Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CCCCCC.CN(C)[CH:23]=[O:24].Cl>O1CCCC1.CCOCC>[Cl:9][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH:23]=[O:24])=[C:6]([F:8])[CH:5]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 3,5-difluoro-1-chlorobenzene (5.0 g, 34 mmol) in tetrahydrofuran (70 mL) at −78° C. was added a solution of n-butyllithium in hexane (12.1 mL, 2.5 M, 30 mmol). After stirring for 1 hour, dimethylformamide (5.2 mL, 67 mmol) was added, and the mixture was stirred for 1.5 hours. The mixture was warmed to ambient temperature, diluted with ether and poured into 150 mL of 0.5 M aqueous HCl. The aqueous phase was extracted 3× into ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo, affording 5.72 g (96%) of 4-chloro-2,6-difluoro-benzaldehyde as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 7.04 (d, 2H, J=7.9 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33][C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:39][O:40][CH:41]([CH3:43])[CH3:42].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33]/[C:34](=[N:39]/[O:40][CH:41]([CH3:43])[CH3:42])/[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CC(C)ON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(C)=N/OC(C)C)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[C:21](=O)([O-])O.[Na+].C(OCC)(=O)C>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH2:12][C:13]([O:15][CH3:21])=[O:14]
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1c(F)cc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)Cc1c(F)cc([N+](=O)[O-])cc1F
Yield: 97 %

Procedure:
A solution of 2-(2,6-difluoro-4-nitrophenyl)acetic acid (27.90 g, 128.5 mmol) and conc. sulfuric acid (1.0 mL) in MeOH (260 mL) was heated under reflux for 18 hr. The reaction mixture was neutralized with aqueous sodium hydrogencarbonate solution, and ethyl acetate and water were added thereto. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→100% ethyl acetate/hexane) to give methyl 2-(2,6-difluoro-4-nitrophenyl)acetate (28.71 g, 128.5 mmol, 97.0%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10](=[O:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][C@@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)c(C#N)c2)[C@@H](CO)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2)[C@@H](CO)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3R)-4-[2-(3-cyano-4-fluorophenyl)-2-oxoethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (20 g, 0.053 mol) in MeOH (400 mL) was added partionwise NaBH4 (15.6 g, 0.424 mol) at 0° C. and the mixture was stirred at r.t overnight. The reaction mixture was added water, extracted with EtOAc. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give the title compound.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[I:5][C:6]1[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)(O)[O-].[K+].CN(C=O)C>C(Cl)Cl.O>[I:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:2][CH2:3][CH3:4])=[CH:10][N:11]=1
Reactant: CCCI
Reactant: Oc1ccc(I)nc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCCOc1ccc(I)nc1
Temperature: 80 °C

Procedure:
Iodopropane (0.18 mL, 1.8 mmol) was added dropwise to a mixture comprising 6-iodopyridin-3-ol (0.32 g, 1.14 mmol), potassium bicarbonate (0.23 g, 1.7 mmol) and DMF (2 mL). The mixture was heated at 80° C. for 1 hour, cooled and diluted with methylene chloride and water. The aqueous layer was separated and extracted with methylene chloride (20 mL). The combined organic layers were washed with water 30 mL, dried (MgSO4) and concentrated under reduced pressure to provide 2-iodo-5-propoxypyridine. MS (ESI); Calculated for C8H10NIO, 266.1, Found (MH+): 222.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([OH:18])[C:14](=[O:19])[C:13]=2[CH:20]=1.[H-].[Na+].[CH3:23]I.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([O:18][CH3:23])[C:14](=[O:19])[C:13]=2[CH:20]=1
Reactant: O=c1c(O)coc2ccc(OCCCCCCCl)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1coc2ccc(OCCCCCCCl)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone (32 g) and benzaldehyde (12 g) was dissolved in 250 mL of ethanol. A solution of 24 g of sodium hydroxide dissolved in 40 mL of water was added. This mixture was allowed to stand at room temperature for 6 hours. A solution of 8 g of sodium hydroxide dissolved in 40 mL of water was added, the solution was cooled to 15°-20° C., and then 20 mL of hydrogen peroxide (30% solution) was added and the solution was allowed to warm to room temperature and was stirred overnight. Then the solution's pH was adjusted to 3 using hydrochloric acid. The yellow precipitate was collected by vacuum filtration and washed with water, ethanol, and ether to give 16 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one. Next, 10 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one was dissolved in 100 mL of tetrahydrofuran. Then 800 mg of sodium hydride was added followed by 8.3 mL of methyl iodide and the resulting solution was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and then with brine. After drying over sodium sulfate, the solvent was removed to give 8 g of 6-(6- chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](Cl)=[N:6][CH:7]=1.[C:10](#[N:12])[CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([CH2:11][C:10]#[N:12])=[N:6][CH:7]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1ncc(Br)cc1Cl
Yield: 84.9 %

Procedure:
27.0 g of 5-bromo-2,3-dichloropyridine was dissolved in 450 ml of anhydrous tetrahydrofuran and 7.33 g of acetonitrile was added at ambient temperature under argon. 262 ml of lithium hexamethyldisilazide (1N solution in tetrahydrofuran) was added dropwise over a period of 45 min, during which the temperature rose to 35° C. Subsequently, the reaction mixture was stirred at ambient temperature for 1h, then the reaction mixture was poured into 800 ml of cold water and was extracted with two 1 L portions of diethyl ether. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. 29.4 g of crude material was obtained as a brown oil. It was purified by chromatography on silica gel, using heptane/ethyl acetate (9:1) as a eluent. Thus, 23.4 g of (5-bromo-3-chloro-pyridin-2-yl)-acetonitrile was obtained as a orange oil. 1H-NMR (CDCl3): 8.60 ppm (s, 1H), 7.92 ppm (s, 1H), 4.00 ppm (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:28])([CH3:27])[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:18])[CH:12]=[CH:13][C:14]=1[F:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:28])([CH3:27])[CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[OH:18])[CH:12]=[CH:13][C:14]=1[F:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1C(=O)C(C)(C)c1ccc(F)c(NC(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(O)C(C)(C)c1ccc(F)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a mixture of 2-[3-(tert-butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propanone (0.59 g) in tetrahydrofuran (7.5 mL)-water (0.75 mL) was added sodium borohydride (0.17 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 2-[3-(tert -butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propanol (0.54 g). This material was dissolved in ethanol (8 mL)-tetrahydrofuran (3 mL). To the solution were added 2 mol/L hydrochloric acid (0.2 mL) and 10% palladium-carbon powder (0.27 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. To the reaction mixture was added sodium hydrogen carbonate, and the mixture was stirred for 10 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/1) to give 2-[3-(tert -butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methylpropane (0.15 g). To this material was added hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.11 g).
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18](OC)=[O:19])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:25][NH2:26]>CCO>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]3[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][C:17]=4[C:18](=[O:19])[NH:26][N:25]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: COC(=O)c1ccncc1C(=O)c1ccc(-n2ccnc2)cc1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2cnccc12

Procedure:
A solution of 0.43 g (1.4 mmol) of 3-[4-(1H-imidazol-1-yl)benzoyl]-4-carbomethoxypyridine in 50 mL of EtOH is treated with hydrazine monohydrate (0.08 g, 1.54 mmol) and heated to reflux for 1 day. The mixture is allowed to cool and the white solid precipitate filtered and dried to produce 4-[4-(1H-imidazol-1-yl)phenyl]-1-oxo-1,2-dihydropyrido[3,4-d]pyridazine. M.P. 377° C. dec.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:35][O:36][CH3:37])=[C:13]([CH:32]=[N:33][OH:34])[N:14]=[CH:15][C:16]=1[N:17]2S(C1C=CC(C)=CC=1)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)C[CH2:41][C:40]1=O.C[Si](C#C)(C)C.[OH-].[Na+]>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:35][O:36][CH3:37])=[C:13]([C:32]3[CH:41]=[CH:40][O:34][N:33]=3)[N:14]=[CH:15][C:16]=1[NH:17]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1c(C=NO)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCc1c(-c2ccon2)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
103 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carbaldehyde oxime is combined in 5 ml of methylene chloride with 22 mg of N-chlorosuccinimide and agitated for one hour at room temperature. Subsequently 30 mg of trimethylsilylacetylene and 0.13 ml of triethylamine are added and the mixture stirred for 2 hours at room temperature. The mixture is then combined with 1 ml of 1N sodium hydroxide solution and agitated for one hour at room temperature, poured on 25 ml of water, extracted with 25 ml of methylene chloride, and the organic phase is dried, filtered, and concentrated. The residue is refluxed for 1.5 hours in 15 ml of methanol with 54 mg of sodium methylate. After concentration, the mixture is taken up in 25 ml of water and extracted with ethyl acetate. After drying and filtration, the organic phase is concentrated and the residue is chromatographed over silica gel with toluene+ethyl acetate in a ratio of 1:1 as the eluent.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1.ClCCl.CO>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:19][CH2:20]3)=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.4.). Starting with 1.50 g (3.43 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{5-[3-(trifluoromethyl)phenyl]-2-pyridyl)-1-piperazine-carboxylate, obtained in step 3.4., and 8.6 ml (17.15 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 1.18 g of product are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[NH2:5].[CH3:17][CH:18]([C:24]([CH3:26])=O)[C:19](OCC)=[O:20].ClC1C(OC2C=CC(Cl)=CC=2)=CC=C2C=1C(O)=C(C)C(C)=N2>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:19]([OH:20])=[C:18]([CH3:17])[C:24]([CH3:26])=[N:5]2)=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cc1nc2ccc(Oc3ccc(Cl)cc3)c(Cl)c2c(O)c1C
Solvent: CCO
Product: Cc1nc2cc(Cl)c(Oc3ccc(Cl)cc3)cc2c(O)c1C
Temperature: 150 °C
Yield: 93 %

Procedure:
A mixture composed of 2.2 g of 3-chloro-4-(4-chlorophenoxy)-aniline, 2.63 g of ethyl 2-methylacetoacetate, and 0.5 mL of ethanol was added dropwise to 3.8 g of polyphosphoric acid heated to 150° C. The mixed solution was stirred at 150 to 160° C. while removing ethanol by evaporation for 3 hr. The reaction solution was poured into 175 mL of iced water containing 2 mL of concentrated hydrochloric acid to produce crystals. The crystals were collected by filtration and were recrystallized from water/methanol to give 2.8 g of a mixture of 5-chloro-6-(4-chlorophenoxy)-4-hydroxy-2,3-dimethyl-quinoline with 7-chloro-6-(4-chlorophenoxy)-4-hydroxy-2,3-dimethyl-quinoline (yield 93%). The mixture (2.8 g) was stirred in 42 mL of acetic anhydride with heating at 120 to 125° C. for one hr. The reaction solution was concentrated, ethyl acetate was then added to the concentrate, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and the solvent was removed under the reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 1.03 g of 4-acetoxy-5-chloro-6-(4-chlorophenoxy)-2,3-dimethyl-quinoline (yield 32.6%) and 0.68 g of 4-acetoxy-7-chloro-6-(4-chlorophenoxy)-2,3-dimethyl-quinoline (yield 21.0%).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8]O)(=[O:6])[O:4][CH3:5].N1C(C)=CC=CC=1C.[F:18][C:19]([F:32])([F:31])[S:20]([O:23]S(C(F)(F)F)(=O)=O)(=[O:22])=[O:21]>ClCCl>[CH3:1][O:2][P:3]([CH:7]([O:23][S:20]([C:19]([F:32])([F:31])[F:18])(=[O:22])=[O:21])[CH3:8])([O:4][CH3:5])=[O:6]
Reactant: COP(=O)(CCO)OC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COP(=O)(OC)C(C)OS(=O)(=O)C(F)(F)F
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of (2-hydroxy-ethyl)-phosphonic acid dimethyl ester (0.250 g, 1.62 mmol) in dichloromethane (4 mL) was added 2,6-lutidine (0.284 mL, 2.44 mmol). The reaction mixture was cooled to −40° C. and trifluoromethanesulfonic anhydride (0.355 mL, 2.11 mmol) was added. The mixture stirred in the cold bath under an inert atmosphere for 2 hours at which point the reaction was completed as shown by 31P NMR (CDCl3) δ 25.7. The mixture was partitioned between dichloromethane and water both cooled by an ice-water bath. The organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo to afford trifluoromethanesulfonic acid dimethoxy-phosphoryl-2-ethyl ester 185 as an oil which was immediately carried forward with no further purification or characterization.
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([I:17])[C:15]=1[OH:16])[CH:11]=[O:12])[CH3:6].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([I:17])[C:15]=1[O:16][CH2:2][O:3][CH3:4])[CH:11]=[O:12])[CH3:6]
Reactant: COCCl
Reactant: CCOc1cc(C=O)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)cc(I)c1OCOC

Procedure:
Chloro(methoxy)methane (6.27 mL) was added to a mixture of 3-ethoxy-4-hydroxy-5-iodobenzaldehyde (16.1 g), potassium carbonate (15.2 g), and DMF (120 mL), and the resultant mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (12.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH:69]2[CH2:74][CH2:73][CH2:72][CH2:71][NH:70]2)[CH:64]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:70]1[CH2:71][CH2:72][CH2:73][CH2:74][CH:69]1[C:65]1[CH:64]=[N:63][CH:68]=[CH:67][CH:66]=1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: c1cncc(C2CCCCN2)c1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3c3cccnc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(pyridin-3-yl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(OC(C)(C)C)=O.[ClH:45].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:45].[NH2:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-phenylalanineamide (1,082 mg, 1.11 mmols) was dissolved in 10 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at room temperature for 1 hour. One-hundred milliliters of diethyl ether were added thereto, and the resulting mixture was filtered. The thus-obtained powder was recrystallized from a mixture of chloroform, methanol and ethyl acetate at a ratio of 4:1:4 to produce 450 mg (0.859 mmols) of the final compound in a yield of 77%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:13][Mg]Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:11][CH2:12]2)([OH:9])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: C[Mg]Cl
Reactant: O=C(c1ccnc(Cl)n1)C1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)(c1ccnc(Cl)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanone (175 mg, 0.958 mmol) in THF (3 mL) at −78° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in diethyl ether, 0.380 mL, 1.15 mmol) dropwise. The solution was warmed to room temperature and stirred for an additional 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford 1-(2-chloropyrimidin-4-yl)-1-cyclopropylethanol (115 mg, 0.579 mmol, 60% yield). MS ESI: [M+H]+ m/z 199.1. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=5.2, 1H), 7.43 (d, J=5.2, 1H), 3.43 (s, 1H), 1.52 (s, 3H), 1.26 (m, 1H), 0.60 (m, 1H), 0.50 (m, 1H), 0.40 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:10])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.O.[SH-:12].[Na+]>>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[SH:12]
Reactant: [SH-]
Reactant: [O-][n+]1cc(Cl)c(Cl)c(Cl)c1
Agent: [Na+]
Solvent: O
Product: [O-][n+]1cc(Cl)c(S)c(Cl)c1

Procedure:
Prepared according to the procedure described for example 17 from 3,4,5-trichloro-1-oxido-pyridin-1-ium (0.75 g, 3.8 mmol) and sodium hydrosulfide hydrate (0.38 g, 4.57 mmol). The title compound was obtained as a brown solid (0.52 g, 70% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.89 (2H, s). MS m/z: 195.9 [M+H]+.