Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:23]=[CH:22][C:14]([CH2:15][N:16]4[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17]4)=[CH:13][CH:12]=3)[S:10][C:3]=12.[Si:24](OS(C(F)(F)F)(=O)=O)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCN(CC)CC.CO.CCOC(C)=O>C1COCC1>[Si:24]([O:21][C@H:18]1[CH2:19][CH2:20][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:9]3[S:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:8]=3)=[CH:23][CH:22]=2)[CH2:17]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O[C@H]1CCN(Cc2ccc(-c3cc4nccc(Cl)c4s3)cc2)C1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(-c3cc4nccc(Cl)c4s3)cc2)C1
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a suspension of 99 (0.5 g, 1.45 mmol) in dry THF (7 ml) at 0° C. was added TBDMSOTf (0.5 ml, 2.2 mmol) and the reaction mixture was stirred for 20 min. Et3N (0.61 ml, 4.4 mmol) was added and mixture was stirred at the same conditions for another hour, quenched by the addition of water (˜2 ml) and concentrated to dryness. The remained solid was partitioned between EtOAc and water. Organic phase was collected, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography, eluents EtOAc/hexane (1:1) then MeOH/EtOAc (5:95) to afford title compound 100 (637 mg, 96% yield) as a white solid. MS (m/z): 459.2/461.2 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][C:17]([OH:28])=[N:16]2)=[CH:11][CH:10]=1.Br[CH2:30][C:31]#[CH:32].C(OCC)(=O)C>CN(C)C=O.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][C:17]([O:28][CH2:32][C:31]#[CH:30])=[N:16]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1nc(-c2ccc(OC)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
Potassium carbonate (279 mg, 2.02 mmol) was added to a solution of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (200 mg, 0.673 mmol) in dimethylformamide (2 mL). After 5 minute stirring, 3-bromo-1-propyne (0.18 mL, 2.02 mmol) was added to the mixture and the mixture was stirred for 4 hours. Ethyl acetate and water were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (toluene-ethyl acetate 4:1). The desired product was washed with isopropyl ether, isolated by filtration, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(2-propynyloxy)-1H-1,2,4-triazole (99 mg, 43.9% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C([Mg]Br)C.[CH2:17]=[O:18].C(N(CC)CC)C>C1(C)C=CC=CC=1.CCOCC.C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH:17]=[O:18])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Into a 1 liter reactor thoroughly dried and purged with nitrogen, 9.68 g (58.93 mmol) of 2-tert-butyl-4-methylphenol and 100 ml of THF were introduced. To the reactor, 23.00 ml of an ether solution containing 69.00 mmol of ethylmagnesium bromide was dropwise added at 0° C. over a period of 30 minutes, then the temperature of the system was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 1 hour. Then, 100 ml of toluene was added, and the system was heated to 95° C. to distill off a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to room temperature, 100 ml of toluene, 4.50 g (149.90 mmol) of paraformaldehyde and 12.50 ml (89.93 mmol) of triethylamine were added, followed by stirring at 95° C. for 2 hours. The reaction solution was allowed to cool to room temperature and then quenched with 300 ml of 1N hydrochloric acid. The organic layer was concentrated and purified by a silica gel column to obtain 7.36 g (yield: 65%) of 3-t-butyl-5-methylsalicylaldehyde.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]([NH2:15])=[O:14])[N:3]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CN(C=O)C.C(O)C>[C:13]([C:4]1[N:3]=[C:2]([OH:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:23](=[O:25])[CH3:24])[CH:10]=2)[N:5]=1)(=[O:14])[NH2:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nc(O)c2cc(O)ccc2n1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2nc(C(N)=O)nc(O)c2c1
Reaction time: 8 h

Procedure:
4,6-Dihydroxy-quinazoline-2-carboxylic acid amide (12 mmol) are dissolved in warm DMF (20 ml) and triethylamine (13.2 mmol) is added to the stirred mixture. After cooling to RT a solution of acetic acid anhydride in DMF (10 ml) is added dropwise and the mixture is stirred overnight. The solvent is removed and the solid material formed is suspended in ethanol and the solid filtered of and dried (vacuum). A powder with mp. 250° C. is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].[F:15][C:16]1[CH:24]=[CH:23][C:22]2[NH:21][C@@H:20]3[CH2:25][CH2:26][NH:27][CH2:28][C@H:19]3[C:18]=2[CH:17]=1>>[F:15][C:16]1[CH:24]=[CH:23][C:22]2[NH:21][C@@H:20]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH:11]=[CH:12][S:13][C:7]5=[N:6][C:5]=4[CH3:14])[CH2:28][C@H:19]3[C:18]=2[CH:17]=1
Reactant: Cc1nc2sccn2c(=O)c1CCCl
Reactant: Fc1ccc2c(c1)[C@@H]1CNCC[C@H]1N2
Product: Cc1nc2sccn2c(=O)c1CCN1CC[C@H]2Nc3ccc(F)cc3[C@@H]2C1

Procedure:
Using the same reaction procedure as described in example B.1, 6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.4 g), prepared as described in EP-A-0,070,053, was reacted with (±)-trans-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, prepared as described in J. Med. Chem. 22:677--(1979), to form (±)-trans-6-[2-(8-fluoro-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (compound 15, mp. 140.9° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11](F)[N:12](F)F)=[O:10])[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([NH:11][NH2:12])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1cccc(Cl)n1)N(F)N(F)F
Solvent: CC(=O)Cl
Product: NNC(=O)Cc1cccc(Cl)n1

Procedure:
A 4.3 g. portion of 2-chloro-6-hydrazinopyridine (prepared in Example 1) is treated with acetyl chloride by the procedure of Example 2. The reaction mixture is evaporated to dryness and the solid is treated with a saturated aqueous solution of sodium bicarbonate and filtered to yield 5.33 g. of crude product. The material is recrystallized from acetone to yield 3.70 g. of the product of the Example m.p. 220°-225° C.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][NH:1][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCOCc1nc2c(N)nc3c(c2n1CCCCON)CCCC3
Product: CCOCc1nc2c(N)nc3c(c2n1CCCCONC(=O)C1CC1)CCCC3

Procedure:
The method described in Example 3 can be used to treat 1-[4-(aminooxy)butyl]-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine with cyclopropanecarbonyl chloride to provide N-{4-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]butoxy}cyclopropanecarboxamide.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)=[CH:24][C:18]=2[C:17]1=[O:32])=[O:15])([CH3:12])([CH3:11])[CH3:10].[Al].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)=[C:24]([I:1])[C:18]=2[C:17]1=[O:32])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)cc2C1=O
Agent: O=S([O-])([O-])=S
Agent: [Al]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)c(I)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
N-iodo succinimide (0.75 g, 3.34 mml) was added to a solution of 2-(2-amino-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester [(1), Q=Boc] (1.0 g, 3.03 mmol) in dry DMF (15 mL) and the reaction mixture was stirred at room temperature overnight, in a flask surrounded by an aluminium sheet. After reaction completion, a solution of Na2S2O3 (10%, 0.100 ml) was added and the product was extracted with DCM (3×0.100 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield the crude 2-(2-amino-pyrimidin-4-yl)-3-iodo-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester as a yellow solid (1.240 g, 2.72 mmol, 90%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])(=O)C.[OH-].[Na+].Cl>CO>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)=[C:19]([F:25])[CH:20]=1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a suspension of 4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (2.78 g) and methanol (30 mL) was added 5 mol/L NaOH (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h, and was adjusted to pH 7 with 0.1 N HCl (aq). The mixture was filtered to give the title compound as a white solid (2.17 g, 87.15%).
Reaction SMILES: [H-].[Na+].C([C:5]([CH2:15][CH3:16])(P(O)(O)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:17]([C:21]1[CH:26]=[CH:25]C(C=O)=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30])([CH3:20])([CH3:19])[CH3:18]>CCCCCC.CN(C)C=O.C(OCC)C>[C:17]([C:21]1[CH:26]=[CH:25][C:16](/[CH:15]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Reactant: CC(C)(C)c1ccc(C=O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)/C=C/c1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
15 8.0 g (0.18 mol) of sodium hydride (as a 55% w/w dispersion in mineral oil) was washed twice with hexane and suspended in 250 ml of dimethyl-formamide. A solution of 31 ml (0.16 mol) of ethyl diethyl-phosphonoacetate in 50 ml of dimethylformamide was then added, with ice-cooling, to the suspension, and the resulting mixture was stirred at room temperature for 40 minutes. At the end of this time, the mixture was ice-cooled and a solution of 27 g (0.13 mol) of 2-t-butyl-5-formyl-1-nitrobenzene [prepared as described in step (i) above] in 50 ml of dimethylformamide was added thereto over a period of 30 minutes, after which the mixture was stirred for 1 hour. The reaction mixture was then diluted with diethyl ether, and the diluted solution was washed with a 10% w/w aqueous solution of hydrochloric acid and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 20.6 g of the title compound as crystals, melting at 77°-78° C. (from ethyl acetate-hexane).
Reaction SMILES: [C@@H]1(N)CCCC[C@H]1N.Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1.[CH:17]1[C:29]2[NH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[Br:16][C:12]1[N:11]=[C:10]([N:28]2[C:29]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc(Br)n1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Brc1cccc(-n2c3ccccc3c3ccccc32)n1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
Under a nitrogen atmosphere, 1.0 g (0.0088 mol) of trans-1,2-cyclohexanediamine was added to a mixture of 14.2 g (0.060 mol) of 2,6-dibromopyridine, 5.0 g (0.036 mol) of carbazole, 0.17 g (0.0019 mol) of copper(I) iodide, 31.8 g (0.15 mol) of tripotassium phosphate, and 300 ml of dehydrated 1,4-dioxane at room temperature with stirring and the mixture was heated with stirring under reflux at 100° C. for 6 hours. The reaction solution was cooled to room temperature, the inorganic salts were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in 200 ml of dichloromethane and washed twice with 100 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by reslurrying in methanol with application of heat to yield 8.2 g of 9-(6-bromo-2-pyridyl)carbazole.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)([CH3:5])[CH2:3][NH2:4].C(N(C(C)C)CC)(C)C.[CH3:21][C:22]([O:25][C:26]([N:28]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:29]([C:37]1[C:42]([F:43])=[C:41](Cl)[N:40]=[C:39]([Cl:45])[N:38]=1)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])([CH3:24])[CH3:23].CCOCC>CN(C=O)C>[CH3:24][C:22]([O:25][C:26]([N:28]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:29]([C:37]1[C:42]([F:43])=[C:41]([NH:4][CH2:3][C:2]([CH3:1])([N:6]2[CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)[CH3:5])[N:40]=[C:39]([Cl:45])[N:38]=1)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[O:27])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CC(C)(CN)N1CCOCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCC(C)(C)N2CCOCC2)c1F
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirred solution of commercially-available [2-methyl-2-(4-morpholinyl)propyl]amine (0.158 g, 1.00 mmol) in DMF (10 mL) under a nitrogen atmosphere at 0° C., was added diisopropylethylamine (0.19 mL, 1.1 mmol) followed immediately by tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.497 g, 1.00 mmol). The reaction was allowed to reach room temperature and was stirred overnight. Then ether was added, and the mixture was washed with water. The aqueous layer was back extracted with ether, and the combined organics were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5-60% ethyl acetate in hexanes, 1% triethylamine) to provide tris(1,1-dimethylethyl)2-(2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate as a clear oil (0.578 g, 94%). LCMS: (M+H)+=619.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:11]([C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:12])[C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: COC(=O)C(OC)(OC)C(=O)Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OC)(OC)C(=O)Nc1cc(Cl)cc(Cl)c1

Procedure:
In a manner similar to the procedure described-in Example I, 3,5-dichloroaniline was reacted with methyl chlorocarbonyl(dimethoxy)acetate, prepared as described in Example LXV Part A, employing triethylamine as the acid acceptor in methylene chloride solution. The methyl 3-[(3,5-dichlorophenyl)amino]-2,2-dimethoxy-3-oxopropanoate product (2.31 grams, 0.007 mole) was obtained as colorless crystals having a melting point of 160° C.-164° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:19]([F:22])=[CH:20][CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(Br)c1)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(N3CCOCC3)c1)N2
Temperature: 120 °C
Yield: 17.2 %

Procedure:
A mixture of 2-(3-bromo-4-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.63 g, 1.55 mmol), morpholine (1.35 g, 15.5 mmol), copper (I) iodide (0.18 g, 0.93 mmol), L-proline (89 mg, 0.78 mmol) and potassium carbonate (0.64, 4.65 mmol) in DMSO (3 mL) was heated for 4 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-(4-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.11 g, 17%) as a white solid: LC/MS m/e calcd for C24H29FN2O3 (M+H)+: 413.5, observed: 413.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[F:8][C:9]1[C:10]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:12]=[CH:13][C:14]=1[CH:15]=[O:16]
Reactant: O=Cc1cccc(B(O)O)c1F
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1cccc(-c2ccccn2)c1F
Temperature: 80 °C

Procedure:
A mixture of commercially available 2-bromopyridine (200 mg; 1.26 mmol), (2-fluoro-3-formylphenyl)boronic acid (212 mg; 1.26 mmol), K2CO3 (699 mg; 5.06 mmol), and PdCl2(dbpf) (11 mg; 0.017 mmol) in MeCN (5 ml) and water (5 ml) was heated to 80° C., under nitrogen, for 2 h. After cooling to rt, MeCN was removed under reduced pressure, and the aq. layer was extracted with AcOEt (2×). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (toluene/AcOEt=8/2) afforded 2-fluoro-3-(pyridin-2-yl)benzaldehyde as a yellow solid. LC-MS (conditions C): tR=0.78 min.; [M+H]+: 202.20 g/mol.
Reaction SMILES: C(NC(=O)NC1C=CC(C2N=C(N3CCOC[C@@H]3C)C3CCN(C(OC(C)(C)C)=O)CC=3N=2)=CC=1)C.Cl[C:38]1[N:39]=[C:40]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]2[CH3:58])[C:41]2[CH2:46][N:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][C:42]=2[N:43]=1.CC1(C)C(C)(C)OB([C:67]2[CH:72]=[CH:71][C:70]([NH:73][C:74](=[O:80])[NH:75][CH2:76][C:77]([OH:79])=[O:78])=[CH:69][CH:68]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:50]([O:49][C:47]([N:45]1[CH2:46][C:41]2[C:40]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]3[CH3:58])=[N:39][C:38]([C:67]3[CH:68]=[CH:69][C:70]([NH:73][C:74](=[O:80])[NH:75][CH2:76][C:77]([OH:79])=[O:78])=[CH:71][CH:72]=3)=[N:43][C:42]=2[CH2:44]1)=[O:48])[CH3:51]
Reactant: CC1(C)OB(c2ccc(NC(=O)NCC(=O)O)cc2)OC1(C)C
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCC(=O)O)cc3)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as described for intermediate 5, using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)acetic acid as starting materials, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by prep HPLC (low pH) yielding (6.5 mg, 0.01 mmol, 9%).
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([NH:8][CH3:1])[CH2:14][CH2:13]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(N2CCC(N(C)Cc3ccccc3)CC2)cn1
Solvent: CO
Product: CNC1CCN(c2ccc(OC)nc2)CC1
Reaction time: 3 h
Yield: 78 %

Procedure:
N-Benzyl-1-(6-methoxypyridin-3-yl)-N-methylpiperidin-4-amine (450 mg, 1.447 mmol, 1.0 eq.) was dissolved in MeOH (6 ml) and degassed with N2. Pd(OH)2 (225 mg, 50%) was then added and hydrogenation was carried out for 3 hours. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure and used in the next stage without being purified further. Yield: 78% (250 mg, 1.13 mmol)
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[CH:8][C:9]([F:34])=[C:10](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:11]=1)(=[NH:5])[NH2:4].Cl.[C:36](=[NH:41])(OCC)[CH3:37].C(N(CC)CC)C.Cl>C(O)C.O1CCOCC1.CO>[ClH:1].[ClH:1].[C:36]([N:31]1[CH2:30][CH2:29][CH:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([N:15]([CH2:14]/[CH:13]=[CH:12]/[C:10]3[CH:11]=[C:6]([C:3](=[NH:4])[NH2:5])[CH:7]=[CH:8][C:9]=3[F:34])[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:22][CH:23]=2)[CH2:33][CH2:32]1)(=[NH:41])[CH3:37]
Reactant: CCOC(C)=N
Reactant: CCS(=O)(=O)N(C/C=C/c1cc(C(=N)N)ccc1F)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CO
Product: CCS(=O)(=O)N(C/C=C/c1cc(C(=N)N)ccc1F)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 144.3 %

Procedure:
To a solution of N-[3-(5-amidino-2-fluorophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]ethanesulfonamide dihydrochloride (534 mg) in ethanol (20 ml) were added ethyl acetimidate hydrochloride (371 mg) and triethylamine (0.70 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. After addition of a 4M solution of hydrogen chloride in dioxane (2 ml), the resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 20% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. The resulting amorphous solid was dissolved in water (10 ml) and the solution was lyophilized to give the title compound (415 mg, yield 75%) as a colorless amorphous solid.