Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C[Mg]Br.[C:12]1(C)C=CC=CC=1.C1COCC1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1>[CH3:12][CH:7]1[CH2:8][C:3](=[O:2])[CH:4]=[CH:5][N:6]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccncc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1CC(=O)C=CN1C(=O)OCc1ccccc1
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
4-methoxypyridine (796 g, 7.29 mole) was stirred in 8 L of anhydrous THF in a 20 L reactor. The reactor was cooled to −30° C., then methylmagnesium bromide (5.1 L, 7.29 mole) was added as a 1.4M solution in 3:1 toluene/THF was added via cannula one 800 mL bottle at a time with 800 mls added over a 5 min time period. After the addition was complete and the reaction temperature was −30° C., benzyl chloroformate (1244 g, 7.29 mole) was added dropwise over a 60 min period via addition funnel. The warmest temperature reached was 16° C. After addition was complete the reaction was warmed to 25° C. and stirred for 1.5 hrs. The reaction was cooled to 0° C. and quenched with 4.0 L of 2 N HCl. 4 L of MTBE and brine was added and the layers separated. The temperature was now 25° C. The aqueous phase was extracted with 2×2 L of MTBE. The combined organics were washed with brine and dried over Na2SO4, filtered and concentrated to give the crude oil. Chromatography using a Varian Metaflash 150 long (15 cm×60 cm long 5 kilo silica) and eluting with 10-35% EtOAc/Heptanes gave the product as an oil.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20].[OH-].[Na+]>CN(C)C=O.O>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:20]/[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)=[O:21])=[CH:8][C:7]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCCC2)c(-c2cccs2)c1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccc(N3CCCC3)c(-c3cccs3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
4-Pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehyde (400 mg, 1.55 mmol) from Ex-20B and 4-acetylbenzoic acid (255 mg, 1.55 mmol) were dissolved in dimethylformamide (30 mL). Sodium hydroxide solution (5 N, 1.25 mL) was added in one portion, and the mixture was stirred at room temperature overnight. The reaction was diluted with water (100 mL) and washed with ethyl acetate (100 mL). The aqueous phase was acidified with conc. HCl and extracted with ethyl acetate (2×100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Silica gel chromatography (100% ethyl acetate) followed by recrystallization from ethanol provided 80 mg (13%) of the title compound as a solid, m.p. 212–214° C. with decomposition. 1H-NMR (300 MHz, CDCl3) δ 8.21 (d, 2H, J=8.4 Hz), 7.06 (d, 2H, J=8.4 Hz), 7.80 (d, 1H, J=15.3 Hz), 7.58 (d, 1H, J=1.9 Hz), 7.52 (dd, 1H, J=8.5 and 1.9 Hz), 7.33 (m, 1H), 7.32 (d, 1H, 15.3 Hz), 7.01–7.06 (m, 2H), 6.82 (d, 1H, 7.9 Hz), 3.12 (m, 4H), 1.84 (m, 4H). MS m/z=403 ([M]+, 100%). HRMS (EI) Calcd. for C24H21NO3S: 403.1242. Found: 403.1251.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[N:13][NH:14][C:3]=12.[CH2:15]([CH2:17][NH2:18])[OH:16]>C1(C)C(C)=CC=CC=1>[OH:16][CH2:15][CH2:17][NH:18][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[N:13][NH:14][C:3]=12
Reactant: Clc1c2c(nc3cn[nH]c13)CCCC2
Reactant: NCCO
Solvent: Cc1ccccc1C
Product: OCCNc1c2c(nc3cn[nH]c13)CCCC2
Yield: 19.7 %

Procedure:
9-Chloro-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-b]quinoline (2.45 g, 0.012 mole) and ethanolamine (2.2 ml, 0.036 mole) were heated under reflux in dry xylene (25 ml) for 24 hours. The solvent was evaporated off and the residue dissolved in water/methanol. The pH of the solution was adjusted to 9 by the addition of 10% sodium carbonate solution. The precipitate which formed was filtered off, washed with water, dried and recrystallised from ethyl acetate to give the title compound as a beige solid (0.55 g, 20%), m.p. 205°-210° C. Found: C, 62.05; H, 6.95; N, 24.00% C12H16N4O requires C, 62.05; H, 6.95; N, 24.10%
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11](Cl)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([NH:28][CH:25]3[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1cccc2nc(Cl)oc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)oc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
To a solution of 2-chloro-benzooxazole-7-carboxylic acid methyl ester (1.50 g, 7.08 mmol, 1.0 equiv; example 252/step 3) in acetonitrile (23 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.42 g, 7.08 mmol, 1.0 equiv) and triethylamine (0.79 g, 7.79 mmol, 1.1 equiv). After stirring for 48 h at rt, the reaction mixture was poured on ice, the solution extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with water (2×100 mL) and a conc. solution of sodium chloride (100 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with hexane/ethyl acetate (1:1) providing 2.27 g (85%) of the title compound. MS (ISP): 376.4 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([C@@H:20]3[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:16]=2)=[CH:11][CH:10]=1.[F:33][C:34]([F:47])([F:46])[O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([S:42]([C:39]4[CH:38]=[CH:37][C:36]([O:35][C:34]([F:33])([F:46])[F:47])=[CH:41][CH:40]=4)(=[O:44])=[O:43])[CH2:22][CH:21]3[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccc([C@@H]2CNCC[C@H]2c2cc(-c3ccc(Cl)cc3)[nH]n2)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(c2cc(-c3ccc(Cl)cc3)[nH]n2)C(c2ccc(F)cc2)C1
Temperature: 60 °C

Procedure:
The product from Example 8 (23 mg, 0.049 mmol) in pyridine (1.0 ml) was treated with 4-trifluoromethoxybenzenesulfonyl chloride (63.8 mg, 0.245 mmol). The reaction mixture was heated to 60° C. for 12 h. The mixture was then concentrated and purified by RP-HPLC(C18, acetonitrile, water, 0.05% TFA) to afford the title compound. HPLC/MS: 580.0, 582.1; Rt=2.33 min (LC-4 HPLC conditions).
Reaction SMILES: C(O)(C)C.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15]Br)([O-:7])=[O:6].[CH3:17][N:18]1[C:23]([NH:24][CH2:25][CH2:26]CNC2C=CC([N+]([O-])=O)=CC=2)=[CH:22][C:21](=[O:38])[N:20]([CH3:39])[C:19]1=[O:40].[CH2:41]([N:43](CC)CC)[CH3:42]>>[CH3:17][N:18]1[C:23]([N:24]2[CH2:25][CH2:26][N:43]([CH2:15][CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N+:5]([O-:7])=[O:6])[CH2:41][CH2:42]2)=[CH:22][C:21](=[O:38])[N:20]([CH3:39])[C:19]1=[O:40]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Reactant: Cn1c(NCCCNc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Reactant: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1c(N2CCN(CCc3ccccc3[N+](=O)[O-])CC2)cc(=O)n(C)c1=O

Procedure:
To 15 ml of isopropanol were added 3.0 g of the above prepared compound 11, 3.2 g of 1,3-dimethyl-6-(piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (compound 2) and 4.2 ml of triethylamine, and the resulting mixture was then treated by the same procedure as in Example 2 in order to obtain 2.2 g of 1,3-dimethyl-6-{4-[2-(2-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([Cl:12])[CH:3]=1.[CH2:13](OC(OCC)OCC)C>>[Cl:11][C:6]1[C:7]2[C:8](=[O:9])[NH:10][CH:13]=[N:1][C:2]=2[CH:3]=[C:4]([Cl:12])[N:5]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1c(N)cc(Cl)nc1Cl
Product: O=c1[nH]cnc2cc(Cl)nc(Cl)c12

Procedure:
In scheme (VII), the tert-butyl 4-(tert-butoxycarbonylamino)-2,6-dichloronicotinate (3) the Boc groups are removed by treatment with trifluoracetic acid (TFA) in dichloromethane (DCM) at room temperature (60° C.) for 3 hours thereby forming the carboxylic acid, 4-amino-2,6-dichloronicotinic acid (7). Subsequent treatment with thionyl chloride under reflux conditions for 50 minutes gives the acid chloride, 4-amino-2,6-dichloronicotinoyl chloride (8). Treatment with of the acid chloride (8) with ammonia gives the amide, 4-amino-2,6-dichloronicotinamide (9). Heating the amide (9) with triethylorthoformate for 6 hours gives 5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (10), which is then used to obtain various compounds of Formula (I) as illustrated in scheme (VII).
Reaction SMILES: Br/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH:2]1[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)/C=C(/C)Br
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In toluene (250 ml), N,N′-dibenzylethylenediamine (12 ml) and triethylamine (12 ml) were dissolved, followed by the dropwise addition of methyl 3-bromocrotonate (7.0 ml) under ice cooling. The resulting mixture was stirred at room temperature for 24 hours. After the addition of triethylamine (2.0 ml), the resulting mixture was stirred at room temperature for 71 hours. The insoluble matter was filtered off and the filtrate was distilled under reduced pressure. The residue was added with 10% hydrochloric acid (300 ml) and crystals so precipitated were removed by filtration. Ethyl acetate was added to the filtrate. Potassium carbonate was added to the water layer so separated to make it alkaline. Ethyl acetate was added to the resulting mixture. The organic layer so separated was washed with saturated saline and dried over anhydrous potassium carbonate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby the title compound (1.07 g, 62%) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[OH:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[OH:19]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccccc1O
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1ccccc1O)C(=O)N2
Yield: 62 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and 2-hydroxy benzaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: [CH2:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[N+:29]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36])([O-:31])=[O:30].O>C(Cl)Cl>[CH2:12]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:35]([C:34]1[CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:40]=[CH:39][CH:38]=1)=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCNCCCCCCCCCC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCN(CCCCCCCCCC)C(=O)c1cccc([N+](=O)[O-])c1
Yield: 83.2 %

Procedure:
To an ice bath cooled solution of 0.80 g (2.69 mmol) of di-decylamine and 0.75 mL (5.4 mmol) of triethylamine in 10 mL of anhydrous methylene chloride was added dropwise a solution of 0.50 g (2.69 mmol) of 3-nitrobenzoyl chloride in 5 mL of methylene chloride with stirring. The mixture was stirred at room temperature for 4 hours. Water was added, the organic layer was separated and dried. The solvent was removed at reduced pressure and the residual oil was purified by chromatography on 30 g of silica gel using 12.5% ethyl acetate-hexane to give 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene as an oil. The nmr and mass spectra were consistent with the structure. A mixture of 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene and 0.2 g of 10% palladium on carbon in 20 mL of ethyl acetate and 20 mL of THF was stirred under a hydrogen atmosphere at room temperature for 2 hours when hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated to give 1.0 g of 3-(di-decylaminocarbonyl)benzenamine as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].[C:24]1([S:30]([CH2:33][CH2:34][NH:35][CH:36]([CH3:38])[CH3:37])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43]>O1CCCC1.CO>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43].[CH3:37][CH:36]([N:35]([CH2:34][CH2:33][S:30]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:31])=[O:32])[C:12]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1)=[O:13])[CH3:38]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)NCCS(=O)(=O)c1ccccc1
Reactant: CN1CCN(CCCN)CC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(CCS(=O)(=O)c1ccccc1)C(=O)NCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 6.00 g (0.035 mole) of 1-(3-aminopropyl)-4-methylpiperazine and 6.97 g (0.043 mole) of 1,1'-carbonyldiimidazole in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 8.17 g (0.036 mole) of N-(2-phenylsulfonylethyl)-2-propanamine in 100 ml of tetrahydrofuran was added, and the mixture was refluxed for 16 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. The solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. The oil was dissolved in methanol; a solution of two equivalents of maleic acid in methanol was added, and a white solid precipitated. This was collected to give 15.48 g (68.8%) of white crystalline solid; m.p. 162°-163° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][C:15]#[CH:16]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:12][N:13]([CH3:17])[CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)CC#Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a stirred solution of 4-bromo-2-nitro-phenylamine (1.08 g, 5 mmol) and dimethyl-prop-2-ynyl-amine (1.0 g, 12 mmol) in TEA (20 mL) was added Pd(PPh3)2Cl2 (0.7 g, 1 mmol) and CuI (360 g, 2 mmol). The solution was stirred at 60° C. under nitrogen for 3 hours. The solution was evaporated with silica gel and purified by flash chromatography on silica to give the title compound (1.1 g, 70% purity). The title compound was taken directly to the next step without further purification. MS (ESI) 221 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1/[CH:10]=[CH:11]/[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.C(OCC)(=O)C>[Br:20][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1/[CH:10]=[CH:11]/[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(CBr)c1
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
To a solution of 2.32 g of tert-butyl (2E)-3-[2-(hydroxymethyl)-4-methylphenyl]acrylate in 46 ml of THF were added 4.64 g of carbon tetrabromide and 3.67 g of triphenylphosphine under ice-cooling, followed by stirring at the same temperature for 2.5 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.73 g of tert-butyl (2E)-3-[2-(bromomethyl)-4-methylphenyl]acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11]C=C)[N:6]1[C:14](=[O:27])[CH:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:17]=[CH2:18])=[O:4].CS(C)=O>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:1][O:2][C:3]([C@H:5]1[N:6]2[C:14](=[O:27])[C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH:17]=[CH:18][CH2:11][C@H:7]2[CH2:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)N1C(CC=C)CCCC1C(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC[C@@H]2CC=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Reaction time: 24 h

Procedure:
6-Allyl-1-(2-tert-butoxycarbonylamino-pent-4-enoyl)-piperidine-2-carboxylic acid methyl ester, 40, (1.0 g, 2.6 mmol) is dissolved in dichloromethane (100 mL). Grubbs catalyst (0.5 g, 0.61 mmol) is added and the mixture is heated at reflux for 24 hours. The reaction is cooled and dimethylsulfoxide (2 mL) is added. After 24 hours, the solution is concentrated to a oil, which is purified over silica (ethyl acetate/hexanes) to afford 680 mg of the desired product. 1H NMR (CDCl3) δ 6.02 (d, J=6.6 Hz,1H), 5.61 (m, 1H), 5.21 (m, 1H), 4.93 (ddd, J=6.6, 6.2, 6.2 Hz, 1H), 4.54 (m, 1H), 3.71 (s, 3H), 2.95 (ddd, J=16.2, 5.9, 5.9 Hz, 1H), 2.63 (ddd, J=17.6, 12.0, 5.5 Hz,1H), 2.42 (ddd, J=16.2, 5.8, 5.1 Hz, 1H), 2.34–2.16 (m, 2H), 1.90–1.58 (m, 5H), 1.48 (s, 9H); 13C NMR δ 173.0, 172.5, 155.6, 129.2, 125.0, 79.9, 52.4, 52.0, 51.2, 50.8, 36.6, 34.5, 30.1, 28.8(3C), 26.4, 16.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27]([O:30][CH2:31][CH3:32])(=[O:29])[CH3:28].CCCCCC>O1CCCC1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]([C:8]#[N:9])([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:28][C:27]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: CCOC(C)=O
Reactant: N#CCc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccnc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Combine 3-pyridineacetonitrile (25 g, 212 mmol) and tetrahydrofuran (200 mL). Cool to about −70° C . using a dry-ice/acetone bath. Add dropwise, a solution of sodium bis(trimethylsilyl)amide (435 mL, 1 M in tetrahydrofuran, 435 mmol) while maintaining the reaction temperature below about −68° C. When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−5° C.) solution of ethyl bromoacetate (84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that the temperature of the reaction mixture does not rise above about 15° C. Allow to stir at ambient temperature. After 18 hours, quench with saturated aqueous solution of ammonium chloride and evaporate in vacuo to remove most of the tetrahydrofuran. Extract the evaporated reaction mixture twice with diethyl ether. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([S:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]([Cl:21])=[CH:11][C:10]=1[Cl:22].[S-:23][C:24]#[N:25].[K+].CCCCCC.C(OCC)(=O)C>C(O)C>[S:23]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([S:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]([Cl:21])=[CH:11][C:10]=1[Cl:22])[C:24]#[N:25]
Reactant: N#C[S-]
Reactant: FC(F)(F)CSc1cc(OCCCCCCBr)c(Cl)cc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: N#CSCCCCCCOc1cc(SCC(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 72.5 %

Procedure:
In 30 ml of ethanol were added 1.51 g (3.43 mmol) of 6-bromohexyl-[2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenyl]ether and 1.67 g (17.2 mmol) of potassium thiocyanate. The mixture was refluxed for 3 hours under heating. The mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. Then extraction was conducted by adding ethyl acetate and water. The organic phase obtained was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 1.04 g (yield: 73%) of an intended product.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:43][O:42][C:40]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)=[O:41]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)CC1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.07 g, 0.151 mmol) was suspended in DCM (1.5 mL) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) was added. Methyl chloroformate (0.018 mL, 0.227 mmol) was added and the resulting solution stirred at RT. After 4 hours the solvent was evaporated. The remaining oil was purified by SiO2 chromatography (11 g SiO2, DCM/MeOH 0-4% MeOH). Obtained 0.052 g of 4-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-ureido}-piperidine-1-carboxylic acid methyl ester as light brown foam (76% yield).