Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].C(=O)=O.Br[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])=[O:8]>C(Cl)Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]=2[NH:9][C:7](=[O:8])[CH2:6][N:1]=1
Reactant: O=C(CBr)Nc1ccc(I)cc1C(=O)c1ccccc1Cl
Reactant: N
Agent: O=C=O
Solvent: ClCCl
Product: O=C1CN=C(c2ccccc2Cl)c2cc(I)ccc2N1
Yield: 89 %

Procedure:
Bromoacetyl bromide, 15 ml, was added to a solution of 52 g (0.145 mol) of (2-amino-5-iodophenyl)(2-chlorophenyl) methanone in 300 ml of methylene chloride cooled to 0° C. A 10% aqueous solution of sodium carbonate, 150 ml, was added slowly with stirring and the two phase system was stirred in the cold for 30 minutes. The organic layer was separated, washed with water and dried over sodium sulfate. The solution was filtered and evaporated. Crystallization of the residue from methylene chloride/ether yielded 61 g (90%) of 2-bromo-N-[2-(2-chlorobenzoyl)-4-iodophenyl]acetamide with m.p. 150°-152° C. A solution of 50 g of this material in 1 liter of methylene chloride was added to 800 ml of liquid ammonia with dry-ice cooling. After refluxing for 16 hours, the cooling was discontinued and the ammonia was allowed to evaporate. The remaining solution was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 1 liter of ethanol and the solution was heated to reflux for 30 minutes after the addition of 15 ml of acetic acid. The crystals separated from the cooled reaction mixture were collected to leave 38 g (89%) of 5-(2-chlorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one which melted at 260°-262° C. after recrysyallization from tetrahydrofuran/ethanol.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.C([N:16](C(C)C)CC)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)(=O)C>Cl.C(O)(C)(C)C.C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[NH2:16]
Reactant: COc1cccc(C(=O)O)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1cccc(N)c1F
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of 2-fluoro-3-methoxybenzoic acid (5.00 g, 29.39 mmol) and diisopropylethylamine (4.56 g, 35.27 mmol) in a mixture of anhydrous toluene (25 mL) and anhydrous tert-butanol (25 mL) was stirred over activated 4 A molecular sieves (4 g) for 1 h. Diphenyl phosphoryl azide (9.71 g, 35.27 mmol) was added and the mixture was heated at reflux for 15 h. The reaction mixture was cooled and filtered. To the filtrate was added ethyl acetate (200 mL) and the solution was washed with water (2×100 mL) and brine (100 mL). The organic phase was separated and dried over MgSO4. Filtration followed by concentration under reduced pressure gave crude tert-butyl 2-fluoro-3-methoxyphenylcarbamate. The crude product was dissolved in a solution of 6M HCl in ethyl acetate (20 mL, 0.12 mol) and the mixture stirred at rt for 2 h. The resulting precipitate was filtered and dried. The solid was taken up in a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and the mixture extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-fluoro-3-methoxyaniline (3.00 g, 72%) as brown oil, which was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.80-7.02 (m, 3H), 3.82 (s, 3H); LC-MS (ESI) m/z 142 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([OH:16])([C:14]#[CH:15])[CH3:13]>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:14]([C:12]([OH:16])([CH3:13])[CH3:11])=[CH:15][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(O)c1cnnn1Cc1ccccc1

Procedure:
Benzyl azide (0.400 g, 3.00 mmol), 2-methyl-3-butyn-2-ol (0.290 ml, 3.00 mmol), Cp*RuCl(PPh3)2 (25 mg, 0.031 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 2.5 hours; yield, 0.63 g (96%). EI-MS: m/z 218 [M+1 ].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:39])=[O:33])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCCCCC(=O)O)cc23)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCCCc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.5 %

Procedure:
To a solution of 6-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]hexanoic acid (885 mg, 1.71 mmol) and potassium carbonate (469 mg, 3.39 mmol) in N,N-dimethylformamide (40 ml) was added methyl iodide (291 mg, 2.05 mmol), and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give methyl 6-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]hexanoate (870 mg, yield 96%) as white crystals. Subsequently, methyl 6-[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]hexanoate was synthesized by a method similar to the method shown in Example 32(2).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:14]=[CH:13][C:10](C#N)=[CH:9][CH:8]=1)[CH2:4][CH2:5][Cl:6])[CH3:2].[C:15](=[O:18])([O-])[O-:16].[Na+].[Na+]>C(O)C.Cl>[CH2:1]([N:3]([C:7]1[CH:14]=[CH:13][C:10]([C:15]([OH:16])=[O:18])=[CH:9][CH:8]=1)[CH2:4][CH2:5][Cl:6])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCN(CCCl)c1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCN(CCCl)c1ccc(C(=O)O)cc1
Yield: 40 %

Procedure:
To a solution of 2.5 g (12.0 mmol) of 4-[N-ethyl,N-(2-chloroethyl)amino]benzonitrile in 25 ml of ethanol, 25 ml of concentrated hydrochloric acid were added, followed by reflux under heat for 12 hours. The reaction mixture was allowed to cool down. Sodium carbonate was then added to basify the solution, followed by washing with chloroform. The water layer was acidified with concentrated hydrochloric acid and then extracted with chloroform. The solvent was distilled out under reduced pressure, followed by washing with IPA, whereby 1.1 g of white powder were obtained (yield: 40%).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH3:23])=[N:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][N:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][N:20]=2)[CH3:23])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CNc1ccc(F)cn1
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1CN(C)c1ccc(F)cn1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 22 from methyl 2-(bromoethyl)-5-chlorobenzoate and 5-fluoro-N-methylpyridin-2-amine (step 1):
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][O:9]2)=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1ccoc2cc(O)ccc12
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(c1)OCCC2
Reaction time: 48 h
Yield: 95 %

Procedure:
To a 1000 mL round bottomed flask, 0.15 mol of 7-hydroxychromone, and then 2.50 g of 5% palladium carbon and 300 mL of ethanol were added. Subsequently, hydrogen was passed into the flask, and the reaction was carried out for 48 hours at 50° C. Palladium carbon was removed by sucking filtration, and ethanol was removed by rotary evaporation. Then 21.39 g of 7-hydroxychroman was obtained, with a yield of 92.4% and MS m/z (M)150.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](OCC)=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[OH:16][CH2:15][C:12]1[N:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(CO)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a stirred solution of ethyl 5-(tert-butoxycarbonylamino)picolinate (112; 8.9 g, 24.0 mmol) in ethyl ether (200 mL) was added LiAlH4 (1.80 g, 48 mmol) in ethyl ether (100 mL) over a period of 30 min at 0° C. The resulting reaction mixture was stirred at 0° C. for 3 h and then carefully quenched by carefully adding water (1.0 mL) and 10% NaOH solution (2.0 mL). The mixture was filtered; the filtrate was dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl 6-(hydroxymethyl)pyridin-3-ylcarbamate 113 (4.20 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(O)(=O)C>N1C=CC=CC=1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 72 %

Procedure:
A mixture of 4-aminophenol (27 g, 0.25 mole) and 4-nitrobenzenesulfonyl chloride (55 g, 0.25 mole) in pyridine (500 ml) was heated under reflux for 4 hours. The reaction mixture was poured in ice water and acidified with acetic acid. The crude product weighed 86 g. Recrystallization from CH3NO2 provided 53 g (73%) of material used in Part B; m.p. 197°-198°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:22])[N:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1c(F)cccc1Cl
Product: O=C(NCc1c(F)cccc1Cl)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-chloro-6-fluorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](Cl)=[O:17]>>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:17]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(Br)c1

Procedure:
3-Bromo-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide was synthesized from 3-trifluoromethylaniline and 3-bromo-4-fluorobenzoyl chloride according to the procedure described in Example 183, affording the title compound as a white solid. MS (M−H+) 360.0; Calculated for C14H8BrF4NO: 361.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O>[Fe].CCO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(I)cc1OCc1ccccc1
Temperature: 100 °C

Procedure:
To a mixture of 2-benzyloxy-4-iodo-1-nitrobenzene (2.35 g, 6.62 mmol) and Fe (1.85 g, 33.1 mmol) is added AcOH (24 mL) and EtOH (12 mL) and it is refluxed at 100° C. for 1.5 h. The mixture is then cooled and filtered through Celite. EtOAc (300 mL) is added and it is then washed with sat. NaHCO3 (2×), brine (1×) and dried with NaSO4. It is then concentrated and the residue is purified by column chromatography to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.CN(C)[CH:22]=[O:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH:12]=[CH:13][C:14]=1[CH:22]=[O:23])([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: CCN(CC)c1cccc([N+](=O)[O-])c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
38 parts of m-nitrodiethylaniline is introduced into a mixture of 48 parts of phosphorus oxychloride in 120 parts of dimethylformamide. After having been stirred for six hours at 60°C the mixture is poured into ice-water and the precipitate is suction filtered, washed free from acid and recrystallized from acetone. 12 parts (27% of theory) of 2-nitro-4-diethylaminobenzaldehyde having a melting point of 75° to 77°C is obtained. ##SPC15##
Reaction SMILES: [CH3:1][O:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH:4]=[O:5].C[Si]([C:22]#[N:23])(C)C.C([O-])(O)=O.[Na+]>CCOCC.CCOC(C)=O.O.[Zn+2].[I-].[I-]>[OH:5][CH:4]([CH:3]([O:2][CH3:1])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)[C:22]#[N:23]
Reactant: C[Si](C)(C)C#N
Reactant: COC(C=O)c1ccc(N2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: COC(c1ccc(N2CCOCC2)cc1)C(O)C#N
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 94.2 %

Procedure:
To a solution of 2-methoxy-2-(4-morpholinophenyl)acetaldehyde (1.27 g, ˜5.1 mmol) in Et2O (35 mL) under a drying tube was added trimethylsilyl cyanide (1 mL, 8 mmol) and ZnI2 (50 mg, 0.16 mmol). After stirring at room temperature for 15.5 hrs, saturated aqueous NaHCO3 was added and the mixture was stirred several hrs. The mixture was diluted with EtOAc and H2O and the layers were separated. The organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 2-hydroxy-3-methoxy-3-(4-morpholinophenyl)propanenitrile as an orange foam (1.26 g). The product was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH:16]([C:24]([O:26]CC)=[O:25])[N:17]2[CH:21]=[CH:20][CH:19]=[C:18]2[CH:22]=[O:23])[C:7]=1[C:31]([O:33]C(C)(C)C)=[O:32])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH:16]([C:24]([OH:26])=[O:25])[N:17]2[CH:21]=[CH:20][CH:19]=[C:18]2[CH:22]=[O:23])[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12)n1cccc1C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)n3cccc3C=O)C2SC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-[(Acetyloxy)methyl]-7-[[2-carboethoxy-2-(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, tert-butyl ester, 0.05 m, is added to 50 ml of trifluoroacetic acid which is maintained at 0° C. The reaction mixture is stirred at 0° C. for 15 minutes and then at 10° C. for 15 minutes. The trifluoroacetic acid is removed in vacuo, the temperature of the mixture not rising above 20° C. The residue was taken up in methanol-water (4:1) and the pH adjusted to about 4 with ammonium hydroxide. The precipitate is filtered and the filtrate is concentrated and cooled to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].Cl>ClCCl>[F:8][C:7]1[C:2]([F:1])=[C:3]2[C:4]([CH:22]=[C:21]([Si:18]([CH3:20])([CH3:19])[CH3:17])[C:10]([OH:11])=[CH:9]2)=[CH:5][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(Cl)Cc1cccc(F)c1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[Si](C)(C)c1cc2ccc(F)c(F)c2cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 50.0 g (0.26 mol) of 2,3-difluorophenylacetyl chloride in 100 ml of dichloromethane is slowly added to a suspension of 71.5 g (0.53 mol) of aluminium(III) chloride in 300 ml of dichloromethane at −20° C. After 30 min at this temperature, trimethylsilylacetylene is metered in, and the mixture is stirred for 30 min. The batch is added to ice-water and acidified using hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed successively with sat. sodium hydrogencarbonate soln. and sat. sodium chloride soln. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:ethyl acetate=9:1), giving 7,8-difluoro-3-trimethylsilanylnaphthalen-2-ol as a brown oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN1CCCC1=O.[CH2:17]([C@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1)[CH3:18].[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[N:40]=[C:39]3[C:35]([N:36]=[C:37](Cl)[N:38]3[CH2:41][C:42]([F:45])([F:44])[F:43])=[C:34]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[N:33]=2)=[CH:28][N:27]=1>O>[CH2:17]([C@@H:19]1[NH:20][CH2:21][CH2:22][N:23]([C:37]2[N:38]([CH2:41][C:42]([F:43])([F:45])[F:44])[C:39]3[C:35]([N:36]=2)=[C:34]([N:47]2[CH2:48][CH2:49][O:50][CH2:51][CH2:52]2)[N:33]=[C:32]([C:29]2[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=2)[N:40]=3)[CH2:24]1)[CH3:18]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Reactant: CC[C@H]1CNCCN1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 100 °C
Reaction time: 96 h
Yield: 81.9 %

Procedure:
Diisopropylethylamine (1.48 ml, 8.49 mmol) was added to an N-methyl-2-pyrrolidone suspension (4 ml) of 2-(S)-ethylpiperazine 2 hydrochloride (529 mg, 2.83 mmol) and 2-(2-aminopyrimidin-5-yl)-8-chloro-6-(morpholin-4-yl)-9-(2,2,2-trifluoroethyl)-9H-purine (391 mg, 0.94 mmol) and the resulting mixture was stirred at 100° C. for 4 days. Water was added to the reaction mixture and the resulting mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform:methanol=97:3 to 90:10) to give the title compound (379 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][NH:7][CH2:6]1)=[O:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:22][C:21]([F:23])([F:24])[C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][C:11]=1[CH2:10][N:7]1[CH2:8][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of methylazetidine-3-carboxylate (5 g) and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (13.3 g) in DMF (100 mL) was added potassium carbonate (7.20 g) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (5.45 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[CH3:2].CN(C=O)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CCCCOc1ccc2c(c1)CCCN2
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1ccc2c(c1)CCCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 39 %

Procedure:
To 70 mg (0.25 mmol) Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine in 1.4 ml DMF 87 μl (0.5 mmol) Huenig's base and 54 μl (0.38 mmol) benzyl chloroformate were added. The solution was stirred at RT over night, was concentrated and the residue was dissolved in ether and 0.1M NaOH. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 5:1 yielded 40 mg (38%) 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester as light yellow oil, MS: 411 (MH+).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6](O)[C:5]=1[CH3:11])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[C:5]([CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=[CH:8][N:7]=1
Reactant: Cc1c(O)ncnc1C(C)C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(Cl)ncnc1C(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
To 6-isopropyl-5-methylpyrimidin-4-ol (0.25 g, 1.6 mmol) was added neat phosphorous oxychloride (5 mL) and the mixture stirred at 70° C. for 3 h. After cooling to room temperature the solution was concentrated, diluted with water then neutralized by portionwise addition of saturated sodium carbonate solution. The aqueous mixture was extracted with ethyl acetate and the organic solution washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration provided 4-chloro-6-isopropyl-5-methylpyrimidine (30 mg, 11% yield) as a brown oil that was used without further purification. MS (EI) for C8H11ClN2: 170 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C2C=C(Cl)C=CC=2F)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O>C1COCC1>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(Cl)ccc1F)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-fluorophenyl]benzenesulfonamide (500 mg, 1.56 mmol), triphenylphosphine (859 mg, 3.28 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pentanol (682 mg, 3.12 mmol) in THF (7 mL) was added diisopropylazodicarboxylate (0.645 mL, 3.28 mol) dropwise at 0° C. under nitrogen. The resulting mixture was allowed to warm to 22° C. with stirring. Stirring was continued for a period of 12 h followed by the addition of 15 mL of H2O. The mixture was extracted with ether (3×15 mL). The combined organic extracts were washed with NaHCO3 and sat. brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 495 mg of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4-[(1,1-dimethylethyl)-dimethylsilyl]oxy)butyl]benzenesulfonamide as a yellow oil in 61% yield.