Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][C:30]1[N:31]=[C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[S:33][CH:34]=1.[CH3:43][C:44]([CH3:46])=[O:45]>C1COCC1>[OH:45][C:44]([C:34]1[S:33][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[N:31][C:30]=1[CH2:29][CH2:28][O:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)([CH3:46])[CH3:43]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)cs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)c(C(C)(C)O)s1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of diisopropylamine (9.5 mL, 67.2 mmol) in THF (100 ml) was added butyllithium (42 mL, 1.6M in hexanes, 67.2 mmol) drop wise at −78° C. and stirred for 30 min. Thus obtained LDA solution was immediately added by cannulation to a solution of Example 89C (7.36 g, 22.4 mmol) in THF (100 ml) at −78° C. and stirred for 30 min at the same temperature. Then, dry acetone (8.2 ml, 112 mmol, Acros) was added slowly and the reaction mixture was removed from cold bath and allowed to reach room temperature for overnight while stirring. The reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.6 g (53%) of the title compound. MS (ESI+) m/z 387 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:19])=[O:12])[NH:6]2
Reactant: Cc1cccc2[nH]c(C(=O)O)cc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2c(C)cccc2[nH]1

Procedure:
Under an argon atmosphere 4-methyl-1H-indole-2-carboxylic acid (0.64 g, 3.65 mmol) was dissolved in 20 ml of methanol. Concentrated sulfuric acid (0.5 ml) was added and the resulting mixture was heated to reflux and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. Some solvent was removed in vacuo and the resulting crystals were removed by filtration. The solids were taken up in diethyl ether, washed twice with saturated sodium bicarbonate, and then once with brine. The organic fraction was dried over magnesium sulfate and the solvents were removed in vacuo.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:27]1[CH:29]=[CH:30][C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:9]3[N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH:20]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 72 °C

Procedure:
To a stirred mixture of N-Boc-pyrrole-2-boronic acid (114 mg, 0.54 mmol) and 4-((2-chloropyridin-4-yl)oxy)aniline (100 mg, 0.45 mmol) in 8 ml of 1,4-dioxane, was added PdCl2(PPh3)2 (10 mg, 0.014 mmol) and 1M Na2CO3 aqueous solution (0.5 ml, 1.0 mmol). The mixture was heated at 72° C. under N2 for one hour, cooled to room temperature and poured into 100 ml of water. The resulting mixture was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (50 ml), dried over Na2SO4, and evaporated to give a brown oil, which was purified by silica gel chromatography with a gradient of 20˜50% EtOAc/hexanes to give tert-butyl 2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate as colorless oil. Yield: 110 mg, 70%.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[CH3:36][CH:37]1[O:42][CH:41]([CH3:43])[CH2:40][NH:39][CH2:38]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:39]5[CH2:38][CH:37]([CH3:36])[O:42][CH:41]([CH3:43])[CH2:40]5)[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: CC1CNCC(C)O1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CC(C)OC(C)C1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2,6-dimethylmorpholino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and 2,6-dimethylmorpholine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[C:10]([O:17][CH3:18])(=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].C(Cl)Cl>O1CCOCC1.[Cu]Br>[CH3:15][O:14][C:12](=[O:13])[CH:11]([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)[C:10]([O:17][CH3:18])=[O:16]
Reactant: Clc1cc(Br)cc(Br)c1
Reactant: COC(=O)CC(=O)OC
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1,3-Dibromo-5-chlorobenzene (25 g, 93 mmol), dimethyl malonate (23.4 mL, 204 mmol), and copper(I) bromide (29.2 g, 204 mmol) were combined in 1,4-dioxane (300 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 8.2 g, 204 mmol) was added slowly, and the reaction was stirred at room temperature for 20 minutes, and then stirred at 105° C. for 4 hours. After cooling to room temperature, the mixture was worked-up with CH2Cl2 and aqueous Na4OH. The organic layer was concentrated, and the residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[O:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:9]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:22]1[O:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([O:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:16]=2[C:23]=1[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCNC4)c23)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Add 300 mg of palladium black to an argon-blanketed solution of 2600 mg (4.69 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]-pyrimidine in 25 ml of a 4.4% solution of formic acid in methanol and stir at room temperature for five hours. Then add another 300 mg of palladium black and 0.9 ml of formic acid and stir at room temperature for a further 16 hours. After filtering off the catalyst, wash the catalyst residue with methanol/water. Concentrate the filtrate under reduced pressure, stir the residue in acetonitrile, filter off and dry under reduced pressure. 1376 mg (68% of theory) of the desired product are obtained.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=1.[OH-].[K+].CO>O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:25])=[O:2])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Yield: 93.1 %

Procedure:
The title compound is prepared by the procedure of Example 2 using 234 g of 3-(tetradecyloxy)benzoic acid methyl ester, 113.0 g of potassium hydroxide, 1 L of methyl alcohol and 120 ml of water. The solid residue is recrystallized from methyl alcohol/ethyl alcohol to give 209 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]([CH2:22][C@@H:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[C@@H:55]([CH3:64])[C:56]([N:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)=[O:57])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH3:13][C@@H:12]([N:14]([CH2:22][C@@H:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][C:7]1[C:6]2[C:10](=[C:2]([O:1][C@H:55]([CH3:64])[C:56]([N:58]3[CH2:63][CH2:62][O:61][CH2:60][CH2:59]3)=[O:57])[CH:3]=[CH:4][CH:5]=2)[NH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)N2CCOCC2)cc1
Reactant: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O)cccc12)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O[C@H](C)C(=O)N3CCOCC3)cccc12)c1cccnc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of tert-butyl (1R)-2-(7-hydroxy-1H-indol-3-yl)-1-methylethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)ethyl)carbamate (300 mg, 0.570 mmol) in N,N-dimethylformamide-(1.0 mL) are added potassium carbonate (98.5 mg, 0.714 mmol), (1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzenesulfonate (JP-A-2000-273085) (196 mg, 0.627 mmol), and the mixture is stirred at 50° C. for one hour. To the reaction solution are added potassium carbonate (45 mg), (1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzene-sulfonate (120 mg), and the mixture is stirred at 60° C. for 10 hours. After allowed to cool, to the reaction solution is added ethyl acetate (50 mL), and the mixture is filtered, washed with water and a saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (chloroform/methanol=100/1→20/1) to give tert-butyl (1R)-1-methyl-2-(7-(((1R)-1-methyl-2-morpholin-4-yl-2-oxo-ethyl)oxy)-1H-indol-3-yl)ethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)-ethyl)carbamate (209 mg, yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:13]1([NH:16][CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([C:18](=[CH:17][NH:16][CH:13]1[CH2:14][CH2:15]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(Cl)nc1Cl
Reactant: CCOC(=O)C=CNC1CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)nc1Cl

Procedure:
In dry dioxane, 2,6-dichloro-5-fluoronicotinoyl chloride, prepared in Reference Example 10-(2), was allowed to react with ethyl β-cyclopropylaminoacrylate in the presence of triethylamine to give ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-cyclopropylaminoacrylate, m.p. 129°-130° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:30]1([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCCc2ccccc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 μL (0.40 mmol) 1,2,3,4-tetrahydroquinoline, 0.15 mL (0.87 mmol) DI PEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[I-:16].[K+]>CC(C)=O>[I:16][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCI
Temperature: 25 °C
Reaction time: 96 h
Yield: 78.9 %

Procedure:
A solution of 50.0 g (0.187 mol) of N-(3-bromopropyl)phthalimide in 1.2 L of acetone was treated with 208.5 g of potassium iodide and stirred at room temperature for 4 days. The reaction was filtered and the filtrate was diluted with 4 L of ether. This was then filtered through CELITE. The filtrate was concentrated under reduced pressure to a yellow solid. This was recrystallized from hexane to yield 46.5 g (79%) of off-white solid.
Reaction SMILES: [Li].C([Li])CCC.[CH:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:18](=[O:20])[CH3:19]>CCCCCC.C(NC(C)C)(C)C>[OH:20][CH:18]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:19]
Reactant: CC=O
Reactant: CCOC(=O)C1CCCCC1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1(C(C)O)CCCCC1

Procedure:
A solution of lithium isopropylamidide was prepared from 300 cm3 butyl lithium 1.5 M in hexane and 52 g of diisopropylamine. At -40° C. 62.4 g (0.4 mole) of ethyl cyclohexyl-carboxylate were added, then at -80° C. 17.6 g of acetaldehyde were also added. The solvent was evaporated off and the mixture was poured into acid ice water. After extraction with benzene the ether was distilled off and a colourless liquid was obtained.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[O:19].[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([C:14]1[N:13]([CH3:12])[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: O=Nc1ccccc1
Reactant: Cn1ccnc1C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1ccnc1C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 1-methyl-1H-imidazole-2-carbaldehyde (110 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:14](=[O:25])[N:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[C:17]([Cl:19])[N:18]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:14](=[O:25])[N:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[C:17]([Cl:19])[N:18]=1
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Reactant: Nc1ccc(Br)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(CC)n1cc(Cl)nc(Nc2ccc(Br)cc2Br)c1=O
Yield: 44.7 %

Procedure:
2,4-Dibromoaniline (500 mg), toluene (8 mL), and sodium hydride (60% in oil, 398 mg) were stirred for 10 minutes at room temperature and then 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone (468 mg, Example 1, part B) was added. The reaction was heated at reflux 3 hours, cooled, and quenched with water (50 mL). The mixture was extracted with ethyl acetate (100 mL), which was washed with brine, then dried and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:19) affording 400 mg of material, which was crystallized from ether/hexane to give the title compound (240 mg). Elemental analysis: calcd. for C15H16N3OClBr2 : C, 40.07; H, 3.597; N, 9.356; Cl, 7.895; Br, 35.55. Found: C, 40.41; H, 3.49; N, 9.34; Cl, 8.27; Br, 35.71.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:28])=[N:10][CH:11]=[N:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([C:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1)#[N:30]>>[NH2:28][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:34]([C:31]3([C:29]#[N:30])[CH2:33][CH2:32]3)=[O:35])[CH:7]=[CH:6][CH:5]=2)=[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[N:12]=[CH:11][N:10]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Product: N#CC1(C(=O)Nc2cccc(-c3c(N)ncnc3Oc3ccc(Oc4ccccc4)cc3)c2)CC1
Yield: 66 %

Procedure:
N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamide was prepared from 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and 1-cyanocyclopropanecarboxylic acid using Method E (66% yield). HPLC: 100%, RT=4.485 min. MS: m/z=465 [M+H]+, RT=2.26 min. 1H-NMR (DMSO-d6) δ 10.07 (s, 1H), 8.10 (s, 1H), 7.64-7.61 (m, 2H), 7.43-7.36 (m, 3H), 7.18 (d, 1H), 7.11 (t, 1H), 7.06 (d, 2H), 7.00-6.97 (m, 4H), 6.58 (broad s, 2H), 1.65 (s, 4H).
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][CH:21]([CH2:23][C:24]([O:26]C)=[O:25])[C:20](=[O:28])[N:19]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:18][C:17]=3[CH:37]=2)=[O:12])=[CH:6][CH:5]=1>C1COCC1.O>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][CH:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20](=[O:28])[N:19]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:18][C:17]=3[CH:37]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)CC1Nc2ccc(C(=O)Nc3ccc(N)nc3)cc2CN(CCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccc3c(c2)CN(CCc2ccccc2)C(=O)C(CC(=O)O)N3)cn1
Reaction time: 22.5 h
Yield: 86.1 %

Procedure:
1.0 N LiOH (1.1 mL, 1.1 mmol) was added dropwise to a mixture of methyl (±)-7-[[(6-amino-3-pyridinyl)amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.23 g, 0.48 mmol) in THF (12 mL) and H2O (17 mL) at RT. After 22.5 h, the dark reddish-brown reaction mixture was concentrated on the rotavap to remove excess THF. The resulting reddish solution was cooled in an ice-bath, and neutralized with 1.0 N AcOH (1.8 mL). The precipitate was collected by suction filtration, washed with water and ether, and air-dried to give the title compound (0.19 g, 86%) as a pinkish-purple solid: 1H NMR (400 MHz, DMSO-d6) δ9.55 (s, 1H), 6.40-8.29 (m, 7H), 5.69 (s, 2H), 5.42 (d, J=17 Hz, 1H), 5.09 (br, 1H), 3.95 (dd, J=17,1H), 3.59-3.65 (m, 2H), 2.51-2.82 (m, 4H); MS (ES) m/e 460.2 (M+H)+. Anal. Calcd for C25H25N5O4.9/4 H2O: C, 60.05; H, 5.98; N, 14.01. Found: C, 59.79; H, 5.92; N, 13.64.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=2)[CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][C:37]([F:40])([F:39])[F:38]>CN(C)C=O>[F:38][C:37]([F:40])([F:39])[CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=2)[CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[CH:27][CH:28]=1
Reactant: FC(F)(F)CI
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cc3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cc3)c2)CC1
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A solution of tert-butyl 4-(3-(4-hydroxyphenoxy)benzylidene)piperidine-1-carboxylate (150 mg, 0.393 mmol) in dimethylformamide (5 mL) was treated with potassium carbonate (218 mg, 1.572 mmol), 18-crown ether (210 mg, 0.786 mmol) and 2-iodo-1,1,1 trifluoroethane (105 mg, 0.491 mmol). The mixture was stirred overnight at a temperature below 50° C. The reaction mixture was washed with water and organic part extracted with ether (2×50 mL). The organic fractions were dried over sodium sulfate and evaporated. The crude material was purified by column chromatography (10-20% ethyl acetate/hexanes) to give the title compound (50 mg, 27%). 1H-NMR (500 MHz, CDCl3): δ ppm 7.26 (m, 1H), 7.00 (d, J=6 Hz, 2H), 6.94 (m, 3H), 6.80 (m, 2H), 6.29 (s, 1H), 4.36 (m, 2H), 3.49 (s, 2H), 3.38 (s, 2H), 2.42 (s, 2H), 2.30 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
A solution of benzyl 2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.140 g, 0.25 mmol) in ethanol (1.4 ml) is hydrogenated with 10% palladium/charcoal (0.03 g) for 4.5 hours at 50° C. under 5 bar of hydrogen. The mixture is filtered, evaporated down in vacuo and the evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=10/1).