Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1F)[CH:11]=[O:12].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.O>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=1)[CH:11]=[O:12]
Reactant: COc1cccc(O)c1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(Oc2ccc(C=O)cc2F)c1
Temperature: 120 °C
Yield: 57.7 %

Procedure:
Cesium carbonate (2.757 g, 8.44 mmol) was added to a solution of 3,4-difluoro-benzaldehyde (1.0 g, 7.037 mmol) and 3-methoxyphenol (875 mg, 7.05 mmol) dissolved in DMF (20 mL). The reaction was heated to 120° C. for 24 hours. The reaction mixture was then poured into 300 mL of water and extracted 3 times with 60 mL of ethyl acetate. The combined organic layers were washed with water (2 times), brine, and dried over sodium sulfate. The organic layer was filtered and concentrated under reduced pressure. 3-Fluoro-4-(3-methoxy-phenoxy)-benzaldehyde (1.0 g) was isolated using flash silica gel and eluting with 10% ethyl acetate and heptane.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: O=Cc1csc2c(F)cccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)NCc1csc2c(F)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluorothiophenol (4.14 g, 32.6 mmol) was dissolved in anhydrous THF (100 mL). Potassium tert-butoxide (1.0 M in THF, 35.8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde dimethyl acetal was added and the mixture was stirred for 3 days. Water (100 mL) was added and the solution was extracted with diethyl ether (3×100 mL). The extracts were concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to yield 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene (6.42 g) as a colorless oil. Chlorobenzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. The 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene was then added slowly turning the solution dark. After 3 hours of heating, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophenyl (0.77 g). The 7-fluorobenzothiophenyl (0.77 g, 5.1 mmol) and dichloromethyl methyl ether (0.872 g, 7.6 mmol) were dissolved in anhydrous DCM (25 mL). Titanium tetrachloride (1.0 M in DCM, 7.6 mL, 7.6 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g). The 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g, 3.77 mmol) and sulfamide (1.7 g, 18 mmol) were combined in anhydrous ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.148 g, 3.92 mmol) was added. After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:18]1([CH2:17][O:9][C:8]([CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[O:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To an acetone solution containing 12.0 g (84.4 mmol) of 4-ketocyclohexane carboxylic acid and 4.7 g (33.8 mmol) of potassium carbonate, 17.3 g (101.3 mmol) of benzyl bromide was added at room temperature. Next, this was agitated at 60° C. for 3 hours. After the reaction ended, crude product was obtained, and after potassium carbonate was removed by filtration and acetone was evaporated, the crude product was purified by silica gel column chromatography, and 16.5 g of 4-ketocyclohexane carboxylic acid phenylmethyl ester was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([C:32]1[CH:33]=[CH:34][C:35](Cl)=[N:36][CH:37]=1)#[N:31]>>[C:30]([C:32]1[CH:33]=[CH:34][C:35]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:36][CH:37]=1)#[N:31]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: N#Cc1ccc(Cl)nc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ccc(C#N)cn2)C3)cc1

Procedure:
Compound ej was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 5-cyano-2-chloropyridine. LC-MS: m/z=+499 (M+H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([NH:13][CH3:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([N:13]([CH3:14])[C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: CNc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)N(C)c1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
3,3-Dimethylacryloyl chloride (3 mL, 27 mmol) was added to a solution of 4-bromo-N-methyl-aniline (4.55 g, 25 mmol) in 150 mL of dichloromethane followed after 5 minutes by triethyl amine (5 mL, 33 mmol). After 2.5 h at ambient temperature, the reaction mixture was washed with water and the organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title product as a brown oil in quantitative yield.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:18]([CH2:23][CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)(Cl)Cl>[OH:1][CH:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:23]([CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(CC(O)c2cccnc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)=Cc1ccc(CC(O)c2cccnc2)cc1
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
4-[2-Hydroxy-2-(3-pyridyl)ethyl]benzaldehyde (1.34 g) and (carboethoxyethylidene)triphenylphosphorane (4.28 g) were dissolved in 50 ml of chloroform, and stirred for 1.5 hours, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with chloroform-methanol(10:1v/v) was obtained 1.84 g of ethyl 4-[2-hydroxy-2-(3-pyridyl)ethyl]-α-methylcinnamate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31](=[O:32])[CH2:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)Cc4ccccc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (100 mg, 0.32 mmol) and phenylacetyl chloride (51 μl, 0.38 mmol). The title compound was obtained as yellow powder (48 mg, 34%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.O>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
A mixture of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanone (2.80 g, 9.11 mmol) in THF (61 mL) at 0° C. (ice/water bath) was treated drop-wise with a mixture of sodium borohydride (689 mg, 18.21 mmol) in water (11 mL) over 5-10 minutes. The resulting mixture was stirred at this temperature for 2.5 hours and was then partitioned between EtOAc (200 mL) and water (200 mL) and the layers separated. The aqueous was re-extracted with EtOAc (200 mL) and the combined organic layer washed with brine (250 mL), dried (MgSO4), filtered and reduced. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 20:1 to 5:1) afforded the title compound as a colourless oil (2.81 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[NH2:25])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([C:21]([F:22])([F:23])[F:24])=[CH:16][C:15]=2[NH:25][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][N:26]=[CH:31][CH:30]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)CCCc1ccncc1
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2N)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2NC(=O)CCCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (step 2, 250 mg, 0.67 mmol), 4-(4-pyridinyl)butanoic acid (200 mg, 1 mmol), and WSC (191 mg, 1 mmol) in dichloromethane (7 ml) was stirred at room temperature for 1.5 h. The mixture was added water (5 ml) and extracted with dichloromethane(30 ml). The organic layer was washed with brine (5 ml), then dried (Na2SO4). The solvent was removed under reduced pressure to afford the title compound as pale brown amorphous. MS (EI) m/z: 519 (M+)
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[N:8]=[CH:7][C:6]=1[C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:23]1)=[O:21])[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:1]([S:4][C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)[N:8]=[CH:7][C:6]=1[C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:34])([F:35])[F:36])[CH2:23]1)=[O:21])[CH2:2][CH3:3]
Reactant: CCCSc1c(C(=O)N2CCC(c3ccccc3C(F)(F)F)C2)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)N2CCC(c3ccccc3C(F)(F)F)C2)cnn1-c1ccc(C(=O)O)cc1
Yield: 67.8 %

Procedure:
Methyl 4-[5-propylsulfanyl-4-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl]pyrazol-1-yl]benzoate (Intermediate#6) (177 mg, 0.34 mmol) was stirred at ambient temperature for 18 h in a mixture of methanol (5 mL) and 2M sodium hydroxide (0.855 mL, 1.71 mmol) for 18 h. The reaction mixture was evaporated to remove the methanol. The residue was dissolved in water (20 mL) and acidified to pH4 with 2M HCl. The resulting white precipitate was recovered by filtration, washed with water and dried under vacuum to give the title compound as a white solid (116 mg, 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH:12][CH2:13][CH2:14][C:15]12[CH2:22][CH2:21][CH2:20][N:19]1[CH2:18][CH2:17][CH2:16]2>>[N:19]12[CH2:20][CH2:21][CH2:22][C:15]1([CH2:14][CH2:13][N:12]([CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:16][CH2:17][CH2:18]2
Reactant: CNCCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: CN(CCC12CCCN1CCC2)c1ccccc1[N+](=O)[O-]

Procedure:
The procedures described in Example 12 were repeated except that 1-chloro-2-nitrobenzene (1.87 g, 11.9 mmol) and 5-(2-methylaminoethyl)-1-azabicyclo[3.3.0]octane (4.00 g, 28.8 mmol) were employed. In th is case, the desired compound was obtained as a orange liquid (2.95 g, 85.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:34])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(Nc3cccc(Cl)c3)n(-c3cccc(Cl)c3)nc2c1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2ccc(F)cc2nn1-c1cccc(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(3-chloro-phenyl)-6-fluoro-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as white solid. MS: m/e=497.3 [M+H+].
Reaction SMILES: [Na].[CH3:2][C:3]([C:6]1[CH:21]=[CH:20][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[CH3:5][C:3]([C:6]1[CH:21]=[CH:20][C:9]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:2])[CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccc(O)cc2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
To a solution of 0.66 g. sodium in 25 ml. ethanol are added 7 g. 4-(1,1-dimethylethyl)-N-(4-hydroxyphenyl)benzamide (Example 2) and 3.2 ml. ethyl bromoacetate. The reaction mixture is boiled under reflux for 10 hours, the solvent is removed in a vacuum and the residue is recrystallised from toluene. There are obtained 5.5 g. (60% of theory) of the title compound; m.p. 119°-122° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12](=[O:14])[CH3:13])=[CH:4][N:3]=1.[CH3:15][S-:16].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH:9]([NH:8][C:6]1[C:5]([C:12](=[O:14])[CH3:13])=[CH:4][N:3]=[C:2]([S:16][CH3:15])[N:7]=1)([CH3:11])[CH3:10]
Reactant: C[S-]
Reactant: CC(=O)c1cnc(Cl)nc1NC(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1ncc(C(C)=O)c(NC(C)C)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1-(2-chloro-4-isopropylamino-pyrimidin-5-yl)-ethanone (11.1 g, 0.052 mol) and sodium thiomethoxide (5.75 g, 0.078 mol) are taken up in 100 mL dioxane and stirred for 16 h at 20° C. The solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and extracted 2× with water. The organic phase is dried, the solvent is eliminated in vacuo and 1-(4-isopropylamino-2-methylsulphanyl-pyrimidin-5-yl)-ethanone (HPLC-MS: tRet.=1.82 min, MS(M+H)+=226; method FECB3) is obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](C)=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH:20]=[CH2:21].F[C:23](F)(F)S(OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=CC=C2)(=O)=O>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[C:3]([CH:20]=[CH2:21])=[C:2]([CH3:23])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:14][CH:15]=1
Reactant: C=Cc1c(Cl)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F
Product: C=Cc1c(C)cc2ncccc2c1-c1ccc(Cl)cc1

Procedure:
Compound 3G was prepared following the procedure used to prepare compound 1G of Example 1, except that 5-(4-chlorophenyl)-7-methylquinolin-6-yl trifluoromethanesulfonate (3F) was used instead of 1F. LCMS-ESI+ (m/z): 280.2, 282.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:26][C:27]1[C:32]([NH2:33])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[NH2:33][C:32]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[Cl:26]
Reactant: CC1(C)OB(c2cnc(Cl)c(N)c2)OC1(C)C
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(Cl)c(N)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (stage 152.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.55 min (Method A); M+H=448 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.19 (s, 1H), 8.14-8.09 (m, 1H), 7.78-7.73 (m, 1H), 7.57-7.53 (m, 1H), 7.50-7.47 (m, 1H), 7.28-7.24 (m, 1H), 5.68 (s, br, 2H), 4.55 (hp, 1H), 3.58 (s, 3H), 1.95 (s, 3H), 1.44 (d, 6H))
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([C:28](OC)=[O:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:13]3[C:18]([N:19]([CH3:22])[C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3.O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH2:28][OH:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:13]3[C:18]([N:19]([CH3:22])[C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCC1(CO)c2ccccc2N(C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
25.7 gm of the fumarate of 3-chloro-9-methoxy-carbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane were suspended in 250 cc of water and after refrigeration, 25 cc of sodium hydroxide solution were added. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo to obtain 20 gm of 3-chloro-9-methoxycarbonyl-9-(β -dimethylaminoethyl)-10-methylacridane. First 10 gm of lithium aluminum hydride and then 20 gm of 3-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methylacridane in solution in 200 cc of tetrahydrofuran were added to 200 cc of cold tetrahydrofuran at a temperature below 10°C and after stirring for 10 minutes at 0°C, it was refluxed for 15 minutes. After cooling the reaction mixture, excess reactants were decomposed by 200 cc of tetrahydrofuran containing 20% of water at a temperature below 10°C. After filtering and distilling the mixture to dryness in vacuo, the residue was dissolved in methylene chloride and the solution was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue was dissolved in 80 cc of ethyl acetate and the resulting solution was filtered and concentrated to 50 cc after which crystallization began. After being iced for 30 minutes, the mixture was filtered and the precipitate was washed with ethyl acetate and then ether and dried to obtain 14.35 gm of 3-chloro-9-hydroxymethyl-9-(β-dimethylaminoethyl)-10-methyl-acridane melting at 120°C.
Reaction SMILES: C[NH2:2].[C:3]([O:13]C)(=O)[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].Cl.[Cl-].[Na+]>>[C:3]([NH2:2])(=[O:13])[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CN
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: NC(=O)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methylamine (40% in water, 3.8 equivalents) is added, at ambient temperature, methyl (S)-mandelate (1.0 equivalent; commercially available), while keeping the temperature below 30° C. and stirred at ambient temperature until full conversion is achieved. After neutralisation with aqueous hydrochloric acid the aqueous solution is saturated with sodium chloride and extracted several times with dichloromethane. The organic layers are combined and the water is removed by azeotropic distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:21]([CH3:30])[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26]C)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:21]([CH3:30])[C:22]([O:28][CH3:29])=[CH:23][C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1
Reactant: COC(=O)C=C(OC)C(C)Br
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy) phenol (6.9 mmol.), methyl 4-bromo-3-methoxy-2-pentenoate (8.9 mmol.) and potassium carbonate (1.5 equis.) in acetone (15 ml.) is refluxed for 48 hours. After filtration, the filtrate was concentrated and the residue chromatographed on silica gel using 20% ethylacetate/hexane to give the methyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy) phenoxy]-3-methoxy-2-pentenoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:12][O:13][C:14](=[O:27])[C:15]1[C:16](=[C:21]([CH2:25]Br)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[CH3:12][O:13][C:14](=[O:27])[C:15]1[C:16](=[C:21]([CH2:25][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[CH3:8])[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(CBr)c1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A solution of methyl-carbamic acid t-butyl ester (5.0 g, 38.0 mmol) in DMF (50 mL) was chilled in an ice bath, and NaH (60%, 1.7 g, 41.8 mmol) was added in portions at 10C. The mixture was stirred for an additional 30 minutes. A solution of 3-bromomethyl-phthalic acid dimethyl ester (10.9 g, 38.0 mmol) in DMF (20 mL) was slowly added, keeping the temperature at 10-15° C. The resulting mixture was stirred at room temperature overnight. The mixture was poured into ice water (400 mL) and extracted with EtOAc (4×70 mL). The combined EtOAc extracts were washed with water (3×50 mL) and brine (50 mL), and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography (SiO2, Hexane:EtOAc 8:2) to give 3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic dimethyl ester (7.7 g, 60%) as an oil: 1H NMR (CDCl3) δ 7.93-7.89 (m, 1H), 7.49-7.46 (m, 2H), 4.46 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 2.87-2.76 (b, 3H), 1.49-1.42 (b, 9H).