Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:22].S(Cl)(Cl)=O.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]1([C:7]([Cl:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: ClC(c1ccccc1)(c1ccccc1)c1ccncc1
Temperature: 25 °C

Procedure:
92.1 g (0.353 mol) of diphenyl(4-pyridyl)methyl alcohol recrystallized from chloroform and 800 ml of simple-distillation benzene were charged in a 2-l three-necked flask provided with a stirrer and reflux condenser. The mixture was treated at 50° C. to form a suspension. 29.6 ml (0.407 mol) of thionyl chloride was poured in the suspension and the mixture was stirred under reflux for 1 h. The resulting solution was cooled to room temperature. 72.5 ml (0.522 mol) of triethylamine was added thereto and the mixture was stirred for 7 h. The reaction solution was filtered and the filtrate was concentrated to obtain crude diphenyl(4-pyridyl)methyl chloride.
Reaction SMILES: [P:1]([O-:19])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])[O-].[Ag+2:24]>C(#N)C.O.[Al]>[P:1]([O-:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2].[Ag+:24]
Reactant: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: [Al]
Solvent: O
Solvent: CC#N
Product: [Ag+]

Procedure:
Dibenzyl phosphate (10 mmole, 2.78 g) is dissolved in a mixture of acetonitrile (20 ml) and water (10 ml). Silver carbonate (10 mmole, 2.76 g) is added, and the mixture is stirred at room temperature in the dark (wrapped in aluminum foil) for 2 hours. Excess of silver carbonate is removed by filtration. The solution is evaporated to dryness, and dried over P2O5 in the dark to constant weight (2 days). Yield of silver dibenzoyl phosphate is 3.61 g.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]([F:47])([F:46])[C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:46])[F:47])[CH:37]=4)(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccc(C(F)(F)F)c3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-trifluoromethylbenzene-1-sulfonyl chloride (44 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 45 mg (60%); 1H NMR (DMSO-d6, 300 MHz): δ 9.466 (s, 1H), 8.523-8.550 (d, 1H, J=8.1 Hz), 8.475 (s, 1H), 8.241-8.268 (d, 1H, J=8.1 Hz), 7.971-8.020 (m, 2H), 7.668-7.989 (m, 5H), 6.749-6.756 (d, 1H, J=2.1 Hz), 1.773 (s, 6H); MS: m/z 615 (M+), 617 (M+2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([NH2:12])[CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26](O)=[O:27].CN(C)CCCN=C=NCC>N1C=CC=CC=1>[NH2:12][C:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]([NH:11][C:26]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:20]=1)=[O:27])[CH3:10]
Reactant: O=C(O)c1cnccn1
Reactant: CC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CC(NC(=O)c1cnccn1)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
1,1-bis(4-fluorophenyl)-1,2-propanediamine (94 mg) and pyrazinecarboxylic acid (53 mg) was dissolved in pyridine (1 mL), and to the solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(103 mg). The mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated, and the obtained residue was dissolved in chloroform, followed by washing with saturated sodium hydrogen carbonate aqueous solution. The aqueous layer was extracted with chloroform twice, and the combined chloroform layers were dried over magnesium sulfate. After evaporating the solvent in vacuo, the obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=1:1→1:3) to give N-[2-amino-2,2-bis(4-fluorophenyl)-1-methylethyl]-2-pyrazinecarboxamide(112 mg) as the mixture with pyrazinecarboxylic acid methyl ester. The mixture was dissolved in methanol (1 mL), and to the solution was added 2N sodium hydroxide aqueous solution (0.5 mL), and the solution was stirred at room temperature for one hr. The reaction mixture was diluted with chloroform, followed by washing with water. The aqueous layer was extracted with chloroform twice, and the combined chloroform layers were dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give the pure amide compound (95 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 77.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (58 mg, 77.4%) as a yellow solid.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:14]>>[CH2:13]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:14]
Reactant: CCCCCCCNCC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CC)CCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N-ethyl-N-heptylamine as starting materials to give the aimed compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:8](=[O:15])([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccn1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=C(Sc1ccccn1)c1ccccc1
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Following a standard procedure,16 a solution of 2-mercaptopyridine (3.33 g, 30.0 mmol) in THF (30 mL) was treated with benzoyl chloride (4.21 g, 30.0 mmol) at room temperature with stirring for 30 min. The standard workup followed by precipitation afforded a pale yellow solid (5.67 g, 88%): mp 48-50° C. 1H NMR spectral data are consistent with reported values:15 1H NMR δ 7.31-7.37 (m, 1H), 7.46-7.53 (m, 2H), 7.59-7.65 (m, 1H), 7.71-7.83 (m, 2H), 8.00-8.06 (m, 2H), 8.66-8.71 (m, 1H); 13C NMR δ 123.7, 127.6, 128.9, 131.0, 134.0, 136.6, 137.3, 150.6, 151.4, 189.4. Anal. Calcd for C12H9NOS: C, 66.95; H, 4.21; N, 6.51. Found: C, 66.63; H, 4.12; N, 6.57.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:50])[CH2:10][C:11]1[CH:49]=[CH:48][CH:47]=[CH:46][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[C:28]([CH3:45])[CH:27]=2)[N:16]=1>C(Cl)Cl.C1CCCCC1>[CH3:45][C:28]1[CH:27]=[C:26]([NH:25][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[CH:46]=[CH:47][CH:48]=[CH:49][C:11]=3[CH2:10][C:9]([NH2:8])=[O:50])[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=2)[CH:31]=[CH:30][C:29]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCCCC1
Product: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
TFA (1 mL) was added to a stirred solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate (A43) (0.16 g, 0.27 mmol) in DCM (4 mL) and the resulting solution was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and 2 M aqueous NaOH (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then and the combined organic layers were washed with water (10 mL), brine (10 mL) and dried over MgSO4. The volatiles were removed in vacuo to give a pale yellow solid. The solid was suspended in cyclohexane and the resulting suspension filtered to give the title compound 11 as a white solid (0.085 g, 64%); 1H NMR (400 MHz, d4-MeOH) δ 8.52 (s, 1H), 7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.29-7.23 (m, 1H), 7.23-7.15 (m, 4H), 3.67 (s, 2H), 3.23-3.11 (m, 4H), 3.10-3.01 (m, 2H), 2.91 (tt, J=11.7, 3.8 Hz, 1H), 2.80 (td, J=12.3, 2.8 Hz, 2H), 2.35 (s, 3H), 1.84-1.59 (m, 4H). LCMS-A: rt 4.962 min; m/z 498.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH2:25][CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:21]2[CH:22]=[CH:23][C:18]([O:24][CH2:25][CH3:26])=[CH:19][CH:20]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2ccc(C)c(Br)c2)cc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid (1.2 g, 4.74 mmol) and oxalyl chloride (0.7 mL, 8.16 mmol) in 8 mL of CH2Cl2 was added 50 μL of DMF. The reaction mixture was stirred overnight prior to removal of the volatiles under reduced pressure using a rotary evaporator. The crude 3-bromo-4-methylbenzoyl chloride was dissolved in 10 mL of CH2Cl2 and then cooled to −5° C. prior to adding phenetole (0.63 mL, 5.0 mmol). AlCl3 (0.945 g, 7.1 mmol) was added via a solid addition funnel over 30 min. After the mixture was stirred at 5° C. for 2 h, the reaction was quenched by pouring over ice. Subsequently, the suspension was diluted with water and extracted 3× with CH2Cl2. The combined organic layers were washed 2× with 1 M HCl, once with H2O, 2× with 1 M NaOH, and 2× with brine prior to drying over Na2SO4. Recrystallization 2× from absolute EtOH provided 1.13 g of (3-bromo-4-methylphenyl)(4-ethoxyphenyl)methanone. 1H NMR (CDCl3, 300 MHz): δ 7.93 (d, J=1.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.60 (dd, J=1.6, 8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 2.48 (s, 3H), 1.46 (t, J=7.0 Hz, 3H); MS ESI (m/z) 319 (M+1)+, calc. 318.
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:25]=2[CH3:35])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:26][C:25]=2[CH3:35])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}benzoic acid (182 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-{methyl[(4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}phenyl)carbonyl]amino}propanoate. Ethyl 3-{methyl[(4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}phenyl)carbonyl]amino}propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (186 mg, 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:22]([NH2:21])=[S:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A solution of 2 g (11.47 mmol) (3-Amino-propyl)-carbamic acid tert-butyl ester in 20 ml THF was treated with 1.62 ml (11.47 mmol) Benzoyl isothiocyanate and stirred for 1 h at room temperature. After removal of the volatiles the residue was suspended in 50 ml methanol and 4.8 g (34.4 mmol) K2CO3 in 50 ml water was added. The mixture was stirred at room temperature for 16 h, concentrated, and extracted with ethyl acetate. The combined organic layers were washed with NaHCO3 sat., brine, dried with MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with ethyl acetate/heptane. The combined product fractions were evaporated under reduced pressure to yield 1.48 g (74%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](S)=[N:7][CH:8]=1.[Cl:12][O-].[Na+].O.[OH:16][S:17]([OH:20])(=O)=O>>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([S:17]([Cl:12])(=[O:20])=[O:16])=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(S)nc1
Reactant: [O-]Cl
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)cn1
Reaction time: 0.75 h
Yield: 79 %

Procedure:
0.8 g (4.47 mmol) of 5-trifluoromethyl-pyridine-2-thiol is placed at −8° C. in 16 mL of H2SO4. 16.96 mL (35.7 mmol) of a 13% sodium hypochlorite solution is poured gently such that the temperature of the reaction medium does not exceed 5° C. This mixture is then stirred for 45 min, taken up by water and then extracted using AcOEt. After drying followed by reduction to dryness of the organic phases, an oil is isolated (yield: 79%) and used as such for the next reactions.
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH2:13]([O:15][P:16]([O-:20])[O:17][CH2:18][CH3:19])[CH3:14].[C:21]1(=[O:27])[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1.Cl>ClCCl>[CH2:13]([O:15][P:16]([CH:23]1[CH2:24][CH2:25][CH2:26][C:21](=[O:27])[CH2:22]1)(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]
Reactant: O=C1C=CCCC1
Reactant: CCOP([O-])OCC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCCC(=O)C1
Reaction time: 1 h
Yield: 95 %

Procedure:
0.52 mmol trimethylsilyltriflate is added dropwise to 11.4 mmol diethylphosphite and 12.4 mmol N,O-bis-(trimethylsilyl) acetamide in 5 ml dichlormethane at 0° C. . After 30 minutes of stirring at the same temperature 0.52 mmol 2-cyclohexen-1-one are added dropwise thereto and is stirred for 1 h. The enolsilane intermediate product is hydrolized by 3 ml 1 n HCl during 3 hours of stirring. The organic phase is separated, dried over magnesiumsulfate and concentrated. The raw product can be chromatographed on SiO2 and after concentration of the desired fractions results in 3-oxo-cyclohexylphosphonic acid diethylester 2(a) in a 95% yield.
Reaction SMILES: [CH3:1][OH:2].[C:3]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])[CH:4]=[CH2:5].O=O.[CH2:14](COC)[O:15]C>Cl[Pd]Cl>[CH3:14][O:15][CH:5]([O:2][CH3:1])[CH2:4][C:3]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: CO
Reactant: COCCOC
Reactant: C=CC(=O)OCCCC
Agent: Cl[Pd]Cl
Agent: O=O
Product: CCCCOC(=O)CC(OC)OC

Procedure:
and 10. 0.07 g (0.4 mmol) of PdCl2, 4 mmol of a Cu compound corresponding to Table 2, 1.14 g (36 mmol) of methanol and 0.51 g of butyl acrylate in 3.5 g of dimethoxyethane was stirred for 20 hours at 50° C. under an O2 atmosphere (O2 -filled air balloon) in a round-bottomed flask with a magnetic core and reflux condenser. The yields of butyl 3,3-dimethoxypropionate as a function of the Cu compound used are compiled in Table 2.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:22]2[CH:5]=[N:4][N:3]=[C:2]2[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 4-methoxybenzylamine (0.5 ml) as described above; yield: 0.083 g (27.2%); MS m/z: 306.4 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.66 (s, 3H); 5.29 (s, 2H); 6.80-6.83 (m, 2H); 6.95-6.97 (m, 2H); 7.61 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.82 (d, 1H, 3J=8.7 Hz); 7.91 (d, 1H, 4J=1.7 Hz); 8.73 (s, 1H); 8.96 (s, 1H); HPLC (METHOD [A]): it 8.18 min (99.6%)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[F:50][C:51]1[CH:59]=[C:58]([F:60])[C:57]([F:61])=[CH:56][C:52]=1[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:55][CH:53]([C:52]1[CH:56]=[C:57]([F:61])[C:58]([F:60])=[CH:59][C:51]=1[F:50])[CH3:54]
Reactant: CC(O)c1cc(F)c(F)cc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cc(F)c(F)cc4F)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 37.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (130 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2,4,5-trifluoro-α-methylbenzyl alcohol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 35%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1)=[O:11].O.[CH2:27]([Mg]Br)CCCCC.[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([C:10]([CH3:27])([OH:11])[CH2:9][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: CCCCCC[Mg]Br
Reactant: CCCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a slurry of 186 g. (7.65 mole) of magnesium in 3.5 l. of tetrahydrofuran was added 1.023 l. (7.29 mole) of 1-bromohexane over 2 hours. The resultant Grignard solution was allowed to cool to 25° C. A solution of 1.098 kg. (4.86 mole) of 3-benzyloxyacetophenone in 1 liter of tetrahydrofuran was added to the Grignard solution over a 3 hour period. The reaction temperature was maintained at 12°-18° C. with an ice bath. Upon completion of the addition the reaction was allowed to stir overnight at 25° C. A solution of 61.5 g. (3.42 mole) of water in 120 ml. tetrahydrofuran was added to the reaction over 15 minutes and, after stirring 20 minutes longer 0.440 l. (1.1 mole) of 2.5 M hexylmagnesium bromide in ether, was added. The reaction was stirred 20 hours longer and then quenched by slow addition to a mixture of 6 l. water and ice and 750 g. (14.2 mole) of ammonium chloride. The organic extract was removed and the aqueous extract was extracted with 1 liter of ether. The combined organic extract was washed with 1 liter of saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 1.424 kg. (94%) of the title compound as an oil.