Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1>>[CH3:18][N:19]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: CNc1cccc(OC)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: COc1cccc(N(C)c2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Yield: 100 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-trifluoromethyl-pyrimidine (180 mg, 0.693 mmol) and N-methyl-3-methoxyaniline (112 mg, 0.816 mmol) in 3 mL of solvent (ethanol:water=2:1) was refluxed for 20 h. The solvent was removed under reduced pressure and the residue was dissolved in 25 mL of ethyl acetate. The ethyl acetate solution was washed with 25 mL of 1M NaOH, and the aqueous layer was reextracted with ethyl acetate (25 mL). The combined organic extracts were washed with saturated NaCl and dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40–45% ethyl acetate/hexanes) to give the title compound as an oil (250 mg, 0.693 mmol, 100%). 1H NMR (CDCl3): 8.86 (dd, J=0.6, 4.5 Hz, 1H), 8.50 (d, J=7.5 Hz, 1H), 7.85 (dt, J=1.8, 7.8 Hz, 1H), 7.42 (m, 2H), 6.95 (dd, J=1.8, 8.4 Hz, 1H), 6.86 (m, 1H), 6.82 (m. 1H), 3.85 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(tert-butoxycarbonylamino)hexanoic acid (1 eq) in acetone (0.2 M) was added potassium carbonate (2 eq) and (bromomethyl)benzene (2 eq) in acetone (2 M). The reaction mixture was stirred at room temperature for 1 hour. Additional amount of DMF was then added to the reaction mixture to facilitate the dissolution of potassium carbonate. The reaction mixture was stirred at room temperature for another 30 minutes. The mixture was then diluted with ethyl acetate, and washed with 5% citric acid, water and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-40% EtOAc/Hex to give the product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][C:15](=[O:16])[N:14]([CH3:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc2c(c1)CCCC2=O)c1ccccc1

Procedure:
The title product was prepared from 6-hydroxy-1-tetralone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (49%, colorless oil). HPLC-MS: m/z=296.2 (M+1); Rt: 3.90 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([Cl:28])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccncc3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([CH:7]([NH:9]CC#C)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCNC(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A solution of N-(1-Phenylethyl)propargylamine (500 mg, 3.1 mmol) in THF (5 ml) was added to the LVT reagent prepared as described in Example 2.1 above, and the resulting mixture stirred for 2 hours at room temperature. The reaction mixture was diluted with hexane-ethyl acetate mixture (70:30) and filtered through celite. The filtrate washed with brine, dried (Na2SO4), and concentrated under vacuum. The crude product was purified using chromatography (SiO2) to yield 1-phenylethylamine (290 mg, 77%). The rotation (αD) of the de-protected 1-phenylethylamine was used to determine the ee of the products in Example 1.11.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[CH3:9]CN(C(C)C)C(C)C.[C:18]1([C:24]#[C:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH3:9][O:7][C:6](=[O:8])[CH:2]([NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:27][CH:28]=1)[CH:3]([OH:4])[CH3:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(C#Cc2ccccc2)cc1
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1ccc(C#Cc2ccccc2)cc1)C(C)O
Reaction time: 12 h
Yield: 99.1 %

Procedure:
A solution of threonine (1.66 g, 9.8 mmol) and DIEA (1.53 ml, 8.8 mmol) in DMF (10 ml) was added to a stirred solution of 4-phenylethynyl-benzoic acid 3 (1.55 g, 7.0 mmol) and DIEA (1.53 ml, 8.8 mmol) in DMF (11 ml) at rt. After 12 h, the reaction was diluted with EtOAc (300 ml) and washed with 0.5M HCl (2×60 ml), sat. aq. NaHCO3 (60 ml), 50% diluted brine (60 ml), sat. brine (60 ml), dried with Na2SO4, filtered and concentrated under reduced pressure. Upon drying in vacuo, 2.34 g of white solid was obtained (approximately quantitative yield in 99% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:33].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCCC>C1(C)C=CC=CC=1.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:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:33])[CH:4]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:19]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(C)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A stirred mixture of 4-(4-chloro-3-methyl-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.8) (0.59 g, 1.03 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.34 g, 1.13 mmol), tetrakis(triphenylphosphine)palladium (0.071 g, 0.062 mmol) in toluene (8 ml) was heated under reflux conditions for 15 h, heptane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.54 g) as a white solid.
Reaction SMILES: [CH2:1]1[O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=2)[O:3][CH2:2]1.P(OCC)(OCC)OCC.C[O-].[Na+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:1]1[O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8](/[CH:11]=[CH:33]/[C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[CH:7][CH:6]=2)[O:3][CH2:2]1
Reactant: ClCc1ccc(C2OCCO2)cc1
Reactant: O=Cc1cccnc1
Agent: CCOP(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C(=C/c1cccnc1)\c1ccc(C2OCCO2)cc1
Temperature: 5 °C
Yield: 84.9 %

Procedure:
10.11 g (50.9 mmol) of 4-chloromethylbenzaldehyde ethylene acetal and 8.46 g (50.9 mmol) of triethyl phosphite were heated without solvent, with magnetic stirring, at an oil bath temperature of 200°-210° C. until gas evolution was complete (about 1 h). After cooling, 70 ml of dimethylformamide (filtered through basic alumina, activity I) and 5.5 g (102.0 mmol) of sodium methylate were added. The mixture was cooled to 5° C. and, with magnetic stirring and cooling, a solution of 5.45 g (50.9 mmol) of pyridine-3-aldehyde in 20 ml of dimethylformamide was added dropwise within 15 min (during which the temperature rose to 25° C.), and the mixture was then stirred at room temperature for 1 h. The reaction mixture was diluted with 250 ml of toluene and washed twice with water. The combined wash phases were extracted twice with toluene. Drying of the combined organic phases over magnesium sulfate and removal of the solvent in vacuo provided 10.94 g of a yellowish solid. Recrystallization from cyclohexane produced 8.74 g, and working up of the mother liquor produced a further 0.60 g.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:43])[N:24]([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:40][O:39]C(C)(C)[O:37]2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:20]=[C:19]([Cl:44])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:44].[Cl:44][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH2:32][CH2:33][O:34][CH2:35][CH:36]([OH:37])[CH2:40][OH:39])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:43]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOCC2COC(C)(C)O2)c2ccc(F)cc2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCOCC(O)CO)c1ccc(F)cc1
Reaction time: 3 h
Yield: 124.9 %

Procedure:
A solution of (2-{3-chloro-5-[[2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-ethyl]-(4-fluoro-phenyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.042 g) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room temperature for 3 h and then the solvent removed under reduced pressure. The residue was dissolved in a mixture of acetonitrile (2 ml) amd 2M aqueous hydrochloric acid (0.5 ml) and subjected to preparative hplc to give title compound (0.022 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]C)=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].B(Br)(Br)Br.O>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1[nH]c2cc(OC)ccc2c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(O)ccc2c1C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Ethyl 3-methyl-6-methoxy-1H-indole-2-carboxylate (1.00 g; synthesized according to the disclosures in the literature (Gan et al., J. Org. Chem., vol. 62, pp. 9298-9304, 1997)) was dissolved in methylene chloride (dehydrated, 13 mL), and boron tribromide (1 M/methylene chloride, 17.2 mL) was added dropwise under ice-cooling. The resulting mixture was allowed to warm to room temperature and stirred for 40 minutes. The reaction solution was then cooled with ice, followed by addition of water. The resulting mixture was extracted with chloroform, washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (3:1-2:1 hexane/ethyl acetate) to yield the title compound (480 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1.CC1C=CC2C(=CC=CC=2N2CCNCC2)N=1.CS(OCCC1C=CC=C([Br:59])C=1)(=O)=O>>[Br:59][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Reactant: CS(=O)(=O)OCCc1cccc(Br)c1
Agent: Cc1ccc2c(N3CCNCC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(Br)c4)CC3)cccc2n1
Yield: 56 %

Procedure:
The title compound was prepared in 56% yield using a similar procedure to description D5 starting from 2-methyl-5-(1-piperazinyl)quinoline (D3) and 2-(3-bromophenyl)ethyl methanesulfonate (D13).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([NH2:20])=[O:19])(=[O:15])[CH3:14]>>[C:13]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:20][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:19])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)(C)C(N)=O
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Product: COC(=O)c1cc(C)nc(NC(=O)C(C)(C)OC(C)=O)c1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (0.89 g, a yellow solid) from methyl 2-chloro-6-methylisonicotinate (0.70 g, 3.8 mmol) and 1-amino-2-methyl-1-oxopropan-2-yl acetate by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[Cl:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[C:25]=1[S:31](Cl)(=[O:33])=[O:32]>>[ClH:23].[Cl:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[C:25]=1[S:31]([N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:32])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)n1ccc2c(N3CCNCC3)cccc21
Product: Cl

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 5-chloro-1,3-dimethyl-1H-pyrazol-4yl-sulfonyl chloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.17 (br, 1 H), 7.78 (d, J=3 Hz, 1 H), 7.49 (d, J=8 Hz, 1 H), 7.28 (t, J=8 Hz, 1 H), 6.93 (d, J=3 Hz, 1 H), 6.87 (d, J=8 Hz, 1 H), 3.72 (s, 3 H), 3.28 (m, 8 H), 2.34 (s, 3 H); MS (ESI+) for m/z 394 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[C:9]([C:13]1[C:14](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:15][N:16]2[C:21]=1[C:20]([CH3:22])=[N:19][N:18]=[C:17]2[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[F:31])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[C:14]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)=[N:15][N:16]2[C:21]=1[C:20]([CH3:22])=[N:19][N:18]=[C:17]2[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=1[F:31])([CH3:12])([CH3:10])[CH3:11]
Reactant: Cn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4c(F)ccc(F)c4F)nnc(C)c3c2C(C)(C)C)cc1
Product: Cc1nnc(-c2c(F)ccc(F)c2F)n2nc(OCc3ncnn3C)c(C(C)(C)C)c12

Procedure:
This compound was prepared using the procedure described in Example 7, step e, using (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (prepared as described in EP-A-170073) instead of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol, and using toluene-4-sulfonic acid 3-tert-butyl-4-methyl-7-(2,3,6-trifluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-yl ester instead of toluene-4-sulfonic acid 3-tert-butyl-7-(2,5-difuorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester. Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 1.55 (9H, s), 3.07 (3H, s), 3.84 (3H, s), 5.38 (2H, s), 7.04 (1H, m), 7.41 (1H, m), 7.86 (1H, s); MS (ES+) m/e 432 [MH]+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11](/[CH:15]=[CH:16]/[C:17]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][C:29]=2[O:30][CH2:31][CH3:32])[N:26]=[CH:25][C:24]([C:33]#[N:34])=[C:23]3[NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[C:38]([Cl:50])[CH:37]=2)=[O:18])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:50][C:38]1[CH:37]=[C:36]([NH:35][C:23]2[C:22]3[C:27](=[CH:28][C:29]([O:30][CH2:31][CH3:32])=[C:20]([NH:19][C:17](=[O:18])/[CH:16]=[CH:15]/[C@@H:11]4[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]4[CH3:14])[CH:21]=3)[N:26]=[CH:25][C:24]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1C[C@@H](O)CN1C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
(E)-3-[(2S,4R)-4-(tert-Butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidin-2-yl]-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]prop-2-enamide 3f (50 mg, 0.07 mmol) and tetrabutyl ammonium fluoride (51 mg, 0.21 mmol) were dissolved in 5 mL of tetrahydrofuran, and the mixture was stirred for 12 hours. The reaction mixture was added with 1 mL of water, concentrated under reduced pressure and extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]prop-2-enamide 3 (17 mg, yield 40.4%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[S:39](Cl)(=[O:41])=[O:40])[CH:32]=[CH:31][CH:30]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:39]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:38]=3[N:29]=[CH:30][CH:31]=[CH:32]4)(=[O:40])=[O:41])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: O=C(O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3cccc4cccnc34)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and quinoline-8-sulfonyl chloride followed the procedure of Example 1 Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 5.66 (s, 2H, 6.90 (d, J=2.0 Hz, 1H, 6,95-7.05 (m, 5H, 7.15-7.28 (m, 3H, 7.30-7.45 (m, 4H, 7.64 (t, J=7.8 Hz, 1H, 7.75 (dd, J=8.3, 4.1 Hz, 1H, 8.17 (dd, J=7.3, 1.3 Hz, 1H, 8.27 (dd, J=8.2, 1.2 Hz, 1H, 8.57 (dd, J=8.3, 1.7 Hz, 1H, 9.12 (dd, J=4.2, 1.6 Hz, 1H, 9.67 (s, 1H, 12.97 (br s, 1H; MS (ESI) m/z 534 (MH+); MS (ESI) m/z 532 [M-H]−; HRMS calcd for C31H24N3O4S: 534.1477; found (ESI+): 534.1481; Anal. calcd for C31H23N3O4S.0.25H2O: C, 69.19; H, 4.40; N, 7.81. Found: C, 69.28; H, 4.31; N, 7.73.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[N:8][C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[Br:19]N1C(=O)CCC1=O>CS(C)=O.O>[Br:19][C:9]1[C:10]([NH2:12])=[N:11][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(-c2ccncc2)c(-c2ccco2)n1
Solvent: O
Solvent: CS(C)=O
Product: Nc1nc(-c2ccco2)c(-c2ccncc2)nc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.1 %

Procedure:
To a 0° C. stirred solution of 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5, 195 mg, 0.82 mmol) in dimethylsulfoxide (1.5 mL) and water (40 μL), was added portionwise N-bromosuccinimide (146 mg, 0.82 mmol). The mixture was stirred at room temperature for 40 min, then poured into water, extracted with dichloromethane (×3), the organic layers washed with brine, dried (MgSO4) and evaporated to furnish the title compound (198 mg, 75%) as a brown solid.
Reaction SMILES: [CH2:1]([N:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10](O)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:30])CC>ClCCl>[CH2:1]([N:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:30])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To ethyl 3-(benzyl(cyclohexyl)amino)-2-hydroxy-2-methylpropanoate (7 g, 21.9 mmol) in 50 ml of dichlormethane at −78° C., was added DAST (4.3 ml, 32.8 mmol) dropwise. The reaction mixture was gradually warmed up to room temperature and stirred for 2 h. It was then diluted to dichloromethane, washed by NaHCO3, brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=40:1 to 20:1) to give 6.8 g product (97%) as light yellow liquid. [M+H] calc'd for C19H28FNO2, 322. found 322.
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O[N:36]1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:27]([NH:34][NH:36][C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[O:2])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)NNCc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 106.9 %

Procedure:
To a stirring solution of (RS) 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (0.500 g, 1.4 mmol) in N,N-dimethylformamide (40 ml) were added sequentially benzylamine (165 mg, 1.1 eq), 1-hydroxybenzotriazole (208 mg, 1.1 eq), and dicyclohexylcarbodiimide (317 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 0.714 grams of the title product as a white foam.