Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(CCC1C=CC(F)=CC=1)=[N+]=[N-].[N:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[N+:14]=[N-:15].[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([C:42]#[CH:43])=[N:39][C:38]=1[CH3:44])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([C:42]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH:43]=2)=[N:39][C:38]=1[CH3:44])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [N-]=[N+]=NCc1ccc(C(F)(F)F)cc1
Reactant: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Agent: [N-]=[N+]=NCCc1ccc(F)cc1
Product: Cc1nc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 81 %

Procedure:
Following the procedure as described in Example 1, making variations as necessary to replace 1-(2-azidoethyl)-4-fluorobenzene with 1-(azidomethyl)-4-(trifluoromethyl)benzene to react with N-benzyl-2-ethynyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 81% yield: mp 131-132° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.65-7.53 (m, 2H), 7.45-7.34 (m, 2H), 7.28-7.19 (m, 5H), 6.60 (t, J=5.6 Hz, 1H), 5.57 (s, 2H), 4.54 (d, J=5.6 Hz, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 157.6, 155.5, 143.1, 137.9, 137.8, 131.3, 128.8, 128.6, 127.8, 127.6, 126.5, 125.2, 123.7, 121.7, 53.8, 44.1, 17.2; MS (ES+) m/z 458.3 (M+1).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=1[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:2][CH2:20][C:17]1[CH:16]=[C:15]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]([C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[F:5])=[N:19][CH:18]=1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2CC(C)(C)C)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ncc(CBr)cc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, phosphorus tribromide (37 μL) was added to DMF (1.0 mL) at 0° C. and the mixture was stirred at 0° C. for 5 min. To the obtained white suspension was added (6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)methanol (100 mg), and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (88 mg) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[NH:6][C:7]=1[CH3:8].C[O-].[Na+].[C:22](OC)(=[O:25])[C:23]#[CH:24]>>[CH3:8][C:7]1[NH:6][C:5]2[N:4]([C:3]=1[CH3:2])[C:22](=[O:25])[CH:23]=[CH:24][C:9]=2[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1
Reactant: Cc1cccc(C(=O)Cc2nc(C)c(C)[nH]2)c1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(C(=O)c2ccc(=O)n3c(C)c(C)[nH]c23)c1

Procedure:
The compound is prepared as described in example 25 with 300 mg (1.13 mmol) of 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(3-methylphenyl)ethanone hydrochloride (example XXII), 65 mg (1.20 mmol) of sodium methylate and 95.3 mg (1.13 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:15]2)=[CH:30][CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Yield: 81.5 %

Procedure:
A mixture of ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (1.79 g), potassium hydroxide (0.75 g) and ethanol (30 ml) was refluxed for 5 hours. After removal of the solvent under reduced pressure, water was added to the reaction mixture, then the mixture was acidified with 1N hydrochloric acid. The crystals obtained were collected by filtration to yield 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-carboxylic acid (1.36 g, yield: 82%). This was recrystallized from acetone-hexane. Melting point: 152–153° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25](O)=O)=[CH:18][CH:17]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:25]([CH2:24][CH2:23][CH2:22][C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NNC(=O)c1ccc2occc2c1
Reactant: COc1ccc(CCCC(=O)O)cc1
Product: COc1ccc(CCCc2nnc(-c3ccc4occc4c3)o2)cc1
Yield: 15 %

Procedure:
In the same manner as in Example 14 and using 1-benzofuran-5-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 4-(4-methoxyphenyl)butyric acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 15%) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4](=[O:13])[C:5]2[N:6]=[CH:7][N:8]([CH2:11]C)[C:9]=2[N:10]=1.[F:21][C:22]1[CH:23]=[C:24]([OH:30])[CH:25]=[C:26]([F:29])[C:27]=1[F:28]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:3]2[C:4](=[O:13])[C:5]3[N:6]=[CH:7][N:8]([CH3:11])[C:9]=3[N:10]=[C:2]2[O:30][C:24]2[CH:23]=[C:22]([F:21])[C:27]([F:28])=[C:26]([F:29])[CH:25]=2)=[CH:15][CH:16]=1
Reactant: CCn1cnc2c(=O)n(-c3ccc(F)cc3)c(Cl)nc21
Reactant: Oc1cc(F)c(F)c(F)c1
Product: Cn1cnc2c(=O)n(-c3ccc(F)cc3)c(Oc3cc(F)c(F)c(F)c3)nc21
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-1-(4-fluorophenyl)-9-ethyl-1,9-dihydro-6H-purin-6-one (55.6 mg, 0.20 mmol) and 3,4,5-trifluorophenol (0.40 mmol) is heated to 140° C. for 36 h. After cooling to RT, the crude mixture is purified by preparative HPLC to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.98 (1H, s), 7.55 (2H, m), 7.45 (2H, m), 7.34 (2H, m), 3.53 (3H, S). m/z=391.05 (M+1); RT=0.78 min.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.2 %

Procedure:
Sodium hydride dispersion, 50% by weight (3.05 grams, 63.47 mmol) is placed into a 125 ml round bottom equipped with a stir bar and condenser under nitrogen and is charged with 32 ml of dimethylformamide. 3-Fluorophenol (3.56 grams, 31.73 mmol) is added portionwise over five minutes. During this addition, an exotherm and vigorous gas evolution is observed. The reaction is allowed to stir for five minutes. 2-Chloronicotinic acid (5.00 grams, 31.73 mmol) is added portionwise over five minutes. Gas evolution is observed. When it subsides, the reaction is heated to reflux for 2 hours. The reaction is cooled to room temperature and 300 ml of water is added. The aqueous layer is extracted with diethyl ether (2×200 ml). The aqueous layer is then pH adjusted to acidic with glacial acetic acid and extracted with ethyl acetate (3×150 ml). The organics are combined and washed with water (2×150 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a yellow oil. The oil is purified by trituration with diethyl ether/hexanes (3/1) to yield 1.42 grams (19.2%) of product as a yellow crystalline solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:6].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O>CN(C=O)C>[C:33]([C:30]1([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][N:7]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:5](=[O:6])[C:4]([F:20])([F:21])[F:3])=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)#[N:34]
Reactant: N#CC1(c2ccc(CBr)cc2)CC1
Reactant: O=C(NCCc1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccc(CN(CCc3cccc(C(F)(F)F)c3)C(=O)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
20 mg (0.51 mmol) of a sodium hydride suspension in mineral oil (60%) were suspended in 4.2 ml DMF. At 0° C. 134 mg (0.42 mmol) of 2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide dissolved in 1 ml DMF were added dropwise and the reaction mixture was stirred for 30 min at 0° C. Then 100 mg (0.42 mmol) of 1-(4-bromomethyl-phenyl)-cyclopropanecarbonitrile dissolved in 1 ml DMF were added and the reaction mixture was stirred at 0° C. for 3 h. Water was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel; heptane/diethyl ether=1:1) to yield 135 mg (72%) of N-[4-(1-cyano-cyclopropyl)-benzyl]-2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide as a yellow viscous oil. MS (ISP) 458.4 (M+NH4)+. MS (ISP). 499.1 (M+OAc)−.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CC(C)=O>[C:18]([O:21][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
A mixture of 4-chloromethyl-2,6-di-t-butylphenol (2.55 g) and potassium acetate (0.98 g) in acetone (30 mL) was stirred at 20° C. for 24 hours. After evaporation of the solvent the residue was partioned between water and n-hexane. The hexane extract was concentrated and the residue slurried in n-hexane (6 mL) at about 0° C. The crystals were collected via filtration and dried to give 1.54 g, 45% yield, of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[S:12])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Br[CH:44]([CH3:49])[C:45](OC)=[O:46]>CCO.C(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[C:45](=[O:46])[CH:44]([CH3:49])[S:12]/[C:11]/2=[N:13]/[N:14]=[CH:15]\[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:31][CH:32]=4)[N:23]=3)=[CH:20][CH:21]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C(C)Br
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(/C=N/NC(=S)Nc4ccccc4C4CC4)cc3)n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC1S/C(=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)N(c2ccccc2C2CC2)C1=O
Temperature: 60 °C
Yield: 29.3 %

Procedure:
To (E)-N-(2-cyclopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (100 mg, 0.191 mmol) and sodium acetate (63.0 mg, 0.765 mmol) in EtOH (4 mL) was added methyl 2-bromopropanoate (0.026 mL, 0.230 mmol). The reaction was heated to 60° C. overnight. The reaction was then heated to 85° C. for 72 hours. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided the title compound as a white solid (32.5 mg, 0.056 mmol, 30%): mp 112-115° C.; 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=8.3 Hz, 2H), 7.87-7.75 (m, 4H), 7.43-7.32 (m, 4H), 7.26-7.24 (m, 2H), 4.23 (q, J=7.3 Hz, 1H), 1.85-1.78 (m, 4H), 0.90-0.78 (m, 2H), 0.78-0.69 (m, 1H), 0.65-0.55 (m, 1H); ESIMS m/z 578 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[N+:11]([CH3:14])([O-:13])=[O:12].C(NCC)C>C1COCC1>[OH:7][CH:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2])[CH2:14][N+:11]([O-:13])=[O:12]
Reactant: N#Cc1cccc(C=O)c1
Reactant: C[N+](=O)[O-]
Solvent: CCNCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)C[N+](=O)[O-])c1

Procedure:
3-Cyanobenzaldehyde (3.0 g, 22.9 mmol), nitromethane (4.2 g, 68.7 mmol) and diethylamine (167 mg, 2.29 mmol) were stirred for 48 h in THF at 55° C. in the presence of 4 Å molecular sieves. The resulting reaction mixture was filtered through celite and the resulting solution was concentrated in vacuo, then partitioned between EtOAc (20 mL) and H2O (100 mL). The EtOAc layer was washed with H2O (2×75 mL) and brine (1×50 mL), then dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was filtered through silica gel, eluting with hexanes:EtOAc (2:1) to obtain 3-(1-hydroxy-2-nitroethyl)benzonitrile as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:18])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CN1c2ccccc2NC(=S)c2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one and 0.5 g. of phosphorus pentasulfide in 5 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The reaction mixture is concentrated to dryness and the residue is stirred with 10 ml. of 1N sodium carbonate solution for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol to give gold crystals, m.p. 203°-204°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[Cl:17].[H-].[Na+].CS(C)=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[C:11]([Cl:17])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Yield: 55.6 %

Procedure:
The publicly known compound 2-amino-4-chloropyridine (5.0 g), 4-amino-3-chlorophenol (11 g), sodium hydride (60% in oil) (3.1 g) and dimethylsulfoxide (80 ml) were stirred at 160° C. for 9.5 hours. Water was added, extraction was performed with ethyl acetate, and the extract solution was washed 5 times with water. The extract solution was then passed through a glass filter coated with silica gel. The silica gel was washed with ethyl acetate, the ethyl acetate layers were combined, and the solvent was distilled off under reduced pressure to obtain 5.1 g of a dark violet solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([O:32][CH2:33][CH3:34])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH2:16][N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.[Mg].N>CO.BrCCBr>[CH3:1][O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([CH2:16][N:17]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15]2)=[CH:11][CH:12]=1
Reactant: CCCCCCCN(CC1(c2ccc(C=C(OCC)C(=O)OCC)cc2)CC1)C(=O)OC(C)(C)C
Agent: N
Agent: [Mg]
Solvent: BrCCBr
Solvent: CO
Product: CCCCCCCN(CC1(c2ccc(CC(OCC)C(=O)OC)cc2)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 3-(4-{1-[(tert-butoxycarbonyl-heptyl-amino)-methyl]-cyclopropyl}-phenyl)-2-ethoxy-acrylic acid ethyl ester (680 mg, 1.40 mmol) in anhydrous methanol (20 mL) in a flame dried round bottom flask under an nitrogen atmosphere was added magnesium turnings (53.50 mmol, 85 mg). After 30 min, 1,2-dibromoethane (1 drop) was added directly to the magnesium turnings via pipette, initiating H2 gas evolution from the magnesium. At this time a dry stir bar was added and the mixture was stirred at room temperature until all of the magnesium solid had dissolved. Two additional portions of magnesium (80 mg) were added and allowed to dissolve (16 h). The mixture was poured over 25 mL of ice cooled 2NHCl. The acidic mixture was brought to pH 8.5 by the addition of concentrated aqueous ammonia, then was extracted with diethyl ether (3×). The organic layers were combined, washed with saturated NaCl (3×), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-(4-{1-[(tert-butoxycarbonyl-heptyl-amino)-methyl]-cyclopropyl}-phenyl)-2-ethoxy-propionic acid methyl ester as a clear oil (580 mg, 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[CH2:11][CH2:10]2)[N:5]=[C:4]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C>[Cl:22][C:18]1[C:17]([F:23])=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[CH:3]=[C:4]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[N:5]=2)[CH2:10][CH2:11]1)=[O:24]
Reactant: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(Br)cc(Nc3nccs3)n2)CC1
Reactant: O=C1CCCN1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(N3CCCC3=O)cc(Nc3nccs3)n2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 25.5 mg of 4-bromo-6-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-N-thiazol-2-ylpyridin-2-amine obtained in Example 81 in 1 mL of 1,4-dioxane was added 0.011 mL of pyrrolidin-2-one, 32 mg of potassium phosphate, 8.7 mg of 9,9-dimethyl4,5-bis(diphenylphosphino)xanthene and 7.8 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, successively. The reaction solution was stirred at 100° C. for 3 hours. The reaction solution was cooled, diluted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the resulting residue was purified by a reversed phase medium pressure liquid chromatography [ODS-AS-360-CC (manufactured by YMC company), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The obtained fraction was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo to give the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[CH:3][CH:2]=1.[CH:15]([Si:18]([C:25]#[CH:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C(N(CC)CC)C>[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:4]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:26]#[C:25][Si:18]([CH:15]([CH3:17])[CH3:16])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:9]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1cccc(Nc2ccccc2)c1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1cccc(Nc2ccccc2)c1)(C(C)C)C(C)C
Yield: 78 %

Procedure:
Into two Biotage microwave process vials (0.5-2.0 ml) were divided 3-Bromodiphenylamine (636 mg, 2.56 mmol), triisopropylsilylacetylene (0.46 g, 2.56 mmol), copper iodide (20 mg, 0.356 mmol), tetrakis(triphenylphosphine)palladium (60 mg, 0.176 mmol) and triethylamine (3.40 g, 3.36 mmol). The vials were quickly agitated then irradiated in a Biotage Initiator™ microwave instrument for 30 minutes at 80° C. The microwave reactions were recombined and purified by column chromatography (5% EtOAc/hexanes) to afford an oil 698 mg (78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 21H) 6.82-6.86 (m, 2H) 7.00-7.12 (m, 4H) 7.15-7.28 (m, 3H) 8.23 (s, 1H); MS (ES) m/z 350.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH3:21][C:22](=O)[CH2:23][CH3:24].C(O)(=O)C>CO>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH:22]([CH3:21])[CH2:23][CH3:24])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CCC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Solvent: CC(=O)O
Solvent: CO
Product: CCC(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the general procedure of PREPARATION 3 and making non-critical variations but starting with 1-[1,1-dimethylethoxycarbonyl]-4-[(3-amino)-2-pyridinyl)piperazine (International Publication No. WO 88/08424, 1.0 g), 2-butanone (0.27 g) sodium cyanoborohydride (0.23 g), acetic acid (5.1 ml) and methanol, the title compound is obtained, NMR (300 MHz, CDCl3) 7.68, 6.94, 6.86, 4.18, 3.56, 3.33, 3.05, 1.53, 1.47, 1.18 and 0.96 δ.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)C.[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1
Reactant: CCC1(C(=O)[O-])CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A THF (5 mL) solution of 1-tert-butyl 3-ethylpiperidine-1,3-dicarboxylate (1 g, 3.89 mmol) was added dropwise to a THF (15 mL) solution of lithium diisopropylamide (5.83 mmol) in a nitrogen atmosphere at −78 degrees over 5 minutes. The mixture was raised to room temperature, and stirred for 50 minutes. The temperature of the reaction mixture was lowered to −78 degrees again, and methyl iodide (1.21 mL, 19.43 mmol) was added dropwise at −78 degrees over 5 minutes. The reaction mixture was then raised to room temperature, and stirred for 5 hours. After being added to a saturated ammonium chloride aqueous solution, the reaction mixture was stirred for a while, and extracted with diethyl ether. The organic layer was collected, washed once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (698 mg, 66%).