Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:22])[C:5](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:23]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[CH:23]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)OC
Product: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(OC)c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of methyl 4-methoxy-3-oxo-2-{[3-(trifluoromethyl)phenyl]hydrazono}butanoate (14.0 g, 44 mmol) in N,N-dimethylformamide dimethyl acetal (100 mL) was refluxed for 4 h. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane/AcOEt (3/1) to give the title compound (12.9 g, 89% yield) as off-white crystals: mp 169-170° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.98 (3H, s), 3.99 (3H, s), 7.66-7.74 (2H, m), 7.83-7.89 (2H, m), 7.95 (1H, s). Anal. Calcd for C14H11F3N2O4C, 51.23; H, 3.38; N, 8.53. Found: C, 51.15; H, 3.47 N, 8.60.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26]Br>>[CH3:32][O:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:30]=1)[CH2:26][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: COc1cc(CBr)cc(OC)c1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(OC)cc(OC)c2)c(=O)[nH]c1=O
Yield: 50.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (212 mg, yield: 50.2%).
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C@@H:28]([CH3:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.[OH-].[Na+]>CO>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]([S:12]([C:9]1[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[C@H:28]2[CH3:29]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 98.4 %

Procedure:
The title compound was prepared from ethyl 4-{[(S)-8-fluoro-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenyl carbonate (0.05 g, 0.11 mmol), 2.5 N aqueous sodium hydroxide (2 mL, 5 mmol), and methanol (2 mL), according to the procedure and in the same manner as described in Example 32, Method A, Step e to yield 4-{[(S)-8-fluoro-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol as a solid (0.04 g, 100%), m.p. 193° C.;
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[C:11]([C:15]3[O:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH:12]=[CH:13][CH:14]=2)=CC=1.C(O)(C(F)(F)F)=O>>[CH3:20][C:17]1[O:16][C:15]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)=[N:19][N:18]=1
Reactant: COc1ccc(COc2cccc(-c3nnc(C)o3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(-c2cccc(O)c2)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{3-[(4-Methoxybenzyl)oxy]phenyl}-5-methyl-1,3,4-oxadiazole (100 mg, 0.338 mmol) was treated with 0.5 mL TFA and was stirred at room temperature for 10 min. Excess TFA was removed under vacuum and the residue was purified by column chromatography using a 24 gram biotage silica gel cartridge eluting with 20-50% ethyl acetate/hexanes (gradient) to give the product as white solid. LRMS calc: 176.1; obs: 177.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:34][C:35]1[C:43]([F:44])=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][CH2:38][NH:39]2>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:39]2[C:40]3[C:36](=[C:35]([F:34])[C:43]([F:44])=[CH:42][CH:41]=3)[CH2:37][CH2:38]2)=[O:10])[CH:3]=1
Reactant: Fc1ccc2c(c1F)CCN2
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)ccn1)N1CCc2c1ccc(F)c2F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.50 g (3.2 mmol) 4-chloropicolinic acid, 1.1 g (3.4 mmol) TBTU and 0.91 mL (6.5 mmol) TEA were placed in 10 mL DMF. 0.63 g (3.3 mmol) 4,5-difluoroindoline hydrochloride were added. The reaction mixture was stirred overnight at RT and then extracted successively with a 15% potassium carbonate solution, water, a 1M HCl solution and EtOAc. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation. The residue was stirred with diisopropylether and the undissolved solid was suction filtered and dried.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:28]2[CH2:27][CH2:26][C@H:25]3[C@@H:20]([CH2:21][CH2:22][CH2:23][NH:24]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@H:20]([C:19]5[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[C:28]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1cccc2c1CC[C@H]1[C@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 49 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-7-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 49% of theory; LC (method 1): tR=2.68 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC1CCNCC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
To (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine (3.78 grams, 9.4 mmol) was added 20% trifluoroacetic acid (50 ml) in dichloromethane. The solution was stirred at room temperature for 4 hours. The solution was concentrated under reduced pressure and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was washed with water, dried over potassium carbonate and concentrated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine as an oil (2.42 grams, 85%), M+H 303.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].Cl>CO.O1CCOCC1>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][Br:1]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCBr)c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The product of step (vi) (35.8 g) was dissolved in methanol (400 ml) and treated with 4M hydrogen chloride in dioxane (100 ml). The mixture was stirred at ambient temperature for 6 hours and concentrated in vacuo. Dichloromethane (500 ml) was added and concentrated in vacuo, which afforded a foam that was taken onto the next step without further purification. Yield 38 g.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[N+:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][C:18](=[O:19])[NH:10][C:8]2[O:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)=[CH:26][CH:25]=1)([O-:29])=[O:28]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of 3-tert-butyl-isoxazol-5-ylamine (2.50 g, 17.83 mmol) in dichloromethane was treated with pyridine (2 mL, 26.7 mmol) followed by p-nitrophenyl chloroformate (3.77 g, 18.73 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was triturated with ether and collected by filtration to afford 2.2 g of product (41% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11].[I:12][C:13]1[C:21]2[C:16](=[N:17][C:18](S(C)(=O)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:14]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:18]1[N:17]=[C:16]2[N:15]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:14]=[C:13]([I:12])[C:21]2=[CH:20][N:19]=1
Reactant: Oc1ccc(F)cc1F
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cnc(S(C)(=O)=O)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cnc(Oc3ccc(F)cc3F)nc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
Sodium hydride (3.88 g of 60% dispersion in mineral oil, 0.097 mol) was added to 150 mL of dry DMF under nitrogen, and the reaction mixture was cooled in an ice bath. 2,4-Difluorophenol (8.85 mL, 0.092 mol) was added dropwise over 10 minutes (maintaining temperature between 5 and 10° C.), after which the reaction mixture was stirred for 15 minutes at 0° C., followed by 15 minutes of stirring at room temperature. A solution of 3-Iodo-6-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (11.91 g, 0.026 mol) in 100 mL dry DMF was added, and the reaction mixture was heated to 140° C. for four hours while stirring under nitrogen. The reaction mixture was cooled to room temperature, and volatiles were removed under reduced pressure. The was added to 200 mL of 10% aqueous ammonium chloride, 50 mL water, and 250 mL EtOAc. The aqueous phase was partitioned off and extracted once with 250 mL EtOAc. The combined organic phases were washed with saturated aqueous brine, dried over MgSO4, filtered, and evaporated under reduced pressure to yield an oil. The oil was eluted through silica gel with hexanes EtOAc (20:1 to 10:1) to afford 6.23 g of 6-(2,4-Difluoro-phenoxy)-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][N:22](C(OC(C)(C)C)=O)[CH:23]=2)=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:23]=[N:22][NH:21][CH:20]=4)=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(C(=O)CBr)cc2)cn1
Reactant: Nc1ccc(I)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Ic1ccc2nc(-c3ccc(-c4cn[nH]c4)cc3)cn2c1

Procedure:
Subsequently, 2-amino-5-iodopyridine (478 mg) and tert-butyl 4-[4-(2-bromoacetyl)phenyl]-1H-1-pyrazolecarboxylate mg) were dissolved in ethanol (20 mL), and sodium hydrogencarbonate (183 mg) was added to the solution, followed by refluxing for 16 hours. The precipitated matter was recovered through filtration and dried, to thereby yield the title compound (535 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[CH:2].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)[CH:17]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
Add 1-ethynyl-3-methoxybenzene (0.56 g, 4.22 mmol) to a mixture of 3,5-dibromopyridine (1.00 g, 4.22 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.06 g, 0.08 mmol) and copper (I) iodide (0.03 g, 0.17 mmol) in triethylamine (8 mL) and heat at 70° C. for 2 h. Cool to room temperature, dilute with ethyl acetate and an aqueous saturated solution of ammonium chloride, and separate the layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify the resulting residue by silica gel chromatography, eluting with 2.5% ethanol in 50:50 chloroform/hexanes, to give the title compound (0.86 g, 71%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]3([F:38])[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:20]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[F:38][C:25]1([CH2:24][NH:23][C:21]2[C:20]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:19][N:18]=[C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=3)[CH:22]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2(F)CCNCC2)cc1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
5-Aminopyrazine-2-carbonitrile (5.45 mg, 0.045 mmol), Xantphos (1.749 mg, 3.02 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.384 mg, 1.511 μmol), and cesium carbonate (24.62 mg, 0.076 mmol) were added to tert-butyl 4-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (17 mg, 0.038 mmol) in a 0.2 mL microwave reaction vial. The vial was sealed and an inert atmosphere was introduced before dry dioxane (291 μL) was added. Nitrogen was bubbled through the mixture for 5 min. The mixture was heated at 150° C. for 1 hr by microwave irradiation. After cooling the mixture was diluted with 20% dichloromethane in MeOH and loaded onto a preparative thin layer chromatography plate. Elution with 50% EtOAc in hexane gave tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (1.5 mg, 2.81 μmol, 7% yield) as a light yellow powder. LCMS (4) Rt=2.35 min; m/z (ESI+) 534 (MH+). Trifluoroacetic acid (0.1 mL, 1.298 mmol) was added to tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (1.5 mg, 2.81 μmol) dissolved in dichloromethane (0.5 mL) and the solution was stirred for 1 hr. The volatiles were removed in vacuo and the crude product was purified by ion exchange on Isolute SCX II acidic resin (1 g), followed by preparative thin layer chromatography, eluting with 10% MeOH/1% NH3/89% dichloromethane, to give 5-(4-((4-fluoropiperidin-4-yl)methylamino)-5-(4-methoxyphenyl)pyridin-2-ylamino)pyrazine-2-carbonitrile (1 mg, 2.307 μmol, 82% yield) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OCC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 108.1 %

Procedure:
In a 50 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 1 g, 1.62 mmol), tert-butyl 2-bromoacetate (316 mg, 240 μL, 1.62 mmol) and cesium carbonate (634 mg, 1.95 mmol) were combined with dry dimethyl formamide (10 mL) to give a white suspension. The tube was capped and heated at 50° C. After 10 min, the reaction mixture was cooled down to room temperature, poured into water and extracted with ethyl acetate (2×). The combined ethyl acetate layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 2-tert-butoxy-2-oxoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as light yellow solid (1280 mg), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:23](O)=[O:24].[CH:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:21]([O:20][C:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=3[C:23]([NH:34][CH2:33][CH2:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[N:8]=2)[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1CCN(c2ccc3c(C(=O)O)c(Cl)ccc3n2)CC1
Reactant: NCCC1CCCCC1
Product: CCOC(=O)C1CCN(c2ccc3c(C(=O)NCCC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 70.8 %

Procedure:
Prepared according to the method of example 4(a), using 6-chloro-2-[4-(ethoxycarbonyl)-1-piperidinyl]-5-quinolinecarboxylic acid (example 76(c)) (217 mg) and cyclohexaneethanamine (277 mg). Purification (SiO2, methanol:dichloromethane 1:99 as eluant) gave the title compound as a solid (200 mg).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[O:6][C@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[NH3:16]>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:5]2[O:6][C@H:4]2[C:3]([NH2:16])=[O:2])=[CH:8][CH:9]=1
Reactant: N
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Yield: 85 %

Procedure:
To a mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionic acid methyl ester (2.08 g) and N,N-dimethylformamide (3 ml) is added 28% aqueous ammonia (6.1 g) under ice-cooling. The mixture is reacted at room temperature for two hours, and the precipitated crystals are collected by filtration, washed with water, and dried at 50° C. to give (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (1.64 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)#[CH:11]>>[N+:18]([C:14]1[CH:13]=[C:12]([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Reactant: N#Cc1cncc(Br)c1
Product: N#Cc1cncc(C#Cc2cccc([N+](=O)[O-])c2)c1
Yield: 21.6 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 5-bromonicotinonitrile (400 mg, 2.19 mmol) and 1-ethynyl-3-nitrobenzene, (prepared as described in PREPARATION 11), (644 mg, 4.38 mmol) to give the title compound (118 mg, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]=O)[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[S:29][CH2:30][C:31](=[O:33])[N:32]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:30]4/[C:31](=[O:33])[N:32]=[C:28]([NH2:27])[S:29]/4)[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1=NC(=O)CS1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(C=O)cc23)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(/C=C4\SC(N)=NC4=O)cc23)CC1

Procedure:
The similar procedure as described in example 35 was used, starting from 4-(6-formyl-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester, 2-Amino-thiazol-4-one (example 48b), sodium acetate and acetic acid to obtain 4-{6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinolin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. Purification was performed with flash chromatography (Merck silica gel 60, 230-400 mesh, 1%-5% methanol in dichloromethane for 30 min. LC-MS m/e 455.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:15]([Cu])#[N:16]>CN1C(=O)CCC1.CCOC(C)=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([CH3:14])([C:10](=[O:12])[CH3:11])[CH3:13])=[CH:3][C:2]=1[C:15]#[N:16]
Reactant: CC(=O)C(C)(C)c1ccc(F)c(Br)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)C(C)(C)c1ccc(F)c(C#N)c1
Temperature: 160 °C
Yield: 69.2 %

Procedure:
To a solution of 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-one (13 g, 50 mmol) in NMP (100 mL) was added CuCN (17.9 g, 200 mmol, 4 eq). The mixture was heated 24 h at 160° C. After cooling, the reaction was diluted with EtOAc, washed with 2N HCl (200 mL), satd NaHCO3 (200 mL) and brine (200 mL) successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give 2-fluoro-5-(2-methyl-3-oxobutan-2-yl)benzonitrile (7.1 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 1H), 7.49-7.45 (m, 1H), 7.20 (t, J=8.4 Hz, 1H), 1.96 (s, 3H), 1.50 (s, 6H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:8]2[N:9]([C:13]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][NH2:32])[CH2:27][CH2:26]3)=[N:14][C:15]=2[C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][N:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:6][C:7]1[C:8]2[N:9]([C:13]([CH:25]3[CH2:26][CH2:27][CH:28]([CH2:31][NH:32][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:30]3)=[N:14][C:15]=2[C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCC1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (4.40 μL, 0.057 mmol was added to a mixture of 1-{trans-4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanamine (20.5 mg, 0.057 mol) and PS-DIEA (3.90 mmol/g loading; 60 mg, 0.2 mmol) in DCM (1.14 mL). The reaction mixture was stirred for 30 min at r.t. for 18 h. The crude reaction mixture was then concentrated and residue purified by mass directed preparative HPLC to afford 4 mg of desired product. MS (ES+): m/z 439.10 (100) [MH+]. 1H NMR (CD3OD, 400 MHz): δ 8.24 (br s, 2H), 7.61 (m, 2H), 7.46 (dd, J=8.4, 0.8 Hz, 1H), 7.19 (ddd, J=7.2, 1.2, 1.2 Hz, 1H), 7.08 (ddd, J=7.2, 1.2, 1.2 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 3.14 (m, 1H), 2.07 (m, 4H), 1.85 (m, 2H), 1.64 (m, 1H), 1.26 (m, 2H).