Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:23]2[CH:24]=[CH:25][NH:26][C:27]=2[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:13][CH2:12]1
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1cccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 7-chloro-3-(piperidin-4-yl)-1H-indole (0.34 g, 1.25 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.275 g, 1.32 mmol) and potassium carbonate (0.41 g, 3.0 mmol). The product was isolated as a white foam. Yield 240 mg (47%). mp 178-182° C. FDMS m/e=407 (M+ of free base). HRMS: calc., 408.184265; found, 408.184300
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[S:5][CH:6]=[C:7]([C:9]#[CH:10])[CH:8]=1.C(OC)(OC)OC>CO.OS(O)(=O)=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1
Reactant: C#Cc1csc(C(OC)OC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COC(OC)OC
Product: CCc1csc(C(OC)OC)c1

Procedure:
2-Dimethoxymethyl-4-ethynylthiophene (15 g, 0.082 mol) was mixed with 1.5 g Pd[C] in 200 mL of methanol and hydrogenated for 4 hr at 44-31 psi. The mixture was filtered through glass fiber paper and concentrated. The residue (11.6 g) was dissolved in 60 mL of methanol and treated with trimethyl orthoformate (19 g, 0.18 mol) and H2SO4 (6 drops) in a flask equipped with a reflux condenser and drying tube. The mixture was heated at reflux for 70 min, cooled, and poured into 200 mL of saturated aqueous NaHCO3. The suspension was extracted with 200 mL of CH2Cl2, and the organic was filtered through 1 PS paper and concentrated at aspirator pressure. The 16 g of residue was dissolved in 200 mL of hexanes and applied to 150 g of silica gel (topped with Na2SO4 and equilibrated with hexanes).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]=[C:10]1[CH2:17][CH2:18][CH3:19].C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C.C1(C)C=CC=CC=1>[Br:33][C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:2]=2[F:1])[C:10]([CH2:17][CH2:18][CH3:19])=[N:11][C:12]=1[CH3:16]
Reactant: BrBr
Reactant: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 70 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 3′-fluoro-4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.4 g) and sodium acetate (0.32 g) in acetic acid (20 mL) was added bromine (0.2 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with toluene and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 1 M aqueous sodium thiosulfate solution, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.65 g, 38%) as a colorless solid.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][N+:12]([CH3:15])=[C:11]2SC)=[CH:5][N:4]=1.[N:18]#[C:19][NH2:20]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[N:20][C:19]#[N:18])=[CH:5][N:4]=1
Reactant: N#CN
Reactant: CSC1=[N+](C)CCC1Cc1ccc(Cl)nc1
Agent: [I-]
Solvent: CCO
Product: CN1CCC(Cc2ccc(Cl)nc2)C1=NC#N

Procedure:
A mixture of 3.7 g of 3-(2-chloropyrid-5-yl-methyl)-1-methyl-2-methylthio-1-azacyclopent-1-enylium iodide and 2.5 g of cyanamide in 20 ml of ethanol is boiled at reflux for 6 hours. The mixture is concentrated by evaporation in vacuo and the residue is chromatographed on silica gel using dichloromethane/methanol (19:1) as eluant. The title compound having a melting point of 53-54° C. (compound 6.4) is obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C(=O)(O)[O-:12].[Na+].ClC1C=C(C=CC=1)C(OO)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3][C:2](=[O:10])[O:12]1
Reactant: O=C1Cc2ccccc2C1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1Cc2ccccc2CO1
Temperature: 20 °C
Reaction time: 20 h
Yield: 90.4 %

Procedure:
To 6.60 g (0.050 mol) of 2-indanone in 50 mL of dry dichloromethane was added 38.0 g (0.45 mol) of powdered anhydrous sodium bicarbonate, followed by 17.0 g (0.10 mol) of m-chloroperoxybenzoic acid. After stirring at 20° C. for 20 hours, further 3.0 g (0.017 mol) of the peracid was added and stirring continued for 24 hours. After addition of 200 mL of 10% aqueous Na2S2O3 stirring was continued until two clear phases had formed. The organic solution was separated and the aqueous phase was extracted with two 100 mL portions of dichloromethane. The combined organic solutions were dried (MgSO4) and concentrated under vacuum at 30° C. Solution in a mixture of ether and pentane, filtration and concentration under vacuum gave 6.7 g (90%) of 1,4-dihydro-3H-2-benzopyran-3-one, which could be recrystallized from ether or sublimed at 30°-40° C. (0.24 mm); mp 78°-79° C.; TLC Rf 0.36 (SiO2, CH2Cl2, brown-orange with iodine).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[NH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.C(N(CC)CC)C>>[OH:16][CH:14]1[CH2:15][N:12]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Yield: 95.7 %

Procedure:
The process is carried out according to the method described in step 5.1, using 7 g (42.83 mmol) of 2-chloro-5-nitropyridine and 5.75 g (51.4 mmol) of 3-azetidinol hydrochloride. In this case, 13 g (128.45 mmol) of triethylamine are also added. 8 g of the expected product are thus isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:27][C:28]([C:30]1[S:31][C:32]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[CH:33][C:34]=1[C:35]#[C:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:28]([C:30]3[S:31][C:32]([C:41]4[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=4)=[CH:33][C:34]=3[C:35]#[C:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:27])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1C#C[Si](C)(C)C
Reactant: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2C#C[Si](C)(C)C)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Dissolve 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (320 mg, 1.09 mmol) in toluene (11 mL) and add 2 M trimethylaluminum (0.65 mL, 1.30 mmol, solution in toluene). Stir the solution at RT for 1 h and then add 5-(4-chloro-phenyl)-3-trimethylsilanylethynyl-thiophene-2-carboxylic acid methyl ester (380 mg, 1.09 mmol). Stir the solution at 50° C. overnight, then carefully quench with saturated Rochelle's salt solution. Stir the mixture for 1 h and then extract with CH2Cl2 (3×30 mL). Combine the organic solutions, dry, filter, and concentrate the filtrate. Purify the crude material by flash chromatography, using 8% MeOH (2 N NH3) in CH2Cl2 as eluent, to give 425 mg (64%) of the title compound as a white solid. LC-MS/ES m/z (35Cl) 555.0 [M−t-butyl+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]#[N:20])=[CH:11][C:10]=1[CH3:21])=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N:45]=[N+:46]=[N-:47])(C)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]#[N:20])=[CH:11][C:10]=2[CH3:21])[N:47]=[N:46][N:45]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1cc(C(F)(F)F)c(C#N)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1cc(C(F)(F)F)c(C#N)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-{[4-cyano-2-methyl-5-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 61, 452 mg, 1.51 mmol) in tetrahydrofuran (10 mL) was added triphenylphosphine (790 mg, 3.01 mmol), di-isopropylazodicarboxylate (0.585 mL, 3.01 mmol) and trimethylsilylazide (0.400 mL, 3.01 mmol). The reaction was stirred at room temperature for 18 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH:11]([N:13]([CH3:15])[CH3:14])[CH3:12].[CH:16](O)=O.C=O.N>O>[CH3:16][N:9]([CH2:10][CH:11]([N:13]([CH3:15])[CH3:14])[CH3:12])[C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8]
Reactant: Cc1cccc(C)c1NCC(C)N(C)C
Reactant: O=CO
Agent: C=O
Agent: N
Solvent: O
Product: Cc1cccc(C)c1N(C)CC(C)N(C)C
Reaction time: 6 h
Yield: 98 %

Procedure:
A mixture of 1.5 g (7.3 mmoles) of 1-(2,6-dimethylphenyl-amino)-2-dimethylamino-propane, prepared as described in Example 8, 1.5 ml of 99% formic acid and 1.5 ml of a 36% aqueous formaldehyde solution is boiled for 6 hours. The mixture is cooled, poured onto 30 ml of water, the aqueous solution is rendered alkaline (pH=9) with concentrated aqueous ammonia, and extracted then thrice with 10 ml of benzene, each. The benzene solutions are combined, dried over anhydrous potassium carbonate, and the solvent is evaporated under reduced pressure. 1.58 g (98,8%) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]2-dimethylamino-propane are obtained as a light yellow oil; b.p.: 102°-104° C./133.3 Pa.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.Br[C:14]1[N:22]=[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:16]2[N:15]=1.CCN(C(C)C)C(C)C>C(O)C>[N:15]1[N:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]2=[N:22][C:14]=1[N:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1
Reactant: Brc1nc2ncccn2n1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OCC[C@@H]1C[C@@H]1C1CCN(c2nc3ncccn3n2)CC1
Temperature: 120 °C

Procedure:
To a mixture of 2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (Intermediate 11; 70 mg, 0.4 mmol) and 2-bromo[1,2,4]triazolo[1,5-a]pyrimidine (9 mg, 0.496 mmol) in ethanol (2 mL) was added DIEA (0.22 mL, 1.21 mmol) and the resulting mixture heated via microwave to 120° C. for 1 hr. HPLC of the reaction mixture proved the reaction was complete with the absence of Intermediate 11. The mixture was filtered (glass wool filter paper, Whatman 1821 110), and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure and the resulting residue purified via preparative TLC plates (2×1000 μM silica gel) eluting with 50% ethyl acetate in hexane. The product was removed from the silica gel by extracting with ethyl acetate and the solvent was removed under reduced pressure to afford the title compound as an off-white solid. MS (Multimode) m/z 288 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)[C:6](=O)[CH3:7])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[CH3:7])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1C
Yield: 79.9 %

Procedure:
A mixture of 2-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester (6.979 g, 26.21 mmol)), aniline (2.9 mL, 31.45 mmol) and p-toluenesulfonic acid (TsOH) monohydrate (249 mg, 1.31 mmol) in toluene (60 mL) was refluxed overnight while the generated water was separated with Dean-Stark distillation head. Then the reaction mixture was diluted with EtOAc, washed with saturated sodium hydrogen carbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified with column chromatography to give the title compound (6.768 g); The title compound, ESI MS (m/z): 324 (M+H+).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:26]=[CH:25][C:18]2[C:19](=O)[O:20]C(=O)[NH:22][C:17]=2[CH:16]=1>CCCCCC.O1CCCC1>[NH2:22][C:17]1[CH:16]=[C:15]([C:14]([F:13])([F:27])[F:28])[CH:26]=[CH:25][C:18]=1[C:19](=[O:20])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2c(=O)o1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1CC(=O)c1ccc(C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 11.1 ml) was added during 2 minutes to a stirred solution of 1,5-dimethyltetrazole (2.94 g) in dry tetrahydrofuran (100 ml) at -10° to -5°. After stirring for 15 minutes, 7-trifluoromethyl-1H-3,1-benzoxazine-2,4-dione (2.3 g) was added during 5 minutes at -10° to -5°. The reaction mixture was stirred at ambient temperature for 1 hour. Industrial methylated spirit (2 ml) was added and the mixture kept at ambient temperature for 1.5 hours. The mixture was evaporated to one quarter volume, then poured on to ice. The mixture was acidified to pH 2 with hydrochloric acid (5N). The solid product was collected, dried and recrystallised from ethyl acetate:diethyl ether to give the novel compound 1-(2-amino-4-trifluoromethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 200°-201°.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)Nc4ccccc4)cc3Cl)c2n1
Yield: 87.7 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (275 mg) was suspended in toluene (10 ml), and phenyl isocyanate (218 mg) was added at room temperature. The mixture was refluxed under heating for 5 hr and concentrated under reduced pressure. Hexane (20 ml) was added, and the mixture was heated and allowed to cool. The precipitated crystals were collected by filtration. The crystals were suspended in ethyl acetate (10 ml), heated and allowed to cool. The precipitated crystals were collected by filtration and dried under reduced pressure and by heating to give the objective compound (328 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:10](=[O:26])[N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][N:15]=[C:14](Cl)[N:13]=1.[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.FC(F)(F)C(O)=O>C(O)(C)C>[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:14]2[N:13]=[C:12]([N:11]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:10](=[O:26])[O:9][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH3:8])[CH:17]=[CH:16][N:15]=2)=[CH:34][CH:33]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: Cc1cccc(C)c1OC(=O)N(Cc1ccccc1)c1ccnc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Cc1cccc(C)c1OC(=O)N(Cc1ccccc1)c1ccnc(Nc2ccc(OCCN(C)C)cc2)n1
Temperature: 100 °C

Procedure:
A resealable tube was charged with the benzyl-(2-chloropyrimidin-4-yl)carbamic acid 2,6-dimethylphenyl ester (0.093 g, 0.253 mmol), 4-(2-dimethylaminoethoxy)-phenylamine (0.050 g, 0.278 mmol), and isopropanol (4 mL). Trifluoroacetic acid (0.072 g, 0.049 mL, 0.633 mmol) was added and the system was flushed with argon. The tube was sealed and the mixture was heated at 100° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated to afford a pale purple oil. The oil was purified via column chromatography (gradient elution with 0-100% dichloromethane-(90: 10:1, dichloromethane/methanol/ammonium hydroxide)) to afford 2,6-dimethylphenyl 2-((4-((2-(dimethylamino)ethyl)oxy)phenyl)amino)-4-pyrimidinyl(phenylmethyl)carbamate as a white solid. MS (MH+) 512.3; Calculated 511.62 for C30H33N5O3.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[NH:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[N:11]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCNN12
Reactant: COC(=O)CCBr
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN1CCCC2(Cc3ccc(Br)cc3)C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)N12

Procedure:
The compound from Example 100 (80 mg) was dissolved in methyl 3-bromopropanoate (0.5 mL) and DIEA (0.089 mL) and heated at 73° C. for 3 days. The reaction mixture was concentrated and purified by chromatography (silica gel; EtOAc/hexanes; chromatotron) to give the titled compound (38 mg). MS (m/z) 557 (MH+); mp. 157° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8]2)C=C.O.C(OCC)(=O)C.CN(C)[C:27]1[CH:32]=CC=C[CH:28]=1>>[CH2:32]([C:6]1[C:5]([OH:4])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10]([CH3:16])([CH3:17])[C:11]2=[O:15])[CH:27]=[CH2:28]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc2c(c1)CCC(C)(C)C2=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(O)ccc2c1CCC(C)(C)C2=O
Temperature: 25 °C

Procedure:
1.69 g of 6-(allyloxy)-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one was dissolved in 10 ml of N,N-dimethylaniline, and the obtained mixture was heated to reflux under nitrogen atmosphere for 7 hours. The reaction solution was cooled to a room temperature. Water and ethyl acetate were added to the reaction solution, so as to obtain an organic layer. The obtained organic layer was successively washed with 5 N hydrochloric acid (3 times), water (4 times), and a saturated sodium chloride solution. The resultant product was then dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. Hexane was added to the residue, and the precipitate was then collected by filtration, so as to obtain 1.06 g of the subject compound.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.O[N:19]1[C:24](=[O:25])[CH2:23][CH2:22][C:20]1=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:2]([C:7]([O:9][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][C:20]1=[O:21])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Boc-Leu-OH.H2O (49.9 g, 0.2 M) and HOSu (23.0 g, 0.2 M) were dissolved in THF (300 ml) in a 1 lit. round flask. DCC (41.3 g, 0.2 M) in THF (200 ml) solution was added dropwise at -10° C. for about 10 minutes and the mixture was stirred at room temperature overnight. Precipitated DCU was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate (300 ml), washed with 1 N-HCl, NaCl solution and a small amount of water and dried with anhydrous sodium sulfate. After removal of the drying agent, the solution was concentrated, and n-hexane was added thereto to obtain Boc-Leu-OSu as a colorless powder (m.p. 106°-110° C., 59.11 g, yield: 90%).
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]([O-:18])=[O:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31]>CN(C)C=O>[O:31]=[C:27]1[N:26]([CH2:25][CH2:24][O:17][C:16](=[O:18])[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH2:30][CH2:29][O:28]1
Reactant: O=C([O-])c1ccccc1Nc1ccnc2cc(Cl)ccc12
Reactant: O=C1OCCN1CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCOC1=O)c1ccccc1Nc1ccnc2cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A mixture comprising 12.8 g of N-(7-chloro-4-quinolyl)-anthranilic acid sodium salt, 6.64 g of 90% 3-(β-chloroethyl)-oxazolidine-2-one and 80 ml of dimethylformamide was heated under stirring at 120° C. for five hours. Upon completion of the reaction, the mixture was cooled, filtered, and the solvent eliminated in vacuo. To the residue, 80 ml of ether were added and the solid thus obtained was collected on filter and purified by chromatography on a silica gel column using ethyl acetate as eluent. The desired product was crystallized from isopropanol to give 11.2 g of N-(7-chloro-4-quinolyl)-anthranilic acid β-(2-oxo-3-oxazolidinyl)-ethyl ester, melting at 122°-124° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:11][C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(I)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
4-Iodo-2-nitro-benzoic acid (20 g, 68 mmol, 1.0 equiv.) was dissolved in 200 mL of EtOAc and then SnCl2.2H2O (46 g, 204 mmol, 3.0 equiv.) was added in three portions. The reaction mixture was stirred at rt for 16 h. Satd. aq. NaHCO3 was carefully added to adjust the mixture to pH=9. The precipitated solid was removed by filtration through diatomaceous earth, washing with water. The aqueous layer in the filtrate was separated and acidified with conc. HCl to pH=2. The precipitated solid was collected by filtration and dried to afford the title compound as white solid (19 g, 68 mmol, 100%). 1H NMR (400 MHz, CD3OD): 1H NMR (500 MHz, CDCl3): 7.56 (d, J=8.5, 1H), 7.08 (s, 1H), 6.99 (d, J=8.5, 1H), 5.71 (br s, 2H).