Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]2[CH:38]=[CH:37][C:20]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([F:36])[CH:24]=3)=[CH:19][CH:18]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH2:16][C:17]2[CH:38]=[CH:37][C:20]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([F:36])[CH:24]=3)=[CH:19][CH:18]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(C(C)(C)C)cc3-c3ccccc3)cc2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2ccccc2)n(Cc2ccc(CNc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a solution of ethyl 3-[4-({4-[(3-tert-butyl-5-phenyl-1H-pyrazol-1-yl)methyl]benzyl}amino)-2-fluorophenyl]propanoate (150 mg, 0.29 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (91 mg, yield 65%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][O:36][C:37]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH2:43][CH2:44][CH:39]([C:37]([O:36][CH3:35])=[O:38])[CH2:40][CH2:41]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: COC(=O)C1CCNCC1
Product: COC(=O)C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
Methyl 1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylate was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Piperidine-4-carboxylic acid methyl ester following General Procedure C.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:17][CH:18]=1.C(N(CC)CC)C>CN(C)C=O.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[Pd]Cl.[Cu]I>[CH2:20]([O:19][C:16]1[N:17]=[CH:18][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1)[CH2:21][CH2:22][CH3:23]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCCCOc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C#CC2(O)CN3CCC2CC3)cn1
Temperature: 90 °C
Yield: 25.2 %

Procedure:
A stirred mixture of 3-ethynyl-3-hydroxyquinuclidine (600 mg), 5-bromo-2-n-butoxypyridine (920 mg), bis-(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and dry triethylamine (10 ml) in dry dimethylformamide (20 ml) was heated at 90° C. under an atmosphere of argon for 6 hours. The reaction mixture was cooled and the dimethylformamide and triethylamine were removed by evaporation. The residue was treated with 2M aqueous sodium hydroxide solution (20 ml) and the resulting mixture extracted with dichloromethane (3×20 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give a brown residue which was crystallised from acetonitrile to yield 3-[2-(6-butoxy-3-pyridyl)ethynyl]quinuclidin-3-ol (300 mg) as a solid, m.p. 149°-151° C.; microanalysis, found: C, 71.3; H, 7.9; N, 8.9%; C18H24N2O2 0.1H 2O requires: C, 71.47; H, 8.08; N, 9.26%; NMR (DHSOd6): 0.9-1.0(3H, t), 1.2-1.35(1H, m), 1.35-1.5(2H, m), 1.5-1.65(1H, m), 1.65-1.75(2H, m), 1.75-2.0(3H, m), 2.6-2.75(4H, t), 2.8-2.85(1H, d), 3.02-3.17(1H, d), 4.2-4.3(2H, t), 5.55(1H, s), 6.75-6.83(1H, d), 7.65-7.72(1H, d) and 8.2(1H, s); m/Z 301 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[O:8][N:7]=[C:6]([CH3:9])[C:5]=1[Cl:10].[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.CO>C1COCC1.O>[Cl:10][C:5]1[C:6]([CH3:9])=[N:7][O:8][C:4]=1[NH:3][S:17]([C:14]1[CH:13]=[CH:12][C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Sodium hydride (188 mg, 4.4 mmol) was suspended in dry THF (1 ml) and cooled to 0° C. A solution of 5-amino-4-chloro-3-methylisoxazole (mg, mmol) in dry THF (1 ml) was added with stirring. Once the addition was complete, the reaction mixture was warmed to room temperature for 10 min. The solution was recooled to 0° C., and 4-biphenylsulfonyl chloride (0.283 ml, 2.2 mmol) was added. Stirring was continued at 25° C. for 2 h. Excess sodium hydride was decomposed by the addition of methanol (0.4 ml) followed by water (0.5 ml). THF was removed under reduced pressure and the residue was dissolved in water (20 ml) and basified by addition of sodium hydroxide (pH 9-10). Neutral impurities were removed by extraction with ethyl acetate (2×10 ml). The aqueous layer was acidified to pH 2-3 using concentrated HCl and extracted with ethyl acetate (3×10 ml). The combined organic layer was dried over magnesium sulfate. Removal of the solvent gave N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide in 83% yield. This product was purified by recrystallization from ethyl acetate/hexanes as a white solid, m.p. 129°-132° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](N)[CH:8]=2)[N:3]=1.Cl.N([O-])=O.[Na+].[C-:19]#[N:20].[K+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]#[N:20])[CH:8]=2)[N:3]=1
Reactant: [C-]#N
Reactant: Nc1ccc2nc(N)nc(N)c2c1
Agent: [Cu+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: N#Cc1ccc2nc(N)nc(N)c2c1

Procedure:
The 2,4,6-triaminoquinazoline derivatives described above may then optionally be treated with 2N hydrochloric acid, sodium nitrite, potassium cyanide, and copper(II) sulfate pentahydrate in water, affording the corresponding 2,4-diamino-6-cyanoquinazoline, for example, 2,4-diamino-6-cyano-5-methylquinazoline. Step A of Example 14 describes in detail this step in the reaction sequence.
Reaction SMILES: [O-2].[Mg+2].O.[OH:4][CH2:5][CH2:6][N:7]([C:31](=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]CCCC)[CH2:8][CH2:9][N:10]([C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CCCC)[CH2:11][CH2:12][OH:13].C(Cl)(=O)CCCCCCCCCCC>O1CCOCC1>[OH:4][CH2:5][CH2:6][N:7]([C:31](=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:8][CH2:9][N:10]([C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:11][CH2:12][OH:13]
Reactant: CCCCCCCCCCCCCCCC(=O)N(CCO)CCN(CCO)C(=O)CCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCC(=O)Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCC(=O)N(CCO)CCN(CCO)C(=O)CCCCCCCCCCC
Yield: 325.6 %

Procedure:
Into a 500 ml rounded-flask, were introduced 4.0 g of magnesium oxide and 80 g of distilled water. The mixture was stirred. Thereto was added 7.3 g of N,N'-bis(2-hydroxyethyl)-1,2-diaminoethane prepared in Example 27, and then was added 250 ml of 1,4-dioxane. 21.3 g of lauroyl chloride was gradually added dropwise to the resulting mixture for 1 hour under violent stirring at a room temperature. After stirring for 2 hours, the mixture was filtered, and the filtrate was mixed with 200 ml of chloroform, and washed twice with 200 ml of distilled water. The organic phase was cooled to produce solid material, which was recovered by filtration. The solid material was dried and recrystallized from acetone, to give 19.5 g of the title compound as white powder, which was identified by IR and NMR. The results are shown in Table 3.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([NH:12]C(=O)C(C)(C)C)=[N:6][C:5]=2[N:4]([CH3:19])[CH:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:12][C:7]1[NH:8][C:9](=[O:11])[C:10]2[C:2]([I:1])=[CH:3][N:4]([CH3:19])[C:5]=2[N:6]=1
Reactant: Cn1cc(I)c2c(=O)[nH]c(NC(=O)C(C)(C)C)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(I)c2c(=O)[nH]c(N)nc21
Yield: 95.9 %

Procedure:
To a solution of N-(5-iodo-7-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide (17.9 g, 47.8 mmol) in tetrahydrofuran (150 ml) was added 2N aqueous solution of sodium hydroxide (57.4 ml, 115 mmol) at 0° C., and the mixture was refluxed for 5 hours After cooling, the solvent was evaporated in vacuo. The suspension was neutralized with 1N hydrochloric acid, and the resulting crystals were collected by filtration and washed with water to give 13.3 g (96%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18].CCN(CC)CC.Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCOC(C)=O>[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:26][C:13]2[CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=[C:11]([F:16])[CH:12]=2)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C=Cc2cc(F)cc(OCc3ccccc3)c2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A mixture of 5-benzyloxy-3-fluorophenyl bromide (2.81 g, 10 mmol), Pd(OAc)2 (0.067 g, 0.3 mmol), tri-o-tolylphosphine (0.18 g, 0.6 mmol), 4-acetoxystyrene (2.03 g, 12.5 mmol), and Et3N (1.26 g, 12.5 mmol) in 20 mL dry DMF was stirred at 100° C. for 24 hours under N2. The dark mixture was distributed between EtOAc and 1N HCl. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered, and evaporated. After flash column, the desired product (3.19 g, 88%) was obtained. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.51-7.34 (m, 7H), 7.11-6.82 (m, 6H), 6.60 (dt, 1H); 13C NMR (CDCl3, 75 MHz) δ 169.66, 165.64, 162.40, 160.47, 150.58, 140.07 (d), 136.59, 134.76, 129.41, 128.91, 128.41, 128.04 (d), 127.79 (d), 122.11, 109.36 (d), 105.86 (d), 101.91 (d), 70.57, 21.37; 19F NMR (CDCl3, 282 MHz) δ-31675.70 (t); HRMS (EI+) found 362.1302 M+, calcd 362.1318 for C23H19FO3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[S:27].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[F:18])=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: Fc1ccccc1N=C=S
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccccc1NC(=S)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (7.48g, 0.03 mol), 2fluorophenyl isothiocyanate (5.0 g, 0.033 mol) and toluene (30 ml) was heated under reflux for 1.5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 7.9 g (59 %), m.p. 145°-147 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)=[C:34]=[O:35]>ClCCl>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])[CH:37]=1
Reactant: O=C=Nc1cccnc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-isocyanato-pyridine (19 mg, 0.16 mmol) (Oakwood). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid pyridine-3-yl-amide as a white solid. (Yield 30 mg, 45%).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:11])[CH3:8].[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:7]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][C:15](=[CH2:1])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (34.1 g, 95.5 mmol) was placed in abs. diethyl ether (420 ml) under a nitrogen atmosphere. At 0° C., potassium tert-butylate (13.1 g, 113.1 mmol) was slowly added. After 30 min, again at 0° C., ethyl-4-oxocyclohexanecarboxylate (10.7 g, 62.9 mmol) was slowly added dropwise as a solution in diethyl ether (80 ml). The reaction mixture was stirred overnight at RT. For working up, the reaction mixture was cooled in an ice bath and mixed with sat. aq. NH4Cl solution (250 ml). The phases were separated and the aqueous phase was shaken out several times with EtOAc (3×200 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. The precipitate thus formed was removed by suction-filtration and dried overnight using a pump. The mother liquor was placed onto a glass frit filled with silica gel and flushed with ether/hexane (400 ml). The filtrate was concentrated and the residue not dried any further. 7.1 g (66% of the theoretical amount) of the desired product 4-methylenecyclohexane carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl-].[OH-].[Na+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccccc2n1CCCCl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 13.2 parts of 2-methyl-1H-benzimidazole, 2 parts of N,N,N-triethylbenzenemathanaminium chloride and 150 parts of a sodium hydroxide solution 60% are added 30 parts of 1-bromo-3-chloropropane. To start the reaction, the whole is heated to about 40° C., whereupon the temperature rises to 50° C. (exothermic reaction). Stirring at about 50° C. is continued for 30 minutes. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-(3-chloropropyl)-2-methyl-1H-benzimidazole as a residue.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[CH:18]2[Si:23]([CH:26]1[C:34]2[C:29](=[C:30](Br)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:36])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH3:37])[CH:18]3[Si:23]([CH:26]2[C:34]3[C:29](=[C:30]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:8]=4)[CH:31]=[CH:32][CH:33]=3)[CH:28]=[C:27]2[CH3:36])([CH3:25])[CH3:24])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3cccc(C(F)(F)F)c3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3cccc(C(F)(F)F)c3)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 28.0 ml of 15 mL of THF with 0.5 M ZnCl2 (14.0 mmol) in THF, 12.3 ml of 1.02 M 3-trifluoromethylphenylmagnesium bromide (12.6 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 9.66 ml of 0.02 M Pd(PtBu3)2 (0.19 mmol, 4 mol. %) in THF and 2.42 g (4.83 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.86 g (98%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[F:12][C:13](I)([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[O:8])[C:13]([F:12])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
Under protective gas, 27.3 g (0.16 mol) of p-methoxybenzoyl chloride and 53.3 g (0.18 mol) of perfluoroisopropyl iodide in 150 ml of CH2Cl2 are initially introduced into a round-bottomed flask. 45 g (0.18 mol) of phosphorous acid trisdiethylamide are metered in at about -20° C. during the course of 3 hours. The mixture is subsequently stirred at about -10° C. for 5 hours and, after warming, worked up analogously to Example 1. 37 g (76%) of 1-(4-methoxyphenyl)-2,3,3,3-tetrafluoro-2-trifluoromethylpropan-1-one of b.p. 97°-99° C./10 mbar are obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14]C)=[O:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH3:16][O-:17].[Na+]>CN(C=O)C.O>[CH3:16][O:17][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc2c(cc1Br)OCCO2
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1C(=O)O)OCCO2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
In a 2 mL microwave vial, methyl 7-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (273 mg, 1 mmol) and CuBr (14.3 mg, 0.1 mmol) were dissolved in dry DMF and was placed in ice bath. Sodium methoxide (540 mg, 10 mmol) was added into the reaction mixture dropwise while stirring at 0° C. The reaction was warmed to room temperature and stirred for 45 minutes. The reaction was then placed in a microwave reactor for 5 minutes at 135° C. The reaction mixture was dissolved in water and washed with ethyl acetate. The water layer was collected and acidified to pH 4 with 1M HCl. The product was extracted using ethyl acetate then dried over sodium sulfate. The solvent was evaporated under vacuum to give the desired intermediate of 7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid which was used directly without further purification. Yield 57%. MS M+H calculated 211.1, found 211.1.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][S:6]([NH:9][C:10]([NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1)=[S:11])(=[O:8])=[O:7].BrBr>CO>[CH3:20][O:19][C:17]1[CH:16]=[C:15]([O:21][CH3:22])[N:14]2[S:11][C:10](=[N:9][S:6]([CH2:5][C:4]3[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=3[C:2]([F:27])([F:1])[F:28])(=[O:7])=[O:8])[N:12]=[C:13]2[N:18]=1
Reactant: COc1cc(OC)nc(NC(=S)NS(=O)(=O)Cc2ccccc2C(F)(F)F)n1
Agent: BrBr
Solvent: CO
Product: COc1cc(OC)n2sc(=NS(=O)(=O)Cc3ccccc3C(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A suspension of 1.0 g of N-(2-trifluoromethylbenzyl) sulfonyl-N'-(4,6-dimethoxy-2-pyrimidinyl)thiourea in 20 ml of methanol is cooled at -10°~-5° C., and a solution of 0.12 ml of bromine in 1 ml of methanol is dropwise added to the solution. The temperature of the mixture is gradually raised to room temperature and the mixture is stirred for 2 hours. The crystals are collected by filtration, washed with methanol, dried and recrystallized from acetonitrile to give 0.8 g of the title compound as white crystals.
Reaction SMILES: Cl.Cl.[N:3]1([CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CN(C)C(N(C)C)=N.F[C:23]1[N:28]=[C:27]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)[CH:26]=[CH:25][CH:24]=1>CS(C)=O.ClCCl>[CH3:41][O:40][C:35]1[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=[C:31]2[C:36]=1[C:37](=[O:39])[NH:38][C:29]([C:27]1[N:28]=[C:23]([N:6]3[CH2:7][CH2:8][N:3]([CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH2:4][CH2:5]3)[CH:24]=[CH:25][CH:26]=1)=[N:30]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: CC(C(N)=O)N1CCNCC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(C(C)C(N)=O)CC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
To a suspension of 2-(piperazin-1-yl)propanamide dihydrochloride (0.305 g, 1.33 mmol) in DMSO (1.5 mL), was added 1,1,3,3,-tetramethylguanidine (0.398 g, 3.45 mmol) at rt. The reaction mixture was stirred for 15 min. After that time 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.20 g, 0.664 mmol) was added as a solid in a single portion. The resulting mixture was stirred at 90° C. for 3.5 h. After that time the reaction was cooled to rt and diluted with dichloromethane (50 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 93:7 dichloromethane/methanol) to give 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanamide (0.080 g, 28%) as a light yellow solid: mp 149-150° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.05 (br s, 1H), 7.65-7.79 (m, 2H), 7.30 (s, 1H), 7.06 (d, J=8.20 Hz, 1H), 6.78 (s, 1H), 6.58 (s, 1H), 4.48 (br s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.64 (br s, 4H), 3.55 (br s, 2H), 2.54 (br s, 4H), 2.45 (t, 2H); ESI MS m/z 439 [M+H]+.