Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[CH:4][C:5]([Cl:9])=[C:6]([F:8])[CH:7]=1.[Cu][C:12]#[N:13]>>[Cl:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([F:8])=[CH:7][C:2]=1[C:12]#[N:13]
Reactant: Fc1cc(Br)c(Cl)cc1Cl
Reactant: N#C[Cu]
Product: N#Cc1cc(F)c(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 4 h

Procedure:
48.8 g (0.2 mol) of 5-bromo-2,4-dichlorofluorobenzene and 17.9 g (0.2 mol) of copper(I) cyanide were introduced into a 100 ml 3-neck flask fitted with a reflux condenser and blade stirrer and stirred at 150° C. for 4 hours (no reaction). The reaction suspension was heated to 200° C. and stirred for a further 4 hours at this temperature: no reaction, 0 GC area-%.
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][N:12]1[C:16]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)=[N:15][C:14]([CH:35]=[O:36])=[N:13]1.O>O1CCCC1>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:35]([C:14]1[N:15]=[C:16]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:23]=2)[N:12]([CH3:11])[N:13]=1)[OH:36]
Reactant: c1ccoc1
Reactant: Cn1nc(C=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(C(O)c2ccco2)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 18 h

Procedure:
n-Butyllithium (1.55M in n-hexane, 5.96 ml) was added dropwise to a stirred solution of furan (0.16 ml) in anhydrous tetrahydrofuran (20 ml), under nitrogen at -40°. The stirred solution was allowed to warm slowly to 20°, heated under reflux for 3 h, added dropwise at 0° to a solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxaldehyde (1.0 g) in tetrahydrofuran (10 ml), and the resulting solution was stirred at 20° for 18 h. Water (20 ml) was added, the mixture concentrated, extracted with ethyl acetate and the extract was dried and evaporated. The residual oil (0.9 g) was chromatographed using System C to give the title compound (0.16 g) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1OC
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)c(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][O:6][C:7]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:8]=1.Cl.[CH3:36][NH2:37]>C(Cl)Cl>[CH3:36][NH:37][C:13]([C:12]1[C:7]([O:6][CH2:5][C:4]2[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=2)=[N:8][C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:11]=1)=[O:14]
Reactant: CN
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a portion of the methylene chloride (1 mL) solution of 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carbonyl chloride (0.044 mmol) was added methylamine hydrochloride (6 mg, 0.088 mmol) and TEA (0.018 mL, 0.13 mmol). The reaction was stirred at rt for 16 h and was then evaporated. The residue was purified by preparative TLC eluted with 25% ethyl acetate in hexanes to yield N-(methyl)-2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3carboxamide. HPLC/MS: 533 (M+1), 535 (M+3); Rt=4.77 min
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (806 mg) in tetrahydrofuran (25 ml) was added triethylamine (1.80 ml). This was cooled in an ice bath under a nitrogen atmosphere, and methanesulfonyl chloride (0.499 ml) was added dropwise, followed by stirring at the same temperature for 30 min. The reaction mixture was partitioned after addition of ethyl acetate (100 ml) and water (70 ml). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound as a colorless oil (1.05 g, 92.0%).
Reaction SMILES: [Cl:1][C:2]1C=C[C:5](C)=[C:6](N2CCN(C/C=C\CN)CC2)[CH:7]=1.[K].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>>[Cl:1][CH2:2]/[CH:7]=[CH:6]\[CH2:5][N:25]1[C:21](=[O:31])[C:22]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:23]2[C:24]1=[O:26]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(Cl)cc1N1CCN(C/C=C\CN)CC1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C/C=C\CCl

Procedure:
Cis-4-[4-(5-chloro-2-methylphenyl)piperazinyl]-2-buten-1-amine: according to the method of Example 5, phthalimide potassium salt was reacted with cis-1,4-dihydro-2-butene to obtain N-(cis-4-chloro-2-buten-1-yl)phthalimide; which was then reacted with 5-chloro-2-methylphenylpiperazine to obtain N-{4-[4-(5-chloro-2-methylphenyl)piperazinyl]-cis-2-buten-1-yl}phthalimide, which was then reacted with hydrazine hydrate. Yield: 85.7%. Hydrochloride mp: 127-129° C. 1HNMR (ppm, CDCl3) δ: 1.56 (br-s, 4H), 2.23 (s, 3H), 2.71 (br-s, 2H, NH2), 2.96 (m, 4H), 3.12 (d, J=7.0 Hz), 3.41 (d, J=6.72 Hz, 2H), 5.60 (m, 1H), 5.73 (m, 1H), 6.96 (m, 2H), 7.08 (d, J=7.84, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[CH:24]([C:26]1([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH2:25]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:25][CH2:24][C:26]2([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC1(O)CCCCC1
Product: O=C1CN(c2ccc(CCC3(O)CCCCC3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 1-vinyl-cyclohexanol analogous to Example 44: (M−1)−=353; HPLC retention time=1.35 min (method A).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(CCCC)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCC)CC2)cc1

Procedure:
1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (8.5 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.5 g (88%); white solid; mp 182° C.; MS: 398 (M+H)+
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][CH2:21][O:22][CH2:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:19]23[O:9][CH:20]2[CH2:21][O:22][CH2:23][CH2:24]3)[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccc(C2=CCOCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1cccc(C23CCOCC2O3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
3-Chloroperbenzoic acid (purity: 80%, 25.1 g) was added to a solution of 4-(3-bromophenyl)-3,6-dihydro-2H-pyran (21.4 g) in dichloromethane (400 mL) in an ice bath. The mixture was stirred at the same temperature for three hours, and then warmed to room temperature and stirred for five hours. Ice and a saturated sodium bicarbonate solution were added to the reaction mixture, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution, a sodium thiosulfate solution and brine. The aqueous layers were combined and extracted with ethyl acetate, and the organic layer was sequentially washed with a sodium bicarbonate solution, a sodium thiosulfate solution and brine. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (17.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[F:36][C:33]1[C:34]2[CH:35]=[C:27]3[C:26]4[N:39]=[C:22]([C:21]5[C:2]([NH:1][S:47]([CH3:46])(=[O:49])=[O:48])=[CH:3][C:4]6[O:8][C:7]([C:9]7[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=7)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=6[CH:20]=5)[CH:23]=[CH:24][C:25]=4[O:38][CH2:37][N:28]3[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a mixture of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1000 mg, 1.914 mmol) and pyridine (1.548 mL, 19.14 mmol) in dichloromethane (30 mL), methylsulfonyl chloride (0.741 mL, 9.57 mmol) was added dropwise at 0° C. The mixture was allowed to room temperature and stirred overnight. The reaction mixture was quenched with NaHCO3 and 20 mL dichloromethane was added. Solid crushed out, the mixture was filtered and washed with water. The crude solid was dried under vacuum and gave the crude product 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1100 mg, 96% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH:20](=[O:22])[CH3:21]>C1COCC1>[OH:22][CH:20]([C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: CC=O
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of N-(6-bromopyridin-2-yl)-2,2-dimethylpropanamide (2 g, 7.77 mmol, 1 eq.) in 25 ml of THF was cooled to −78° C. and n-BuLi (1.6 M, 9.72 ml, 15.55 mmol) was added dropwise. After 1 h, acetaldehyde (0.376 g, 8.55 mmol, 1.1 eq.) was added and the mixture was warmed to 0° C. within 1 h. The reaction was quenched with H2O, and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc. The organics were combined, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give N-[6-(1-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide (1.45 g, 83% yield) as a white solid.
Reaction SMILES: C([Li])CCC.[N:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)=[N+:7]=[N-:8].[CH:18](N1CCOCC1)=[O:19]>C1COCC1.C(OCC)C>[N:6]([CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH:18]=[O:19])=[N+:7]=[N-:8]
Reactant: [N-]=[N+]=NCCc1cccc(Br)c1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: [N-]=[N+]=NCCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (1.50M in hexane, 10.8 mmol, 7.23 ml) was added dropwise at -78° C. to a solution of 1-azido-2-(3-bromophenyl)ethane [Example H(c )] (2.45 g, 10.8 mmol) in THF (80 ml). The bright yellow solution was stirred for 20 min., N-formylmorpholine (2.4 ml) in THF (10 ml) was added dropwise, the solution stirred for a further 30 min. and then warmed room temperature over 1 h. The solution was diluted with diethyl ether, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography, eluting with 10% diethyl ether/hexane, to furnish the product as a pale yellow oil (750 mg). [M-N2 ]+ 146; 360 MHz 1H n.m.r (CDCl3) 10.02 (1H, s), 7.79-7.76 (2H, m), 7.52-7.50 (2H, m), 3.57 (2H, t, J 7.0 Hz), 2.98 (2H, t, J 7.0 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].I[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:9]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH2:10][CH3:11]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1ccnc1C=O
Temperature: 50 °C
Yield: 95.9 %

Procedure:
1H-imidazole-2-carbaldehyde (800 mg, 8.3 mmol), 1-iodopropane (1.7 g, 10 mmol) and potassium carbonate (1.4 g) were added in DMF (30 mL) and the mixture was heated to 50° C. overnight. Then the mixture was evaporated under reduced pressure, and extracted with ethyl acetate (100 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to give 1-propyl-1H-imidazole-2-carbaldehyde (1.1 g). LC-MS (ESI) m/z 139 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[C:28]([N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].[H-].[Na+]>>[C:28]([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:3]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Reactant: CC(C)(C)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)N1CCC(Oc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1

Procedure:
The title compound was prepared from 40 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2), 55 mg of 1-tert-butylpiperidin-4-ol, and 8 mg of NaH by a procedure analogous to that described in COMPOUND HHH6. Mass spectrum (ESI) 556 (M+1). 1H NMR (500 MHz, CDCl3; doubling of peaks due to restricted rotation) δ 1.44 and 1.42 (2 s, 9H); 2.20-2.53 (m, 4H); 2.77 (m, 0.6H); 3.05 (br s, 1.6H); 3.50 (m, 1.5H); 3.70 (m, 0.8H); 4.60-5.40 (m, 2.9H); 5.39 (br s, 0.8H); 5.75 and 5.80 (2 s, 1H); 6.54 and 6.56 (2 d, J=8.5 Hz and J=10 Hz, 1H); 7.36-7.66 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[C:10](=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])/[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C[Si]([C:25]#[N:26])(C)C>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])([C:25]#[N:26])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: C/C(COCc1ccccc1)=N\S(=O)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C#N)(COCc1ccccc1)NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of (E)-N-(1-(benzyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide (CAN 393536-49-7, 3.1 g, 11.6 mmol) in dry THF (55 ml) under an argon atmosphere was added cesium fluoride (1.94 g, 12.8 mmol) followed by addition of trimethylsilyl cyanide (1.27 g, 1.71 ml, 12.8 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and poured into a separatory funnel. Organic phase was extracted with a 1M aqueous solution of sodium bicarbonate and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (2.53 gr, 74%); MS (ESI, m/z): 295.6 (M+H+).
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=S)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(OC)nc1C
Yield: 85 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridine-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1>CN(C=O)C>[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:59]1[CH:64]=[CH:63][C:62]([NH:65][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])=[CH:61][CH:60]=1
Reactant: Nc1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3ccc(-c4nc5ccccc5[nH]4)cc3)c(=O)oc12
Temperature: 25 °C
Yield: 75 %

Procedure:
DIEA (43.5 μL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (95.0 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4-(1H-benzoimidazol-2-yl)-phenylamine (47.5 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 71.0 mg of product in 75% yield: LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[CH:18]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)=[CH2:19]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:20]([CH:18]=[CH2:19])=[CH:21][CH:22]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: C=Cc1ccc(N)cc1
Product: C=Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 88.4 %

Procedure:
Following General Procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.200 g, 0.75 mmol) was reacted with 4-vinylaniline (0.099 g, 0.83 mmol) to afford the title compound (0.230 g, 100%) as a tan solid. MW=346.85. 1H NMR (CDCl3, 500 MHz) δ 7.88-7.85 (m, 1H), 7.73-7.68 (m, 1H), 7.47-7.42 (m, 2H), 7.35-7.29 (m, 2H), 7.21 (s, 1H), 7.20-7.16 (m, 2H), 6.72 (q, J=10.5 Hz, 1H), 5.78 (s, 1H), 5.74-5.70 (m, 1H), 5.24-5.22 (m, 1H), 3.09 (t, J=7.6 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.22 (quin, J=7.6 Hz, 2H); APCI MS m/z 347 [M+H]+.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1>>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([O:7][CH:17]([F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C(=O)O)C(C)C)cc1
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Product: COc1ccc(C(C(=O)OC(F)c2cccc(Oc3ccccc3)c2)C(C)C)cc1

Procedure:
This compound was prepared from α-isopropyl-(4-methoxyphenyl)acetic acid and α-fluoro-3-phenoxybenzylbromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δ ppm (solvent CDCl3): 0.72(3H, d, J=6Hz, CH3); 1.06(3H, d of d, J=6Hz and J=2Hz, CH3); about 2.25(1H, m, --CH(CH3)2); 3.17(1H, d, J=10Hz, CH); 3.76(3H, s, CH3O); 7.18(1H, d of d, J=56Hz and J=2Hz, CHF); about 7.2(13H, m, aromatic protons).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:25]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[C:38]([OH:40])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN(C(C)C)C(C)C.[N+:50]([C:53]1[CH:58]=[C:57]([NH2:59])[CH:56]=[CH:55][C:54]=1[NH2:60])([O-:52])=[O:51]>CN(C=O)C>[NH2:60][C:54]1[CH:55]=[CH:56][C:57]([NH:59][C:38]([C@H:33]2[CH2:34][CH2:35][CH2:36][CH2:37][N:32]2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:40])=[CH:58][C:53]=1[N+:50]([O-:52])=[O:51]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 4.96 g, 13.1 mmol) was added to a stirred solution of (R)—N-Boc-2-piperidinecarboxylic acid (3.00 g, 13.1 mmol) and DIPEA (9.0 mL, 51.2 mmol) in anhydrous DMF (50 mL). The mixture was stirred at room temperature for 5 min and then 2-nitro-1,4-phenylenediamine (3.00 g, 13.1 mmol) was added. The mixture was stirred for a further 18 hr, then the DMF was removed by evaporation. The residue was partitioned between water (200 mL) and EA (100 mL) and the phases separated. The aqueous phase was extracted with two further portions of EA (100 mL each) and the combined organic extracts washed with water, 1M sodium carbonate solution, water, and brine (100 mL each). The solution was dried over magnesium sulfate and concentrated to give (R)-tert-butyl 2-[(4-amino-3-nitrophenyl)aminocarbonyl]-piperidine-1-carboxylate as a brown solid (4.80 g).