Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH2:21][CH2:22][O:23][CH2:24][CH:25]=4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1>[Pd].CO>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(C3=CCOCC3)cc12
Agent: [Pd]
Solvent: CO
Product: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(C3CCOCC3)cc12
Reaction time: 60 h

Procedure:
A 25-mL flask was charged with (S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (211 mg, 0.601 mmol) and MeOH (75070 μL). The mixture was sonicated for 1 min to give an opaque mixture. Palladium on carbon (63.9 mg, 0.060 mmol) was added, and H2 (g) was bubbled through the mixture for 1 min. The mixture was stirred further under a balloon of H2 (g) for 60 hours. The mixture was filtered through celite with the aid of methanol. The filtrate was evaporated, and the residue was chromatographed on a 40-g Redi-Sep column with 0-100% of a 90:10:1 mix of DCM/MeOH/NH4OH to give (S)-2′-amino-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]\C#N)=[CH:10][CH:9]=1.[Mg].CI.S(=O)(=O)(O)O.CC[O:29][CH2:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](/[C:14](/[CH3:18])=[CH:15]/[C:30](=[O:29])[CH3:31])=[CH:12][CH:13]=1
Reactant: CCOCC
Reactant: C/C(=C/C#N)c1ccc(-c2ccccc2F)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClCCl
Solvent: CI
Product: CC(=O)/C=C(\C)c1ccc(-c2ccccc2F)cc1
Temperature: 0 °C

Procedure:
A solution of 23.7 gm (0.1 mol) of 3-(2'-fluoro-4-biphenylyl)-crotononitrile in 500 ml of dry methylene chloride was added dropwise over a period of 75 minutes to a Grignard reagent prepared from 12.2 gm (0.5 mol) of magnesium and 71 gm (0.5 mol) of methyl iodide in 500 ml of anhydrous ether, and the resulting mixture was refluxed for 4.5 hours. Thereafter, the cooled reaction mixture was stirred into a mixture consisting of 2 kg of ice and 100 ml of concentrated sulfuric acid. The organic phase was separated, washed with aqueous 1% sulfuric acid, then with water, then with a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate, and evaporated in vacuo. The solid residue was recrystallized from cyclohexane, yielding 7.2 gm (28% of theory) of fallow crystalline (E)-4-(2'-fluoro-4-biphenylyl)-3-penten-2-one, m.p. 92°C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:6][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C/C=C/C(=O)OCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
Crotonic acid (17.2 g, 200 mmol) was dissolved in N,N-dimethylformamide (100 ml) with cooling in an ice bath under nitrogen, and powdered potassium carbonate (15.2 g, 110 mmol) was added. The mixture was stirred for 30 minutes, and 4-methoxybenzyl chloride (29.8 g, 190 mmol) was then added dropwise over 15 minutes. The reaction mixture was stirred at mom temperature for four hours and at 45° C. for 14 hours. Ethyl acetate (500 ml) and water (200 ml) were added to the reaction liquid. The separated organic layer was washed with water (100 ml×2) and brine (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a crude product of the title compound (40.51 g, yield: 98.2%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH:23]1CC(=O)NC1=O>CO>[CH3:23][O:20][C:19](=[O:21])[C@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1CC(O)C(=O)N1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h

Procedure:
N-Boc-O-benzylserine-hydroxysuccinimide (16.0 g, 40.8 mmol) was dissolved in methanol (300 ml) and stirred at 50° C. for 24 hours. The solvent was evaporated and the residue was taken up in ethyl acetate (120 ml), washed with aqueous saturated sodium bicarbonate (2×50 ml) and water (50 ml). The organic solution was dried with sodium sulphate and after evaporation of the solvent the N-Boc-O-benzylserine methyl ester was isolated as a colourless oil. Yield 9.9 g (83%). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH:22]=3)=[C:14]([Br:19])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:36][CH3:37])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:36][CH3:37])[CH:11]=3)[N:16]=[CH:15][C:14]=2[Br:19])=[CH:22][CH:23]=1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)c(Br)cnc2cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)c(Br)cnc2cc1O

Procedure:
A mixture of N-[4-(7-benzyloxy-3-bromo-6-methoxy-quinolin-4-yloxy)-phenyl]-benzamide (35 mg, 0.063 mmol) in TFA (1 ml) and thioanisole (80 μl) was refluxed for 4 hours, cooled and concentrated under high vacuum.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[C:16]4[CH:22]=[C:21]([C:23](O)=[O:24])[S:20][C:17]=4[NH:18][N:19]=3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.C(OC(Cl)=O)C.[CH3:43][C:44]([NH2:52])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45]>CN(C)C=O.ClCCl>[CH3:43][C:44]([NH:52][C:23]([C:21]1[S:20][C:17]2[NH:18][N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:27][CH:26]=3)[C:16]=2[CH:22]=1)=[O:24])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45]
Reactant: CC(C)(N)c1ccccc1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)O)cc34)cc2)CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NC(C)(C)c5ccccc5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To an ice-cooled suspension of 3-([4-(4-methylpiperazin-1-yl)benzoyl]amino}-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (113 mg, 0.27 mmol) and N,N′-diisopropylethylamine (2.1 mmol, 0.38 mL) in 3 mL of N,N-dimethylformamide were added, dropwise, 0.154 mL of ethylchloroformate (1.6 mmol). After 20 minutes, 1-methyl-1-phenyl-ethylamine (0.302 mL, 2.1 mmol) was added to the obtained solution and the reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and washed with an aqueous solution of sodium bicarbonate. After solvent evaporation the residue was taken up with methyl alcohol (9 mL) and triethylamine (1 mL) and stirred at 40° C. for 2 hours. The reaction mixture was then evaporated to dryness to give an oil, which was purified by flash chromatography over silica gel, using dichloromethane/methanol/ammonia 7N solution in methyl alcohol (93:6:1) as eluent, to afford the title compound as a white solid (61 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:25]1(C2C=CC(C=O)=CC=2)CCC1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:22])[F:21])[CH:13]=3)=[CH:23][CH:24]=2)[CH2:3][CH2:2][CH2:25]1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: O=Cc1ccc(C2CCC2)cc1
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)c1cccc(CCNCc2ccc(C3CCC3)cc2)c1

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 180 mg of 4-cyclobutyl-benzaldehyde (1.23 mmol) (described in example S113), 213 mg of 2-(3-trifluoromethylphenyl)-ethylamine (1.23 mmol) and 64 mg of sodium borohydride (1.69 mmol). The isolated yellow oil (343 mg, 92%) was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.85 (m, 1H), 1.92-2.21 (m, 3H), 2.33 (m, 2H), 2.89 (m, 4H), 3.53 (quint, J=9 Hz, 1H), 3.78 (s, 2H), 7.19 (m, 4H), 7.39 (m, 2H), 7.46 (m, 2H).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH:5]=O.O.[NH2:17]N>C(O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[N:2][NH:17][CH:5]=1
Reactant: COc1ccccc1C(C=O)=CN(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1cn[nH]c1
Yield: 68 %

Procedure:
A solution of 3-dimethylamino-2-(2-methoxyphenyl)propenal (4.68 g, 22.8 mmol) and hydrazine hydrate (6.7 ml) in ethanol (100 ml) is heated at reflux for 30 minutes. The solvent is removed in vacuo and the residue is chromatographed (silica gel, dichloromethane/ethanol 95:5) to give 2.69 g of 4-(2-methoxyphenyl)pyrazole (68%).
Reaction SMILES: O.C(O)(=O)C1NC(=O)NC(=O)C=1.O.[F:14][C:15]1[C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20][C:16]=1C(O)=O>>[F:14][C:15]1[C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20][CH:16]=1
Reactant: O=C(O)c1[nH]c(=O)[nH]c(=O)c1F
Agent: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Solvent: O
Product: O=c1[nH]cc(F)c(=O)[nH]1
Temperature: 260 °C

Procedure:
In the reaction, the conversion of the orotic acid monohydrate was 100% and the yield of 5-fluoro-orotic acid monohydrate was 85.0%. The crystals were heated at 260° C. under a reduced pressure of lower than 1 mmHg to perform the decarboxylation to obtain 22.5 g of 5-fluorouracil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH3:13]>[Pd].CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[CH3:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)ccc1C
Yield: 99.3 %

Procedure:
A solution of 2-methyl-5-nitro-benzoic acid methyl ester (1.96 g, 10.0 mmol) in 4:1 MeOH/EtOAc (25 mL) was shaken at room temperature with a suspension of 10% Pd/C (200 mg, 0.19 mmol) under hydrogen atmosphere (35 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give an orange oil (1.64 g, 99%). 1H NMR (CDCl3) δ2.47 (s, 3H), 3.62 (br s, 2H), 3.87 (s, 3H), 6.75 (dd, 1H, J=8.1, 2.7 Hz), 7.02 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=2.7 Hz).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+]>CO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][C@H:16]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCN1CC[C@H](CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a solution of tert-butyl 3-((S)-3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidin-1-yl)propanoate (108 mg, 0.245 mmol) in methanol (3 mL) was added sodium hydroxide (6M, 0.5 mL, 3.00 mmol) and the mixture was stirred at r room temperature for 18 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 51 mg of product (HCl salt) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1ccc(F)nc1
Product: Cc1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=308.2 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-5-methyl-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22](N)=[CH:21][N:20]=1)=[CH:12][CH:11]=3)=[O:4].N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cu][C:37]#[N:38].[C-]#N.[K+]>O.Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:37]#[N:38])=[CH:21][N:20]=1)=[CH:12][CH:11]=3)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccc(Oc3ccc(N)cn3)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: COC(=O)c1cc2c(cn1)[nH]c1ccc(Oc3ccc(C#N)cn3)cc12

Procedure:
A suspension of 1.7 g of amino derivative (Example 24) in 10 ml of water and 2.5 ml of hydrochloric acid (37%) is combined dropwise at -5° C. with a solution of 0.4 g of NaNO2 in 1.5 ml of water, then stirred for another hour at 0°-5° C. By adding sodium carbonate, the solution is then adjusted to pH 5.5-6 and poured into a mixture, preheated to about 60° C., of 0.5 g of copper (I) cyanide and 1.6 g of potassium cyanide in 10 ml of water. After the reaction is completed, the cooled-off solution is extracted with dichloromethane, the organic phase is washed with water and concentrated. The residue is purified over silica gel, thus obtaining 1.12 g (65%).
Reaction SMILES: [OH:1][C:2]1[C:3](=O)[CH:4]=[CH:5][C:6]([N:9]=[O:10])=[CH:7][CH:8]=1.[OH-].[NH4+:13]>>[NH2:13][C:3]1[C:2](=[O:1])[CH:8]=[CH:7][C:6]([N:9]=[O:10])=[CH:5][CH:4]=1
Reactant: O=Nc1ccc(O)c(=O)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ccc(N=O)ccc1=O

Procedure:
Conc. ammonium hydroxide solution (50 ml) is added dropwise to a suspension of 2-hydroxy-5-nitroso-2,4,6-cycloheptatrien-1-one [10 g, described by T. Nozoe et al., Sci. Repts. Tohoku Univ., 35, 274- 82 (1952), (CA 47 3291a)] collected and washed with water then acetone to give 2-amino-5-nitroso-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [NH2:1][C@@H]1C2CCN(CC2)[C@H]1CC1C=NC=CC=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:21](O)=[O:22].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:21]([NH2:1])=[O:22]
Reactant: N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1
Reactant: O=C(O)c1cc(F)cc(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a suspension of (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (20 mg, 0.092 mmol, prepared as described in PCT WO 09/018505, herein incorporated by reference with regard to such synthesis), o-(benzotriazol-1-yl)-N,N,N,1-tetramethyluronium hexafluorophosphate (HBTU, 41.7 mg, 0.110 mmol) and 3,5-difluorobenzoic acid (17.4 mg, 0.110 mmol) in N,N-dimethylformamide (DMF, 2 ml) was added triethylamine (28 mg, 0.28 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (200 ml) and washed with 20% aqueous potassium carbonate. The residue was purified by silica gel chromatography with the eluent methanol:triethylamine=300:1. The solvent was removed to give (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide (30 mg, 76%), purity by HPLC: 100% (214 nm), 98.2% (254 nm); 1H NMR (400 MHz, CDCl3) d 8.48 (d, j=2.0 Hz, 1H), 8.36 (dd, j=1.7 Hz, j=4.9 Hz, 1H), 7.56-7.60 (m, 1H), 7.14-7.20 (m, 1H), 7.05-7.14 (m, 2H), 6.87-6.96 (m, 1H), 6.23 (d, j=7.8 Hz, 1H), 3.88-3.96 (m, 1H), 3.02-3.13 (m, 1H), 2.82-3.00 (m, 4H), 2.65-2.82 (m, 2H), 1.97-2.05 (m, 1H), 1.58-1.84 (m, 3H), 1.43-1.55 (m, 1H); ESI-MS 358.1(MH)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][CH3:15])[NH:12][C:11](=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:25]([CH3:26])=[C:24](I)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@H:9]1[CH2:10][C:11](=[O:16])[N:12]([C:24]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([Cl:17])[C:25]=2[CH3:26])[C@H:13]1[CH2:14][CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1C

Procedure:
Using (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (1.00 g), 2-chloro-4-iodo-3-methylbenzonitrile (1.31 g), cesium carbonate (2.08 g), tris(dibenzylideneacetone)dipalladium(0) (193 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (490 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 134.5 mg, yield: 8%).
Reaction SMILES: Cl.Cl.C([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:27]=[C:26]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:32]=4)=[O:30])[CH:25]=[CH:24][C:23]=3[CH3:43])=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:44][CH3:45])C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:27]=[C:26]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:32]=4)=[O:30])[CH:25]=[CH:24][C:23]=3[CH3:43])=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:44][CH3:45]
Reactant: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1O
Temperature: 25 °C

Procedure:
A mixture of 7-benzyloxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline dihydrochloride (4.45 g) and trifluoroacetic acid (20 ml) was stirred and heated to reflux for 90 minutes. The mixture was cooled to ambient temperature and evaporated. A mixture of a dilute aqueous sodium bicarbonate solution and methylene chloride was added to the residue and the resultant mixture was stirred for 30 minutes at ambient temperature. The precipitated solid was collected, washed with water and, dried under vacuum at 60° C. to give 7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (3.67 g; NMR: 2.17 (s, 3H), 3.52 (t, 4H), 3.71 (t, 4H), 3.98 (s, 3H), 7.09 (d, 1H), 7.19 (s, 1H), 7.23 (s, 1H), 7.37 (d, 1H), 7.6 (d, 1H), 7.84 (s, 1H), 8.05 (s, 1H), 8.25 (d, 1H), 8.66 (s, 1H), 10.42 (s, 1H), 11.06 (s, 1H); m/s: M+H+ 487.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[N:11]=[CH:10]2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N1C=C(C(OC)=O)N=C1.BrC1C(F)=C(C)C=CN=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:1][C:2]1[C:3]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]=[CH:10]2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1cn(-c2nccc(C)c2F)cn1
Agent: [Cu]I
Agent: COC(=O)c1c[nH]cn1
Agent: Cc1ccnc(Br)c1F
Solvent: CS(C)=O
Product: Cc1ccnc(-n2cnc(C(=O)O)c2)c1F
Yield: 3 %

Procedure:
Methyl 1-(3-fluoro-4-methylpyridin-2-yl)-1H-imidazole-4-carboxylate: A suspension of methyl 1H-imidazole-4-carboxylate (83 mg, 0.658 mmol), 2-bromo-3-fluoro-4-methylpyridine (200 mg, 1.053 mmol), copper (I) iodide (125 mg, 0.658 mmol) and potassium carbonate (546 mg, 3.95 mmol) in DMSO (2 mL) was heated at 120° for 90 min under microwave conditions. The reaction mixture was quenched with H2O, and the solid was suspended in EtOAc and MeOH. The combined organic layer was concentrated in vacuo, yielding oily residue, which was purified by reverse phase HPLC to give the desired product (5 mg, 3%). MS(ESI) m/z: 236.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH:10]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:12][C:13]([O:15]CC=C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:31])[CH:10]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)CCC(NC(=O)CCCCCCCCC)C(=O)OCc1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)NC(CCC(=O)O)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Pd(O)-catalyzed deprotection of the allyl ester proceeded as follows to yield 2-Decanoylamino-pentanedioic acid 1-benzyl ester (8). To a solution of 752 mg (1.74 mmol) of 2-decanoylamino-pentanedioic acid 7 in 10 mL of CH2Cl2 was added 100 mg (0.087 mmol) of tetrakistriphenylphosphine Pd(O) followed by 0.52 mL (1.9 mmol) of tributyltin hydride. After 15 min, the reaction mixture was quenched with 10 mL of a 10% HCl solution. The aqueous layer was reextracted with 15 mL of CH2Cl2 and the organic layer dried (Na2SO4), concentrated in vacuo, and chromatographed on SiO2 (Hexanes/EtOAc, 9:1) to provide 545 mg (79.9%) of 8 as a thick oil: [α]D +2.8° (c 1.2, CHCl3, 21° C.); IR (neat) 3351, 3064, 2995, 2852, 1738, 1712, 1657, 1536, 1454, 1380, 1364, 1265, 1209, 1183, 1121, 739 cm-1 ; 1H NMR δ 10.9-10.7 (bs, 1 H), 7.22 (s, 5 H), 6.58 (d, 1 H, J=7.8 Hz), 5.09 (s, 2 H), 4.63 (dd, 1 H, J=8.1, 12.9 Hz), 2.4-2.25 (m, 2 H), 2.2-2.1 (m, 3 H), 2.0-1.9 (m, 1 H), (m, 6 H), 1.53 (t, 2 H, J=6.6 Hz), 1.19 (bs, 12 H), 0.81 (t. 3 H, J=6.0 Hz); 13C NMR δ 176.9, 174.0, 171.8, 134.9, 128.5, 128.4, 128.1, 67.3, 51.4, 36.2, 31.7, 29.9, 29.3, 29.2, 29.1, 27.0, 25.5, 22.5, 14.0; MS (El) m/z (relative intensity) 391 (54), 373 (62), 279 (13), 256 (19), 178 (27), 178 (23), 155 (13), 146 (6), 130 (7), 102 (100); HRMS (El) m/z calculated for C22H33NO5 :391.2358, found: 391.2350.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].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].C(#N)C>[CH3:11][C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:3]=2)[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:9]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1nn(C2CCCCO2)c2cnc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1nn(C2CCCCO2)c2cnc(-c3ncccn3)cc12
Temperature: 130 °C
Yield: 95.4 %

Procedure:
In a microwave reaction vials was charged with 5-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (296 mg, 1.0 mmol), Pyrimidine-5-boronic acid (185 mg, 1.5 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (81.7 mg, 0.1 mmol), 1.00 M of Potassium acetate in Water (1.5 mL, 1.5 mmol), 1.00 M of Sodium carbonate in Water (1.5 mL, 1.5 mmol), and Acetonitrile (10 mL). The reaction mixture was heated under microwave at 130° C. for 30 minutes. The mixture was concentrated and the residue was purified on silica eluted with 0 to 5% MeOH in DCM with 1% NH4OH to afford 3-methyl-5-(pyrimidin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (281.9 mg, 95.45%).