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[CH2:20])=[CH:3][CH:4]=1)[C:13]([F:16])([F:15])[F:14]
Reactant: COCCOCCOC
Reactant: FC(F)(F)C(c1ccc(Br)cc1)C(F)(F)F
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
Crude 1-bromo-4-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-benzene, (approximately 100 mg of starting material, contaminated with diglyme) was dissolved in toluene (3 ml) in a sealed tub under a nitrogen atmosphere. Tetrakispalladium (15 mg, 0.013 mmol) and LiCl (42 mg, 1 mmol) were added, followed by the addition of tributylvinyltin (155 mg, 0.49 mmol).The reaction mixture was heated to 80° C. for 18 h, and then purified by silica gel column chromatography (100% hexane -2% ethyl acetate/hexane) to yield the title product, whose volatility made yield calculations impossible. 1H NMR (CDCl3) δ=7.49 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.71 (dd, J=10.9, 17.6 Hz, 1H), 5.82 (d, J=17.7, 1H), 5.33 (d, J=10.9 Hz, 1H), 4.06 (septet, JH,F=8.3 Hz,1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1.I[CH3:28]>>[CH3:28][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:25])([F:1])[F:26])=[CH:5][CH:6]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: FC(F)(F)Oc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: CI
Product: CSc1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Yield: 80 %

Procedure:
In the same manner as in Example 1 and using 5-[3-[4-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using iodomethane instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: [H-].[Na+].COCCOC.COP([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:17])(=O)OC.[CH2:31]([O:33][C:34](=[O:49])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C@@H:42]1[CH:47]=O)[CH3:32]>C(OCC)(=O)C>[CH2:31]([O:33][C:34](=[O:49])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C@@H:42]1/[CH:47]=[CH:15]/[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)[OH:17])[CH3:32]
Reactant: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)c1cccc(Cc2ccccc2)c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.1 %

Procedure:
To 60% sodium hydride in mineral oil (20 mg, 0.51 mmol) was added a DME solution (5 mL) of [2-(3-benzyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (164 mg, 0.51 mmol). After 1.5 h a DME solution (5 mL) of 7-((R)-2-formyl-5-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester (126 mg, 0.47 mmol) was added. The reaction mixture was stirred for 45 min. at room temperature then diluted with ethyl acetate and washed with an aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The residue was subjected to column chromatography (2.5 ethyl acetate: 1 hexanes) to provide 7-{(R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxy-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (112 mg, 0.24 mmol) as an oil.
Reaction SMILES: [C:1]([C:3]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].C(N(C(C)C)CC)(C)C.[ClH:37].[N:38]1([C:43](N)=[NH:44])C=CC=N1>CN(C)C=O>[ClH:37].[ClH:37].[C:1]([C:3]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][N:24]([C:43]([NH2:44])=[NH:38])[CH2:25]3)=[CH:20][CH:19]=2)[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)#[N:2]
Reactant: N=C(N)n1cccn1
Reactant: N#CC1(CCOc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(CCOc2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.7 %

Procedure:
To a solution of 7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline (70 mg) in dimethylformamide (5 ml)solution were added diisopropylethylamine (0.1 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (85 mg), and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by HPLC (0.05% aquesous trifluoroacetic acid:methanol=1:1). The obtained residue was treated with dil. hydrochloric acid and dried under reduced pressure to give the title compound (67 mg).