Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:23][N:24]([CH3:32])[CH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>C1COCC1>[CH3:23][N:24]([CH3:32])[CH:25]1[CH2:30][CH2:29][CH:28]([O:31][C:2]2[C:3]3[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:27][CH2:26]1
Reactant: CN(C)C1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(Cl)ncnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCC(Oc2ncnc3sc(CCNC(=O)OC(C)(C)C)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of tert-butyl N-(2-[4-chlorothieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (100 mg, 0.32 mmol, 1.00 equiv) in freshly distilled THF (20 mL) was added sodium hydride (64 mg, 1.6 mmol, 5.0 equiv, 60% dispersion in mineral oil) at 0° C. under nitrogen. After stirring for 30 min at room temperature, a solution of 4-(dimethylamino)cyclohexan-1-ol (50 mg, 0.35 mmol, 1.06 equiv) was added and stirred overnight at room temperature. The reaction was then quenched by the addition of brine and extracted with EtOAc. The organic layers was combined and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was applied onto a silica gel column with DCM/MeOH (50:1-30:1) to provide 70 mg (52%) of tert-butyl N-[2-(4-[[4-(dimethylamino)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate as a light yellow solid. MS (ES): m/z 421 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][NH:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[C:10](=[C:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]2=[O:23])[O:9][CH2:8]3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(NCCCl)ccc21
Product: O=C1Nc2ccccc2C1=C1OCc2cc(NCCN3CCCCC3)ccc21
Temperature: 110 °C
Yield: 89.3 %

Procedure:
A mixture of 3-[5-(2-chloro-ethylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (1.10 g, 3.37 mmol) and piperidine (8 ml, 80.9 mmol) was heated at 110° C. for 4 hours. After cooled to room temperature, the mixture was poured into an ice water (150 ml) with stirring. The solid was filtered, washed with water and dried to give a crude product. Trituration of the crude product with CHCl3/hexanes afforded 3-[5-(2-piperidin-1-yl-ethylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (1.13 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[S:27])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2nc3ccccc3s2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4s3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenylthio)benzothiazole (10.0 mmoles, 2.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate 10.0 mmoles, 2.4 g) were reacted according to procedure C to yield of the title compound, 1.5 g, 30%. Mass Spec (FD) 495. Calculated for C21H13ClF3 N3S3 : C, 50.85H, 2.64N, 8.47. Found: C, 51.02; H, 2.71; N, 8.31.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:12][CH2:13][CH2:14]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH2:1]([O:8][C:9]([N:11]([CH2:16][CH2:17][C:18]([NH2:20])=[O:19])[CH2:12][CH2:13][CH2:14][Br:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CCN(CCCO)C(=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: NC(=O)CCN(CCCBr)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of acrylamide (2 g) in ethanol (30 mL) was added 3-amino-1-propanol (3.23 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added tetrahydrofuran (30 mL) and N-(benzyloxycarbonyloxy)succinimide (14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=40/1-20/1-5/1) to give 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)amino]propionamide (3.51 g). To a solution of the obtained 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)amino]propionamide (0.5 g) and carbon tetrabromide (0.65 g) in dichloromethane (5 mL) was added triphenylphosphine (1.03 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/4-dichloromethane/methanol=10/1) to give the title compound (0.41 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.Cl>CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)c1cc(CCc2ccccc2)[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a mixture of 3-tert-butyl-5-(2-phenylethyl)-1H-pyrazole (1.57 g, 6.87 mmol), sodium hydride (60% in oil, 280 mg, 7 mmol), and N,N-dimethylformamide (15 mL) was added methyl 4-(bromomethyl)benzoate (2.29 g, 10.0 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (1.75 g, yield 68%) as a yellow oil.
Reaction SMILES: N1C(N)=NC(N)=NC=1N.[C:10]1(=[O:20])[O:15][C:13](=[O:14])[CH:12]2[CH2:16][CH2:17][CH:18]=[CH:19][CH:11]12.[OH2:21]>>[C:10]([OH:15])(=[O:20])[CH:11]1[CH:19]=[CH:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:21])=[O:14]
Reactant: O
Reactant: O=C1OC(=O)C2CCC=CC12
Agent: Nc1nc(N)nc(N)n1
Product: O=C(O)C1C=CCCC1C(=O)O

Procedure:
In a beaker having an inner volume of 2 liters, 800 ml of deionized water was charged and, with stirring pieces immersed therein, was stirred and boiled on a stirrer provided with a hot plate. In this hot water, 12.6 g of melamine was thoroughly dissolved. Separately, in a beaker having an inner volume of one liter, 500 ml of deionized water was charged and, with stirring pieces immersed therein, was stirred and boiled on a stirrer provided with a hot plate. In this hot water, 15.2 g of tetrahydrophthalic anhydride was added and the resultant mixture was stirred for one hour with heating to give an aqueous solution of tetrahydrophthalic acid. This aqueous solution was added to the aqueous melamine solution mentioned above and the resultant mixture was stirred. The resultant mixed solution, when cooled with ice water, precipitates crystals. The crystals were separated by filtration and then dried in a vacuum drier. By the thermal analysis (DSC), the infrared absorption analysis and the titration with KOH performed in the same manner as in Synthesis Example 1, the crystals were confirmed to have formed a salt of melamine and tetrahydrophthalic acid at a molar ratio of 1:1. This salt will be referred to hereinafter as "melamine-THPA salt".
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([OH:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19]I>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1O
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OC

Procedure:
E1 was prepared from D1 following the general procedure reported in Preparative Example 16 Step 2 using methyl iodide for the alkylation. MS (ES) C13H13FN2O3 requires: 264. Found: 265 (M+H)+ and 287 (M+Na)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:36](=O)[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)[CH3:37]
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (1) (0.020 g, 0.041 mmol) in anhydrous methanol (1.5 mL) were added acetaldehyde (0.0090 mL, 0.17 mmol) and sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under an atmosphere of nitrogen The reaction was stirred at room temperature for 18 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (10) (0.016 g, 76% yield) as an white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.57 (d, J=8.9 Hz, 2H), 7.43 (s, 1H), 7.26-7.13 (m, 4H), 6.97-6.87 (m, 3H), 3.50 (s, 2H), 3.13-2.94 (m, 8H), 2.36 (q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). 4 Aliphatic protons obscured by the residual DMSO. LCMS Method C: rt 4.82 min; m/z 513.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][C@@H:43]2[O:45][CH2:44]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:42][C@H:43]1[CH2:44][O:45]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (1.35 g, 4.2 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (1.74 g, 12.6 mmol) and (2R)-(−)-glycidyl tosylate (1.92 g, 8.4 mmol) in DMF (25 ml) was stirred at 60° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate solution. The organic layer was then dried (MgSO4), filtered and solvent removed in vacuo to give a solid. This was triturated with ether and the solid filtered off and dried to give (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (842 mg, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=1.O(C)[Na]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CO[Na]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc(N)c2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
To a mixture of 4-aminophenol (218 mg, 2 mmol) and 4-chloropyridin-2-amine (256 mg, 2 mmol) in DMSO (2.5 mL) was added NaOCH3 (216 mg, 4 mmol). The reaction was microwaved at 180° C. for 40 minutes, then cooled down to rt and quenched with water (10 mL). The mixture was extracted with EtOAc (10 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=30/1) to give the title compound as a brown solid (103 mg, 26%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[CH2:8](C(O)=O)[C:9](CC(O)=O)=[O:10]>C(O)(=O)C>[CH3:8][C:9]([CH:6]1[C:1](=[O:3])[O:4][C:5]1=[O:7])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC(=O)CC(=O)O
Solvent: CC(=O)O
Product: CC(=O)C1C(=O)OC1=O
Yield: 86 %

Procedure:
To a solution of 60 ml of acetic acid and 43 ml of acetic anhydride at 0° C., was added slowly 40 g (0.27 mol) of acetonedicarboxylic acid. The mixture was stirred and the temperature was not allowed to rise above 10° C. The acid was dissolved slowly and a pale yellow precipitate formed. After 3 h the product was filtered, washed with 30 ml of glacial acetic acid and 100 ml of benzene. The white powder obtained was dried at high vacuum to afford 30 g of acetonedicarboxylic acid anhydride (yield 86%). Mp 137-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:19])([CH3:18])[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24].C(N(CC)CC)C>C(O)(=O)C>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])([CH3:19])[C:10](=[O:20])[NH:9]2)=[CH:6][CH:7]=1)=[O:24]
Reactant: CC1(C)C(=O)NC(c2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
30.0 g. (0.1125 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4,4-dimethyl-3(2H)-isoquinolinone are reacted in 280 ml. of glacial acetic acid with 14.7 g. (0.13 moles) of chloroacetyl chloride, in the presence of 13.5 g. (0.13 moles) of triethylamine. The reaction conditions are the same as described in Example 1. The crude product is recrystallized from ethanol to yield 25.15 g. of the title compound; m.p.: 218°-219°C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]([C:28]1[CH:38]=[CH:37][C:31]([O:32]CC(O)=O)=[CH:30][CH:29]=1)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:32][C:31]2[CH:30]=[CH:29][C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:38][CH:37]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: COC(=O)c1ccc(OCC(=O)O)cc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCC(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-yl-sulfonyl)piperazin-1-yl)ethanone (compound 4, 0.2 g, 0.64 mmol) and 2-(4-(methoxycarbonyl)phenoxy)acetic acid (134 mg, 0.64 mmol) taken in dry DCM (20 mL), DIPEA (495 mg, 3.86 mmol) followed by HATU (486 mg, 1.27 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) and brine (2×10 mL) The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.189 g, 63.21%) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[CH:21]=[O:22]>C1COCC1.ClCCl>[CH3:19][N:18]1[C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[C:15]([CH:21]=[O:22])[C:16]([CH3:20])=[N:17]1
Reactant: OCC(F)(F)F
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nn(C)c(OCC(F)(F)F)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.4 %

Procedure:
2,2,2-Trifluoroethanol (7.11 ml, 97.6 mmol) was added dropwise to potassium tert-butoxide (1M in THF) (97.6 ml, 97.6 mmol) at 0° C. A solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (10.3 g, 65.1 mmol) in THF (28 ml) was added slowly to the solution at 0° C. The solution was allowed to warn to room temperature and stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and concentrated to give the product as a yellow oil (15.82 g, 109% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3): 2.42 (s, 3H, Me), 3.65 (s, 3H, Me), 4.93 (q, 2H, CH2), 9.72 (s, 1H, CH).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:43]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:48]([C:44]3[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=3)(=[O:50])=[O:49])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (4 mL) were added dropwise a solution (2 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and pyridine-3-sulfonyl chloride (266 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 421 mg, 89%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:46](/[CH:49]=[CH:50]/[C:51](=[O:64])[C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=2)=[CH:45][C:39]=1[O:40][CH2:41][C:42](O)=[O:43]>ClCCl.O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:42](=[O:43])[CH2:41][O:40][C:39]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51](=[O:64])[C:52]4[CH:53]=[C:54]([O:62][CH3:63])[C:55]([O:60][CH3:61])=[C:56]([O:58][CH3:59])[CH:57]=4)[CH:47]=[CH:48][C:38]=3[O:37][CH3:36])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(C(F)(F)F)cc2s1
Yield: 796.6 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9i) (480 mg, 80% yield)
Reaction SMILES: [Na].[CH2:2]1[O:13][C:12]2[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][C:4]=2[O:3]1.CN(C)[C:16]1[CH2:20][CH2:19][CH2:18][N+:17]=1[CH3:21].COS([O-])(=O)=O>C(O)C>[C:8]([C:7](=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])[C:6]1[CH:10]=[CH:11][C:12]2[O:13][CH2:2][O:3][C:4]=2[CH:5]=1)#[N:9]
Reactant: CN(C)C1=[N+](C)CCC1
Reactant: N#CCc1ccc2c(c1)OCO2
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CN1CCCC1=C(C#N)c1ccc2c(c1)OCO2

Procedure:
Add (dropwise at 80°, with stirring) a solution of 3.5 g of sodium in 80 ml of ethanol to a mixture of 16.1 g of 3,4-methylenedioxybenzylcyanide and 36 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate. Continue boiling the resulting reaction mixture for a further 2 hours. Then distil off the solvent under a vacuum and take up the residue with water/diethyl ether. Collect the ethereal layer. Dry it over sodium sulfate and concentrate it to obtain 18 g (67% of theory) of the title compound as oily liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.[NH4+].[Cl-]>CN(C=O)C>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH3:19])=[O:17])=[C:7]2[CH3:12])=[CH:27][CH:26]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1Cc1c(C)[nH]c2ccc(OC)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To the product of Step 1 (210 mg, 0.68 mmol) in dry DMF (5 mL) at 0° C. was added Nail (30 mg, 0.74 mmol, 60% in oil) followed by 4-bromobenzyl bromide (174 mg, 0.7 mmol). The mixture was stirred at r.t. for 0.5 h. NH4Cl solution was added. The mixture was extracted with EtOAc. Chromatography of the concentrated organic extract gave 272 mg of the title compound.