Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:13])[CH:9]=2)[NH:4][C:3]=1[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:42](=[O:50])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:36])=[CH:30][CH:29]=1.[C:51]([Cu])#[N:52]>CN(C=O)C>[C:51]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:13])[CH:9]=2)[NH:4][C:3]=1[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:42](=[O:50])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:36])=[CH:30][CH:29]=1)#[N:52]
Reactant: N#C[Cu]
Reactant: O=C(Nc1ccc(-c2[nH]c3ccc(NC(=O)[C@@H]4CCCN4C(=O)Cc4ccccc4)cc3c2Br)cc1)[C@@H]1CCCN1C(=O)Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(NC(=O)[C@@H]3CCCN3C(=O)Cc3ccccc3)cc2)[nH]c2ccc(NC(=O)[C@@H]3CCCN3C(=O)Cc3ccccc3)cc12

Procedure:
A mixture of the bromo compound from Example 126 (150 mg, 0.2 mmol), CuCN (50 mg, 0.6 mmol) and DMF (3 mL) was refluxed under N2 protection overnight. The mixture was purified by RPLC to afford the product. MS (ESI) m/e (M+H+): 679. 1H NMR (CDCl3) δ: 7.73-7.70 (m, 4H), 7.38-7.29 (m, 4H), 7.21-7.04 (m, 6H), 4.63-4.60 (m, 1H), 4.49-4.47 (m, 1H), 3.81-3.59 (m, 4H), 2.48-1.97 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]([CH2:17][CH:18]=[CH2:19])([CH3:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]([CH2:17][CH2:18][CH3:19])([CH3:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC1(C)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CCCC1(C)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1

Procedure:
A solution of N-tertbutoxycarbonyl-4-allyl-4-methylproline (400 mg, 1.48 mmol) (see Example II Step 4) and 10% Pd on carbon (400 mg) in methanol (20 mL) was hydrogenated at 50 psi for 4 hours. The mixture was filtered and concentrated.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[C:20]#[CH:21]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:22][CH2:19][C:20]#[CH:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C#CCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C#CCNc1nc(NCC=C)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.6 %

Procedure:
To 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was added 1.61 g (29.16 mmol) of 2-propynylamine, followed by stirring at room temperature for 6 hours. After water was added to the reaction solution was water added, crystals thus precipitated were filtered and recrystallized from ethyl acetate-hexane to give 143 mg (yield: 88.6%) of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22](=O)[C:23]([O:25]C)=O)=[CH:12]1)(C(C)(C)C)(C)C.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[CH2:38][C:39]([NH2:41])=[O:40])[CH:31]=[CH:30]1.CC(C)([O-])C.[K+].Cl>CN(C=O)C>[OH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22]2[C:23](=[O:25])[NH:41][C:39](=[O:40])[C:38]=2[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[N:29]([CH3:28])[CH:30]=[CH:31]3)=[CH:12]1
Reactant: COC(=O)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2cc(OC)ccc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)cn(CCO)c2c1
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of methyl {1-[2-(tert-butyldimethylsilyloxy)ethyl]-6-methoxy-1H-indol-3-yl}oxoacetate (10.4 g, 26.5 mmol) and 2-(1-methyl-1H-indol-7-yl)acetamide (5.0 g, 26.5 mmol) in DMF (250 mL) was added a 1.0 M solution of potassium tert-butoxide (79.5 mL, 79.5 mmol) at room temperature and under nitrogen. The reaction was stirred overnight. A solution of concentrated HCl (10 mL) was added and the mixture was stirred at room temperature for 1 h, then quenched with water (200 mL) and diluted with EtOAc (300 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (3×200 mL). The organic phases were combined and washed with water (3×300 mL), brine (500 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 30% hexanes/EtOAc) gave the title compound (9.5 g, 86%) as a red solid. 1H NMR (300 MHz, DMSO-d6) 11.10 (s, 1H), 8.08 (s, 1H), 7.65 (d, J=6.1 Hz, 1H), 7.22 (d, J=2.8 Hz, 1H), 7.00–6.83 (m, 3H), 6.49 (d, J=2.8 Hz, 1H), 6.03 (d, J=5.8 Hz, 1H), 5.94 (d, J=6.3 Hz, 1H), 4.88 (t, J=5.3 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.70–3.55 (m, 8H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH3:32])[C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:25]=[N:26][C:27](F)=[CH:28][C:29]=3[CH3:30])=[O:23])[CH2:18][CH2:17]2)=[N:14][CH:15]=1.O>CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH3:32])[C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([N:3]4[CH2:4][CH2:5][O:1][C:2]4=[O:6])=[N:26][CH:25]=3)=[O:23])[CH2:20][CH2:21]2)=[N:14][CH:15]=1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCOC2=O)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of oxazolidin-2-one (174 mg) in DMF (4 mL) was added sodium hydride (80 mg) at 10° C., and the mixture was stirred for 30 min. Furthermore, [4-(5-bromo-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (590 mg) described in Preparation Example 113 was added, and the mixture was stirred at 80° C. for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 3-{5-[4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}oxazolidin-2-one (423 mg).
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N:24]1([C:23]2[C:6]3[C:5]4[CH:4]=[C:3]([C:1]#[N:2])[N:11]=[CH:10][C:9]=4[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=3[N:20]=[CH:21][CH:22]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CCNCC3)ccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)piperazine-1-carboxylate (440 mg, 0.8 mmol) in methylene chloride (3 mL) was treated with trifluoroacetic acid (0.6 mL, 8.0 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated aqueous sodium carbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-10% methylene chloride in methanol) to afford the title compound as a white foam, which was used in the next step without any further purification (200 mg, 60%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(OCC)C.[Cl:20][C:21](Cl)([Cl:25])[C:22](Cl)=[O:23].C(=O)(O)[O-].[Na+]>C(COC)OC.[Cu].[Zn]>[Cl:20][C:21]1([Cl:25])[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:1][C:22]1=[O:23]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2(Cl)Cl
Reaction time: 5.5 h
Yield: 81.1 %

Procedure:
49.3 g of tert-butyl 4-methylene-1-piperidine carboxylate was added to a mixture of 157.2 g zinc-copper alloy and 500 ml diethyl ether, and 900 ml solution of 181.8 g trichloroacetyl chloride in dimethoxyethane was added dropwise thereinto over 5.5 hours. After stirred for 30 min, the reaction solution was cooled and saturated aqueous sodium bicarbonate was added thereto at 0° C. or less. The mixture was filtered through Celite and evaporated. The resulting residue was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated, and the resulting residue was subjected to silica gel column chromatography to give 62.5 g of tert-butyl 1,1-dichloro-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]2([OH:25])[C:17]3[C:12](=[CH:13][CH:14]=[C:15](C)[CH:16]=3)[N:11]([CH2:19][CH2:20]C(C)C)[C:10]2=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:26]C1C=C2C(=CC=1)N(CC)C(=O)C2=O.CC1C=CC=CN=1>>[Cl:26][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:19][CH3:20])[C:10](=[O:24])[C:9]2([OH:25])[CH2:8][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Solvent: Cc1ccccn1
Product: CCN1C(=O)C(O)(Cc2ccccn2)c2cc(Cl)ccc21

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-chloro-1-ethylindoline-2,3-dione and 2-methylpyridine (purchased from Fisher Scientific). 1H-NMR δ 8.60 (d, 1H), 7.65 (dd, 1H), 7.27 (m, 3H), 7.09 (d, 1H), 6.75 (m, 2H), 3.72 (m, 2H), 3.35 (d, 1H), 3.09 (d, 1H), 1.21 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[NH:28]1[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:28]4[CH2:33][CH2:32][S:31][CH2:30][CH2:29]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCSCC4)c3)nc12
Temperature: 140 °C
Yield: 55.4 %

Procedure:
A stirred suspension of 500 mg (1.11 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide. 1.5 g (11.1 mmol) thiomorpholine and 725 mg (2.23 mmol) cesium carbonate in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 48 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether/ethyl acetate/hexane afforded 290 mg (55%) N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-thiomorpholin-4-yl-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%)): 472 (M+H+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([CH2:22][N:23]([C@@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])[C:24]4=[O:27])=[CH:20][CH:19]=3)=N[CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38](C1C=CC(C(Cl)=O)=CC=1)(C)(C)[CH3:39]>>[C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([CH2:22][N:23]([C@@H:28]([CH:33]([CH3:34])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[C:24]4=[O:27])=[CH:20][CH:19]=3)=[C:38]([CH3:39])[CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3C)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 467 was prepared analogous to the compound of example 403 by reaction of the compound of example 466 with 4-(t-butyl)benzoyl chloride.
Reaction SMILES: [K+].[C:2]1([S:8]([NH-:11])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1>CN1CCCC1=O.[OH-].[Na+]>[CH3:12][NH:13][C:14]1[N:19]=[C:18]([NH:11][S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])[CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: [NH-]S(=O)(=O)c1ccccc1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccccc2)n1
Temperature: 150 °C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
5.38 g (0.0275 mol) of benzenesulfonamide potassium salt and 2.45 g (0.0138 mol) of 2-methylamino-4,6-dichloro-pyrimidine were suspended in 22 ml of 1-methyl-2-pyrrolidone and stirred at 150° C. for 24 hours. The solvent was removed in a high vacuum and the residue was suspended in 250 ml of water. The mixture was extracted three times with 100 ml of ethyl acetate each time and the combined organic phases were washed with 200 ml of saturated NaHCO3. The combined aqueous phases were made acid with 3N HCl and the precipitate which thereby separated was filtered off under suction. It was chromatographed on silica gel with dichloromethane/methanol 99:1→98:2. The yellowish crystals obtained after the chromatography were suspended in 70 ml of 1N NaOH, the suspension was filtered and the clear filtrate was adjusted to pH 3.5 with 1N HCl. The precipitate which thereby separated was isolated and dried. There were obtained 1.9 g (46%) of N-(2-methylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide as colorless crystals; m.p.: 186-187° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]>CN(C)C=O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Clc1ccccc1CBr
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1Cl)P(=O)(OCC)OCC
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a stirred solution of ethyl (diethoxyphosphoryl)acetate (10.0 g, 44.6 mmol) in N,N-dimethylformamide (100 mL) was added 60% sodium hydride in mineral oil (1.96 g, 49.1 mmol) at 0° C. and the mixture was stirred for 1 h at the same temperature. To the mixture was added 1-(bromomethyl)-2-chlorobenzene (6.35 mL, 49.1 mmol) at 0° C. and the resulting mixture was stirred for 18 h at the room temperature. The reaction mixture was quenched by the addition of water, then extracted with diethyl ether (200 mL×2), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (500 g) eluting with hexane/ethyl acetate (1/1) to afford 14.6 g (93%) of the title compound as a colorless oil:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[F:34].[N:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)=[CH:37][CH:36]=1>O1CCOCC1>[F:8][C:7]1[CH:6]=[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:29]([F:31])([F:32])[F:30])[C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[O:10])[CH:4]=[C:3]([F:34])[C:2]=1[NH:1][C:42]([NH:41][C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1)=[O:43]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1c(F)cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1c(F)cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 80 °C
Yield: 21.3 %

Procedure:
(4-Amino-3,5-difluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.342 mmol, 170 mg) and phenyl pyridin-4-ylcarbamate (0.513 mmol, 110 mg) were combined in dioxane (2 mL) and heated to 80° C. overnight in a reactivial. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (dichloromethane—4% methanol/dichloromethane) to afford title compound (45 mg). MS (ESI) m/z 618.3 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5](/[CH:6]=[N:7]/[S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Br.CCOC(C)=O.CCCCCCC>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C@@H:6]([NH:7][S@@:8]([C:10]([CH3:12])([CH3:13])[CH3:11])=[O:9])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cc1F
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.73 g, 25.2 mmol) in CH2Cl2 (252 mL), cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33.7 mL, 101 mmol) in Et2O. Reaction mixture allowed to stir for 30 min at 0° C., then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (4.93 g, 15.3 mmol, 60% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCL3) δ 1.20 (s, 9H) 1.56 (d, J=6.70 Hz, 3H) 3.34 (br. s., 1H) 4.77-4.87 (m, 1H) 7.19-7.31 (m, 3H). LCMS m/z 324.0 (M+H)+, Rt 0.90 min.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Br:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>CCCCC.O1CCCC1>[Br:29][CH2:30][CH2:31][CH2:32][C:33]([O:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:34]
Reactant: O=C(Cl)CCCBr
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)CCCBr)c1coc([Si](C)(C)C)c1
Reaction time: 0.33 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.25 ml, 0.43 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (120.4 mg, 0.36 mmol) in tetrahydrofuran (6 ml) at 0° under argon. After 20 minutes, a solution of 4-bromobutyryl chloride (66 mg, 0.43 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued at room temperature for 16 hours and the mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 500μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a yellow oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18]N1CCNCC1.C(N(C(C)C)CC)(C)C>CC(O)CC>[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Fc1cccc(CN2CCNCC2)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(N2CCN(Cc3cccc(F)c3)CC2)nc[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A mixture of 6-chloro-3H-pyrimidin-4-one (Intermediate 4; 100 mg, 0.77 mmol), 1-(3-fluorobenz-yl)piperazine (Aldrich; 194 mg, 1.0 mmol), and diisopropylethylamine (200 μL, 1.1 mmol) in 2-butanol (5 mL) was heated in a sealed scintillation vial on a hot plate at about 80° C. for 8 hours and then allowed to cool and stand at room temperature overnight. The mixture was filtered. The solid was washed with 2-butanol and air-dried to give 6-[4-(3-fluoro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one (145 mg, 65%), as a white solid, mp 273-275° C. (dec.). 1H NMR (d6-DMSO) δ 2.36-2.39 (m, 4H), 3.44-3.47 (m, 4H), 5.23 (s, 1H), 7.04-7.16 (m, 3H), 7.32-7.40 (m, 1H), 7.86 (s, 1H), 11.60 (s, 1H). LRMS ES+M+H 289. HRMS Calcd. for C15H18FN4O (M+H), 289.1459. Found, 289.1459.
Reaction SMILES: C([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C([O-])(O)=O.[Na+].C1C(=O)N([O:30][C:31]([O:33][CH2:34][CH:35]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]3[C:36]2=[CH:37][CH:38]=[CH:39][CH:40]=3)=O)C(=O)C1.Cl>O1CCOCC1.O>[CH:46]1[C:47]2[CH:35]([CH2:34][O:33][C:31]([NH:8][C@H:7]([C:6]([OH:5])=[O:17])[CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[O:30])[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]=2[CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.2 %

Procedure:
To a stirring suspension of L-tyrosine O-t-butyl ester (1.00 g, 4.21 mmol) and NaHCO3 (354 mg, 4.21 mmol) in 1,4-dioxane/water (1:1, 20 mL) was added 9-fluorenylmethyl-N-succinimidyl carbonate (1.42 g, 4.21 mmol) and the resulting mixture was stirred for 18 hr at room temperature. The solvent was reduced to 10 mL followed by the addition of 50 mL of cold 1N HCl. The product was extracted with ethyl acetate (3×). The organic extracts were washed with H2O and saturated aqueous NaCl then dried over Na2SO4. The solution was then concentrated after filtration to give the colourless solid 83 (1.94 g, 100%) which was used without purification: 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.97-3.06 (m, 2H), 4.21 (bt, J=7.1, 1H), 4.33 (dd, J=7.1, 10.5, 1H), 4.41-4.53 (m, 2H), 5.01 (bs, 1H), 5.30, (d, J=8.2, 1H), 6.73 (d, J=8.5, 2H), 7.00 (d, J=8.5, 2H), 7.31 (t, J=7.5, 2H), 7.40 (t, J=7.5, 2H), 7.57 (dd, J=3.3, 7.3, 2H), 7.76 (d, J=7.5, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=1[F:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(F)cccc1F)C(=O)OC
Reactant: N#CCCN(c1ccc(I)cc1)c1ncccn1
Product: COC(=O)C(C/C=C/c1ccc(N(CCC#N)c2ncccn2)cc1)NC(=O)c1c(F)cccc1F
Yield: 58 %

Procedure:
In the same manner as in Example 1, 2-(2,6-difluorobenzamido)pent-4-enoic acid methyl ester (17 mg) was reacted with 3-(N-(4-iodophenyl)-N-(pyrimidin-2-yl)amino)propanenitrile (24 mg) to obtain ((E)-5-[4-((2-cyano-ethyl)-pyrimidin-2-yl-amino)-phenyl]-2-(2,6-difluorobenzamido)-pent-4-enoic acid methyl ester (18 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.