Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([OH:9])[CH2:4][CH:3]1[Si:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][CH:3]1[Si:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(O)CC1[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(OS(C)(=O)=O)CC1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
16 g (0.11 mole) of a trans isomer, a cis isomer or a trans/cis isomer mixture of 1-methyl-1-hydroxy-2-(trimethylsilyl)cyclopropane, prepared in Section (1) was dissolved in 150 ml of dichloromethane and 25 ml of triethylamine was added thereto. The reaction solution was cooled to 0° C., 16 g (0.14 mole) of methanesulfonylchloride was gradually added thereto and the mixture was vigorously stirred for 1 hour. 50 mL of a saturated aqueous NaHCO3 solution was added to the reaction mixture to complete the reaction. An organic layer was separated from the reaction solution, dried over anhydrous magnesium sulfate (MgSO4), and concentrated by distillation of the solvent. Although the concentrate may be used directly without any further purification, it was finely purified by vacuum distillation (55-60° C./0.1 mmHg). As a result, 21.4 g (0.0096 mole, yield: 87%) of 1-methyl-1-(methanesulfonyloxy)-2-(trimethylsilyl)cyclopropane was obtained as a trans isomer, a cis isomer and a mixture thereof.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:20][CH3:21]>CN(C=O)C.CCOC(C)=O>[CH3:16][O:15][C:13](=[O:14])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=1)[CH2:20][CH3:21]
Reactant: CCCCOc1ccc(CC(=O)OC)cc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(CC)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
(Scheme 2, Compound E) The mixture of methyl 4-butoxyphenylacetate (1.20 g, 5.4 mmol) and NaH (60% in mineral oil, 0.50 g, 12.5 mmol) in DMF (25.0 mL) was stirred at 50° C. for 40 min. Bromoethane (2.0 g, 18.3 mmol) was added and the stirring continued at rt for one hour. The reaction mixture was diluted with EtOAc (300 mL), washed with H2O, and then was dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a yellow oil (0.85 g, 3.4 mmol, 63% yield). 1H NMR (DMSO-d6) δ 7.16 (d, 2H, J=7.0 Hz), 6.87 (d, 2H, J=8.5 Hz), 3.92 (t, 2H, J=6.5 Hz), 3.55 (s, 3H), 3.45 (t, 1H, J=9.0), 1.93 (m, 1H), 1.63 (m, 2H), 1.42 (m, 2H), 0.97 (t, 3H, J=7.2 Hz), 0.79 (t, 3H, J=4.0 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].O.Cl>CC(C)=O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[N:14]=[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[N:12]=2)=[CH:34][CH:35]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(CNc2nc(Nc3ccc(C(=O)OC)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 115 °C
Yield: 95.1 %

Procedure:
A mixture of methyl 4-(4-(4-(methoxycarbonyl)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (2.9 g) and K2CO3 (3.26 g) in acetone (20 mL)/water (20.00 mL) was heated at 115° C. for 24 hours. After cooling to room temperature, the mixture was acidified with 1 N HCl to pH=3. The white precipitate was collected, washed with water and dried under vacuum to give 4-(4-(4-carboxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (2.6 g).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]=1[CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:18][CH2:19][CH3:20].O>CN(C)C=O>[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](/[CH:32]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]=1[CH2:39][NH:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C=O)cc12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.4 mL, 7 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.28 g, 7 mmol) (60% in oil) and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (3.01 g, 7 mmol) in N,N-dimethylformamide (10 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenate (3.11 g, 88.9%) as crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH2:20][CH2:21][OH:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>>[OH:22][CH2:21][CH2:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:25])[C:13]2=[O:24])[C:16]([CH3:23])=[N:17]1
Reactant: Cc1nn(CCO)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CCO)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-[1-(2-hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 103.1.1, 37.4 mg, 0.093 mmol) and 2-methoxypyridine-5-boronic acid (Aldrich, Buchs, Switzerland, 20 mg, 0.131 mmol) to give the title compound as a white solid. (HPLC: tR 2.42 min (Method A); M+H=431 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 8.10-8.05 (m, 1H), 7.95-7.88 (m, 1H), 7.81-7.75 (m, 1H), 7.51-7.46 (m, 1H), 6.93-6.86 (m, 1H), 5.00-4.94 (m, 1H), 4.24-4.17 (m, 2H), 3.88 (s, 3H), 3.86-3.74 (m, 2H), 3.57 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16]C(Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:12]([C:3]1[C:2]([OH:1])=[C:7]([C:6]([O:8][CH3:9])=[C:5]([O:10][CH3:11])[CH:4]=1)[CH:15]=[O:16])(=[O:14])[CH3:13]
Reactant: COc1cc(O)c(C(C)=O)cc1OC
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(O)c(C=O)c1OC
Temperature: 0 °C
Yield: 10.5 %

Procedure:
A solution of 2′-hydroxy-4′,5′-dimethoxyacetophenone (1.0 g, 5.1 mmol) in methylene chloride (20 mL) was added with dichloromethyl methyl ether (1.6 g, 14 mmol) under an argon atmosphere. Then, the mixture was slowly added with titanium(IV) chloride (2.2 mL, 20 mmol) at 0° C., and then the mixture was refluxed for 18 hours by heating. The reaction mixture was added with ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (3:1→1:1)) to obtain 3-acetyl-2-hydroxy-5,6-dimethoxybenzaldehyde (0.12 g, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].C(OC(=O)[CH:20]=[CH:21][C:22](=[O:30])[CH:23]=[CH:24]C(OCC)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:24][CH2:23][C:22](=[O:30])[CH2:21][CH2:20]1
Reactant: CCOC(=O)C=CC(=O)C=CC(=O)OCC
Reactant: CCOC(=O)C(C)c1ccc(N)c(Cl)c1
Product: CC(C(=O)O)c1ccc(N2CCC(=O)CC2)c(Cl)c1

Procedure:
Moreover, the 4-fluoro-phenyl-acetonitrile can be reacted with 4-oxo-piperidine, to yield the 4-(4-oxo-piperidino)-phenyl-acetonitrile, which can be hydrolyzed to the free acid and the acid esterified, or the ethyl α-(3-chloro-4-aminophenyl)-propionate reacted with 4-oxo-2,5-heptadienedioic acid diethyl ester, saponifying and decarboxylating the reaction product, to yield the α-[3-chloro-4-(4-oxo-piperidino)-phenyl]-propionic acid. In corresponding esters, the carbonyl group can be reduced with one equivalent of Grignard compounds, e.g. methyl-, ethyl-, n-propyl-, phenyl- or 4-chlorophenyl-magnesium bromide, to yield, inter alia, the ethyl 4-[4-hydroxy-4-(methyl, ethyl, n-propyl, phenyl or 4-chlorophenyl)-piperidino]-phenyl acetate or α-[3-chloro-4-(4-hydroxy-4-methylpiperidino)-phenyl]-propionate. Said esters or the corresponding acids can be dehydrated wtih sulfuric or phosphoric acid, to yield, for example, the 4-(3-n-propyl-pent-2-enyleneimino)-phenylacetic acid or the α-[3-chloro-4-(3-methylpent-2-enyleneimino)-phenyl]-phenyl]-propionic acid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:2]2[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:22][CH:23]=1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(O)cc1
Product: COCCN1C(=O)C(Nc2ccc(O)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-aminophenol in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 3.37 (s, 3H), 3.72 (t, 2H), 3.90 (t, 2H), 6.40-6.45 (m, 2H), 6.65-6.71 (m, 2H), 6.82 (bs, 1H), 7.10-7.20 (m, 4H), 7.23-7.29 (m, 1H), 7.63 (bs, 1H); Mass Spectrum: M−H+ 373.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH2:13][S:14](Cl)(=[O:16])=[O:15])#[N:12].C(NS(CC#N)(=O)=O)C1C=CC=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:14]([CH2:13][C:11]#[N:12])(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCS(=O)(=O)Cl
Reactant: NCCCc1ccccc1
Agent: N#CCS(=O)(=O)NCc1ccccc1
Product: N#CCS(=O)(=O)NCCCc1ccccc1

Procedure:
N-3-Phenyl-n-propyl cyanomethylsulfonamide was prepared with 3-phenyl-n-propylamine and cyanomethylsulfonly chloride under similar conditions as described for N-benzyl cyanomethylsulfonamide (Part A, M40).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:30][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CBr)c(F)c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a stirred solution of 2-fluoro-1-methyl-4-nitrobenzene (1 g, 6.446 mmol) in carbon tetrachloride was added benzoyl peroxide (497 mg, 1.2847 mmol) and N-bromosuccinimide (1.377 g, 7.736 mmol). The reaction mixture was refluxed for 18 h, then cooled to room temperature. The mixture was dissolved in ethyl acetate, then washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo to obtain 1-(bromomethyl)-2-fluoro-4-nitrobenzene (1.335 g) as a crude.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:17][NH2:18]>C(O)C>[C:7]1([C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[NH:18][N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C

Procedure:
To a stirred mixture of 4,4,4-trifluoro-1-phenylbutane-1,3-dione (5.0 g, 23.13 mmol) in dry ethanol (100 mL) was added hydrazine hydrate (1.737 g, 34.7 mmol) dropwise. The resulting solution was refluxed for 16 h. The reaction was cooled to room temperature and concentrated. The oil was diluted with saturated NaHCO3 solution and extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a clear liquid which was crystallized in hexanes/ethyl acetate (3.25 g). LCMS m/z=213.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 6.77 (s, 1H), 7.36-7.51 (m, 3H), 7.53-7.64 (m, 2H), 11.59 (s, 1H).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][C:4]=1[CH:12]=[C:13]([Cl:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:1])=[O:11])=[CH:5][C:4]=1[CH:12]=[C:13]([Cl:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: N
Reactant: CCOC(=O)C(Cl)=Cc1cc(N=C=O)ccc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)=Cc1cc(NC(N)=O)ccc1Cl
Reaction time: 1 h

Procedure:
Gaseous ammonia was passed into a solution of 14.3 g of 4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl isocyanate in 200 ml of tetrahydrofuran at 20° C. in the course of 1.5 hours until saturation had been reached, and stirring was carried out for 1 hour. The precipitate was removed and washed with ether. The filtrate was evaporated down, the residue was stirred with ether and the product was removed. The solids were combined.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[N:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]1([CH2:21]Br)[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>>[OH:9][N:8]([CH:6]1[CH2:7][C:2]([CH3:12])([CH3:1])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]1)[CH2:21][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:8]([OH:9])[CH:6]2[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:7]2)=[CH:15][CH:14]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1
Product: CC1(C)CC(N(O)Cc2ccc(CN(O)C3CC(C)(C)NC(C)(C)C3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-one oxime and p-xylylene dibromide
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:23])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:54][C:55]1[CH:60]=[CH:59][C:58]([CH:61]2[CH2:66][CH2:65][N:64]([CH2:67][C:68]([NH2:70])=[O:69])[CH2:63][CH2:62]2)=[CH:57][C:56]=1[O:71][CH3:72]>CN(C)C=O>[CH3:21][S:18]([N:17]([CH3:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:4]2[C:5]([CH:6]=[N:7][C:2]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([CH:61]4[CH2:66][CH2:65][N:64]([CH2:67][C:68]([NH2:70])=[O:69])[CH2:63][CH2:62]4)=[CH:57][C:56]=3[O:71][CH3:72])=[N:3]2)=[C:8]([CH3:23])[CH:9]=1)(=[O:20])=[O:19]
Reactant: Cc1cc(-c2ccccc2N(C)S(C)(=O)=O)n2nc(O)ncc12
Reactant: COc1cc(C2CCN(CC(N)=O)CC2)ccc1N
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(CC(N)=O)CC2)ccc1Nc1ncc2c(C)cc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into an 8-dram vial, N-[2-(2-Hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (87 mg, 0.26 mmol), N,N-Dimethylformamide (0.948 mL), N,N-Diisopropylethylamine (0.100 mL, 0.576 mmol), and N-Phenylbis(trifluoromethanesulphonimide) (0.112 g, 0.314 mmol) were added. The reaction was stirred at room temperature for 30 minutes. 2-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetamide (0.152 g, 0.576 mmol) was then added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum overnight. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid. The solid was partitioned with NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-[4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-phenyl]-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-piperidin-1-yl]-acetamide as a yellow solid. LCMS (E/I+) 578.16 (M+H). NMR 1H (DMSO-d6)-8.95 (s, 1H), 7.93-7.98 (m, 1H), 7.88 (d, 1H, J=8.18 Hz), 7.61-7.67 (m, 1H), 7.57 (s, 1H), 7.51-7.56 (m, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 6.89 (s, 1H), 6.81 (s, 1H), 6.68 (d, 1H, J=8.51 Hz), 3.84 (s, 3H), 3.05 (s, 3H), 2.85-2.95 (m, 7H), 2.35-2.45 (m, 4H), 2.08-2.28 (m, 2H), 1.64-1.81 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>C1(C)C=CC=CC=1>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][CH:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH2:23][CH2:24]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(NCCC(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
In a reactor equipped with a water trap, a solution of 3,3-diphenylpropylamine (4.9 g) and 1-ethoxycarbonyl-4-piperidone (4.0 g) in toluene (100 mL) was refluxed for 2 hours. This reaction mixture was concentrated under reduced pressure and the residue was dissolved in 80 mL of ethanol. After this solution was cooled with ice, 1.8 g of sodium cyanoborohydride and a small amount of bromocresol green were added. Then, 4N-hydrogen chloride solution in ethanol was added dropwise until the reaction mixture had turned yellow and, after completion of dropwise addition, the mixture was further stirred for 30 minutes. This reaction mixture was poured into an excess of aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to give ethyl 4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate. This product was dissolved in 80 mL of N,N-dimethylformamide, followed by addition of 2.8 mL of benzyl bromide and 3.2 g of potassium carbonate, and the mixture was stirred at room temperature for 2 hours. This reaaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1 to 7:3 ) to provide 7.8 g of the title compound. Yield based on 3,3-diphenylpropylamine was 73%.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15](O)=[O:16])=[CH:13][N:12]([CH3:18])[C:9]=32)=[CH:4][N:3]=1.C1C=CC2N(O)N=[N:25]C=2C=1.N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15]([NH2:25])=[O:16])=[CH:13][N:12]([CH3:18])[C:9]=32)=[CH:4][N:3]=1
Reactant: Cn1cc(C(=O)O)c2c1-c1nc(N)ncc1CC2
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(N)=O)c2c1-c1nc(N)ncc1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 8-amino-1-methyl-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid M2 (0.08 mmol) in dry DMF (4 mL), HOBT.NH3 (0.164 mmol), TBTU (0.164 mmol) and DIEA (0.328 mmol) were added. The mixture was stirred at rt for 24 h then the solvent was evaporated. The residue was suspended in 10 mL of water, filtered, washed with water and dried in vacuo, providing the title compound (55% yield). ESI (+) MS: m/z 244 (MH+). 1H NMR: 2.73 (t, J=7.44, 2H), 3.00 (t, J=7.44, 2H), 4.04 (s, 3H), 6.94 (bs, 1H), 7.35 (bs, 1H), 7.73 (s, 1H), 7.96 (s, 1H), 7.76 (bs, 3H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[C:6]([Cl:14])[CH:5]=1)(=[O:3])[CH3:2].[Cl-:15]>C(O)(=O)C>[Cl:14][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][Cl:15])[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=1
Reactant: [Cl-]
Reactant: COC(=O)c1cc(Cl)cc(C(C)=O)n1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(C(=O)CCl)n1

Procedure:
A solution of methyl 6-acetyl-4-chloro-2-pyridinecarboxylate (6.55 g) and surfuryl chloride (2.73 ml) in acetic acid (33 ml) was stirred at ambient temperature for 14 hours and further at 50° C. for three hours. The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and washed with water to give methyl 4-chloro-6-chloroacetyl-2-pyridinecarboxylate (6.75 g).
Reaction SMILES: BrBr.[C:3]([NH:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=O)[CH:15]=[CH:14][N:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:29]([NH2:32])(=[S:31])[CH3:30].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:32]=[C:29]([CH3:30])[S:31][C:18]=2[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)cc1
Reactant: CC(N)=S
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(C)sc2-c2ccnc(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
Bromine (0.18 mL, 3.5 mmol) was added to a solution of 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (1.2 g, 3.4 mmol) in acetic acid (10 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in N,N-dimethylformamide (20 mL), thioacetamide (0.30 g, 19 mmol) was added to the solution and the mixture was stirred at room temperature for 20 hours. An aqueous saturated solution of sodium hydrogencarbonate (20 mL) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1) to obtain 0.68 g (yield 50%) of the title compound.