Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]2[C:30](=[O:31])[N:12]3[CH:13]=[CH:14][C:15]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]3=[N:10]2)=[CH:6][CH:5]=[C:4]([C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH3:36][N:37](C=O)C>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:15]2[CH:14]=[CH:13][N:12]3[C:30](=[O:31])[N:9]([CH2:8][C:7]4[C:2]([C:36]#[N:37])=[N:3][C:4]([C:32]([F:34])([F:33])[F:35])=[CH:5][CH:6]=4)[N:10]=[C:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 90 °C
Yield: 69 %

Procedure:
Into a 25 mL flame-dried three necked flask equipped with a condenser under argon was placed 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (250 mg, 0.484 mmol), Pd(dba)3 (44 mg, 0.048 mmol) and dppf (107 mg, 0.194 mmol). The reaction apparatus was purged with argon, and anhydrous DMF (1.5 mL, degassed by bubbling with argon) was added. The resulting suspension was stirred in a pre-heated oil bath at 90° C. To the resulting clear brownish solution, a suspension of zinc cyanide (85.3 mg, 0.73 mmol) in anhydrous DMF (1.5 mL) was added in five portions over 5 min. The reaction mixture was then stirred at 90° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (30 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (50-100%) in hexanes to afford 170 mg (69%) of the title compound as a brown foam. A portion of the product was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 100% B over 20 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford the title compound as a yellow powder. HPLC/MS: retention time=2.82 min, [M+H]+=507.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:15][S@@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])([CH2:12][CH:13]=[O:14])[CH:9]([F:11])[F:10])[C:5]([F:22])=[CH:4][CH:3]=1.[F:23][C:24]([Si](C)(C)C)([F:26])[F:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.O>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:15][S@@:16]([C:18]([CH3:19])([CH3:21])[CH3:20])=[O:17])([CH2:12][C@@H:13]([OH:14])[C:24]([F:26])([F:25])[F:23])[CH:9]([F:11])[F:10])[C:5]([F:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](CC=O)(c1nc(Br)ccc1F)C(F)F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](C[C@@H](O)C(F)(F)F)(c1nc(Br)ccc1F)C(F)F
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 21.4 %

Procedure:
To a solution of (R)-N-((R)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1-difluoro-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (0.12 g, 0.299 mmol) in THF (3 ml) at −78° C. was added (trifluoromethyl)trimethylsilane (0.475 ml, 2.99 mmol) dropwise. After 25 min, tetrabutylammonium fluoride, 1.0m in tetrahydrofuran (0.299 ml, 0.299 mmol) was added. The reaction mixture was stirred at −78° C. for 6 h (warmed up to −20° C.). Aqueous 1N HCl (0.8 mL) was added at −78° C. and the reaction was warmed up to rt, diluted with water, extracted with EtOAc (2×), washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane in 20 min to give (R)-N-((2S,4R)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1,5,5,5-pentafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (30 mg, 0.064 mmol, 21.29% yield) as white solid. MS m/z=471, 473 M+, Calculated for C14H17BrF6N2O2S: 471.26.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:12][C:13]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:33]3[C:28]([CH:29]=[CH:30][CH:31]=[CH:32]3)=[C:27]([OH:34])[C:26]=2[CH3:35])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].Cl>CN(C=O)C.O>[NH2:12][C:13]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:33]3[C:28]([CH:29]=[CH:30][CH:31]=[CH:32]3)=[C:27]([O:34][CH2:2][CH2:3][O:4][CH3:5])[C:26]=2[CH3:35])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COCCBr
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(O)c3ccccn23)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1c(C)c(C(=O)c2ccc(N)c(C(=O)OC)c2)n2ccccc12
Yield: 40.4 %

Procedure:
0.161 g (1.16 mmol) of 1-bromo-2-methoxyethane and 0.359 mg (1.16 mmol) of caesium carbonate are added, under an inert atmosphere at ambient temperature, to 0.313 g (0.97 mmol) of methyl 2-amino-5-{[1-hydroxy-2-methylindolizin-3-yl]-carbonyl}benzoate in 10 ml of DMF. The reaction medium is stirred for 24 hours at ambient temperature, hydrolysed with water, and then acidified with a 1N aqueous solution of hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The organic phase obtained is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 150 mg of a yellow oil are obtained.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=4)[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O.O>[C:1]1([C:7]2[N:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:21]([NH:26][CH:27]5[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]5)=[O:22])=[CH:24][CH:25]=4)[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Nc2nc3cccc(-c4ccccc4)n3n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(Nc3nc4cccc(-c5ccccc5)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
tert-Butyl 4-(4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzamido) piperidine-1-carboxylate. A mixture of 4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid (200 mg, 0.6 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (121 mg, 0.6 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (460 mg, 1.2 mmol) and N-methylmorpholine (306 mg, 3.0 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. Water (5 mL) was added, and the precipitate was collected by filtration and washed with water to give tert-butyl 4-(4-(5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzamido)piperidine-1-carboxylate (220 mg, 72% yield) as a solid. MS (ESI): m/z 535.1 [M+23]+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:12][NH2:13]>>[F:11][C:7]1[C:5]2[NH:6][C:2]([NH:13][CH3:12])=[N:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Fc1cccc2nc(Cl)[nH]c12
Reactant: CN
Product: CNc1nc2cccc(F)c2[nH]1
Temperature: 160 °C
Yield: 74.7 %

Procedure:
3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES-) M-H−, 151.19. b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (Care: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3×20 ml). The combined organic layers were washed with saturated brine and then dried over Na2SO4, filtered and evaporated to afford 2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z: (ES+) MH+, 171.20. c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was charged to a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and fractions containing product were evaporated to leave a brown oil. The oil was was purified by flash chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. Pure fractions were evaporated to afford 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m/z: (ES+) MH+, 166.00.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.COC[O:11][C:12]1[CH:39]=[CH:38][C:15]2[CH2:16][C:17]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH2:27][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[CH3:29])=[CH:22][CH:21]=3)([CH3:19])[O:18][C:14]=2[CH:13]=1>C(OCC)(=O)C>[ClH:1].[ClH:1].[NH2:30][C@@H:28]([CH3:29])[CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2([CH3:19])[CH2:16][C:15]3[CH:38]=[CH:39][C:12]([OH:11])=[CH:13][C:14]=3[O:18]2)=[N:25][CH:24]=1
Reactant: COCOc1ccc2c(c1)OC(C)(c1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn1)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)COc1ccc(C2(C)Cc3ccc(O)cc3O2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4 M hydrogen chloride/ethyl acetate (10 mL) was added dropwise to a solution of diastereomer of tert-butyl [(1S)-2-({6-[6-(methoxymethoxy)-2-methyl-2,3-dihydro-1-benzofuran-2-yl]pyridin-3-yl}oxy)-1-methylethyl]carbamate (1000 mg) in ethyl acetate (20 mL) at room temperature. The mixture was stirred at room temperature for 3 hr. The resulting precipitate was collected by filtration to give the title compound (650 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH:29]=[CH2:30])=[O:22]>CS(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH:29]=[CH2:30])=[O:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: C=CCOCCCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOCCCOC(=O)COc1ccc(Cl)c2cccnc12
Temperature: 25 °C

Procedure:
3.78 g (0.021 mol) of 5-chloro-8-hydroxyquinoline and 2.91 g (0.021 mol) of potassium carbonate are heated at 60° C. in 100 ml of dimethylsulfoxide (DMSO) for 30 minutes. The mixture is allowed to cool again to room temperature, 5.0 g (0.021 mol) of 3-(allyloxy)propyl bromoacetate are then added dropwise and the solution is subsequently heated at 90° C. for 4 hours. The DMSO is then distilled off in vacuo, the residue is taken up in ethyl acetate and the solution is washed with water and 5 percent strength sodium hydroxide solution. The organic phase is dried over magnesium sulfate, the desiccant is filtered off and the solvent is stripped off under reduced pressure. After recrystallization of the residue from n-heptane, 5.4 g (76.3% of theory) of 3-(allyloxy)propyl
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:31].CCOCC>CO>[IH:31].[IH:31].[N:11]1([C:15]2[N:19]([CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2cccn2)CC1
Agent: I
Solvent: CCOCC
Solvent: CO
Product: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1cccn1
Reaction time: 1 h

Procedure:
Reflux 4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.71 g, 1.73 mmol) in methanol (15 mL) with hydroiodic acid (57%, 0.5 mL) for 12 hours. Cool, add ether (80 mL) to afford a suspension and stir the suspension for one hour. Collect the solid by filtration and dry to provide 2-[1,4]diazepan-1-yl-1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazole dihydroiodide (0.81 g).
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[O-])=[CH:6]/[C:7]([O:9]CC)=[O:8])C.[Na+].C(O)(=O)C.[CH:19](=[NH:21])[NH2:20].[OH-].[Na+]>O>[OH:3][C:4]1[N:21]=[CH:19][N:20]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: N=CN
Reactant: CCOC(=O)/C=C(\[O-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
To a solution of sodium (Z)-1,4-diethoxy-1,4-dioxobut-2-en-2-olate (55.0 g, 262 mmol) in H2O (500 mL) was added formimidamide acetate (27.3 g, 262 mmol) and NaOH (10.5 g). After addition, the resulting mixture was stirred at 25° C. for 16 h then concentrated and then acidified by added aqueous HCl (1N) until pH=1. The resulting solid was collected by filtration, washed with H2O and ether to give 6-hydroxypyrimidine-4-carboxylic acid (6.0 g, yield: 16.3%). 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.24 (s, 1H), 6.83 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].B.Cl.[OH-].[Na+]>O1CCCC1>[F:15][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][NH2:2])=[CH:8][C:7]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)c(-c2ccccc2)c1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1ccc(F)c(-c2ccccc2)c1
Reaction time: 22 h
Yield: 62.5 %

Procedure:
To a solution of 5-cyano-2-fluorobiphenyl (1.96 g) in tetrahydrofuran (35 mL), a solution of borane in tetrahydrofuran (1 M, 35 mL) was added dropwise at room temperature, and the mixture was stirred for 22 hours. Hydrochloric acid (1 M, 7 mL) was gradually added dropwise to the reaction solution, and the mixture was stirred for 2 hours. A 2 M aqueous sodium hydroxide solution was added thereto for separation into organic and aqueous layers. The aqueous layer was subjected to extraction with ethyl acetate. All the organic layers were combined, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: hexane/ethyl acetate) to obtain the title compound (1.25 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccccc2)cc1
Reactant: [H][H]
Solvent: CCO
Product: Nc1ccc(/C=C/c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
38 g of 4-nitrostilbene are hydrogenated in 120 g of ethanol with 6 g of a CoSx paste prepared according to Example 1, which was digested with ethanol and contains approx. 30% of CoSx, in a stainless steel stirred autoclave at 115° C under 80 bars of H2. The calculated amount of hydrogen for the reduction of the nitro group has been take up within 1 hour. The mixture is stirred for a further 10 minutes at 120° C and 80 bars of H2. The reduction mixture is filtered and the resulting solution gives 30 g of 4-amino-trans-stilbene; melting point 151° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][CH2:17][C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:42]([O:49][C:50]([CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.O>[CH2:42]([O:49][C:50]([CH:52]1[CH2:57][CH2:56][N:55]([C:18](=[O:20])[CH2:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:54][CH2:53]1)=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: O=C(OCc1ccccc1)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCN(C(=O)CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 41.3 %

Procedure:
DIPEA (7 g, 9.44 mL, 54.6 mmol) was added to a stirred solution of 3-phenyl-propionic acid (3.27 g, 21.8 mmol) in DMF (15 mL). HOBT (2.94 g, 21.8 mmol) and EDCI (4.16 g, 21.8 mmol) were then added at room temperature. After 2 minutes, piperidine-4-carboxylic acid benzyl ester (4 g, 18.2 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using 60-120 silica gel and EtOAc in hexane as eluent) to afford 2.64 g (41.25% yield) of 1-(3-phenyl-propionyl)-piperidine-4-carboxylic acid benzyl ester. LCMS Purity: 86.15%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16]CC=C)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si](Cl)(C)C.[OH-].[Na+].O1C[CH2:40][CH2:39][CH2:38]1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:40][CH:39]=[CH2:38])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C1CCOC1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Product: C=CCC1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 3-allyl ester 1-tert-butyl ester (62.5 g) in tetrahydrofuran (625 ml) cooled to −72° C. was added lithium hexamethyl disilazide (1.6M tetrahydrofuran solution, 160 ml). The mixture was stirred at the same temperature for 30 minutes, and then the reaction mixture was warmed to 0° C. over 12 minutes and cooled to −67° C. again. To the mixture was added trimethylsilyl chloride (35.2 ml). The reaction mixture was warmed to 2.5° C. over 1 hour, and stirred at the same temperature for additional 2 hours. To the mixture were sequentially added methanol (250 ml) and 1M aqueous sodium hydroxide solution (250 ml), and the mixture was washed with n-hexane (940 ml). The separated aqueous layer was washed with n-hexane (250 ml) again. The separated aqueous layer was acidified by 1M hydrochloric acid water, and then extracted with ethyl acetate (800 ml). The organic layer was sequentially washed with water (800 ml) and saturated aqueous sodium chloride solution (400 ml), and the separated aqueous layer was extracted with ethyl acetate (500 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was slurry-washed with n-hexane/ethyl acetate (10/1, 660 ml) to give the titled compound (53.4 g).
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>>[F:19][C:18]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH3:27])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: C#CC(C)(O)c1ccccn1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)c1ccccn1
Yield: 7 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol to give the titled compound as a white solid (18 mg, 7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:14]1([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:6]([CH2:5][CH:4]([OH:13])[CH2:3][CH2:2][N:17]1[CH2:16][CH2:15][N:14]([C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Product: N#Cc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
Following the procedure of Example 25, the title compound is prepared from 4-chloro-1-phenoxy-2-butanol and 4-(1-piperazinyl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([C:16](=[CH:24][C:25]3([CH3:29])[CH2:28][O:27][CH2:26]3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.[Cl-].[NH4+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:29])[CH2:26][O:27][CH2:28]3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(=CC2(C)COC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cn(C(CC2(C)COC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At room temperature, 350 mg (766 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)prop-2-enoate (isomer mixture) were admixed with 20 ml of a “Hot Stryker's” reagent solution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292]. The reaction mixture was stirred at room temperature for 1 h, and saturated aqueous ammonium chloride solution was then added. After phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (40 g silica cartridge, flow rate 40 ml/min, cyclohexane/ethyl acetate gradient). Yield: 345 mg (97% of theory)