Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][C@@H:22]([OH:25])[CH2:23][OH:24])[CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH3:20])[CH:5]=[CH:6][CH:7]=1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Si:30]([O:24][CH2:23][C@H:22]([OH:25])[CH2:21][N:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:16]2[C:11]([N:12]([CH3:20])[C:13](=[O:19])[N:14]([CH3:18])[C:15]2=[O:17])=[CH:10]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(C[C@@H](O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Reaction time: 1 h

Procedure:
A solution of (R)-5-(3-chlorophenyl)-6-(2,3-dihydroxypropyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.39 g, 3.8 mmol), tert-butylchlorodimethylsilane (633 mg, 4.2 mmol), imidazole (520 mg, 7.6 mmol) and DMAP (47 mg, 0.38 mmol) in DMF (14 mL) was stirred at room temperature for 2 hours. A further portion of tert-butylchlorodimethylsilane (172 mg, 1.1 mmol) was added and the mixture stirred for a further 1 hour. The reaction mixture was diluted with EtOAc (70 mL) and washed with 0.5M HCl (3×35 mL) and brine (1×35 mL). The organic phase was dried over magnesium sulfate and evaporated under vacuum. Trituration with hexane afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][NH:11][C:12](=[O:18])[C:13](OCC)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:9][C:3]1[C:2]2[N:1]=[C:13]([C:12](=[O:18])[NH:11][CH3:10])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=O)NC
Reactant: Cc1cccc(N)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc2c(C)cccc2[nH]1
Temperature: 175 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2,3-diaminotoluene (2.0 g) and ethyl N-methyloxamate (2.36 g) in N,N-dimethylformamide (10 ml) was stirred at 175° C. for 8 hours. After being cooled to ambient temperature, the mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (50:1) to give 4-methyl-2-(N-methylcarbamoyl)-1 H-benzimidazole (1.17 g) as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[OH-].[Na+].O.NC(C)(CC1C=CC=CC=1OC)C(O)=[O:24]>C(#N)C>[C:13]([NH:14][C:10]([CH3:17])([CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:11]([OH:24])=[O:16])(=[O:15])[NH2:12]
Reactant: COc1ccccc1CC(C)(N)C(=O)O
Reactant: COc1ccccc1CC1(C)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1CC(C)(NC(N)=O)C(=O)O

Procedure:
First, 4.40 g of 5-(2-methoxyphenylmethyl)-5-methyl-hydantoin was mixed with 2.64 g of sodium hydroxide and 3.5 g of water, and the mixture was subjected to reaction at 94° C. to 96° C. for 30 hours. The HPLC analysis (column: COSMOSIL 5C18-ARII (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=20/80, flow rate: 1.0 ml/min, detection wavelength: 210 nm, column temperature: 40° C.) of the reaction mixture showed the production of the title compound, 2-amino-3-(2-methoxyphenyl)-2-methyl propionic acid, and the raw material at an area ratio of 78.8:5.5:15.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[CH2:31](O)[CH2:32][OH:33].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[O:33][CH2:32][CH2:31][O:30]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: OCCO
Reactant: COc1cc(CCCCCCC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CCCCCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
A mixture of 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptanal (3.8 g), ethylene glycol (1 g), p-toluenesulfonic acid monohydrate and toluene (50 ml) was stirred for 4 hours under reflux. The reaction mixture was cooled, which was then washed with water and dried (MgSO4), followed by distilling off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:3), was obtained 2-[6-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]hexyl]-1,3-dioxolan (3.9 g, 94%) as an oily product.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:25]([O:27]C)=O.Cl>CO>[O:27]=[C:25]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10][NH:9]1
Reactant: COC(=O)c1nc2ccc(C(=O)O)cc2n1CCCN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Yield: 29.4 %

Procedure:
Triethylamine (14.3 g, 141.7 mmol) is added to a solution of the crude 1-(3-aminopropyl)-2-(methoxycarbonyl)-1H-benzimidazole-6-carboxylic acid hydrochloride (20 g, 47.2 mmol) in methanol (100 mL) and reaction mixture is refluxed for 1 h. The reaction mixture is cooled and acidified with 1M HCl. The solvent is evaporated and water is added. The resultant solid is collected by filtration and purified by acid-base neutralization using sodium bicarbonate and conc. HCl to afford the title compound (3.4 g, 30%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:16]1)=[C:6]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(C3CCCN(S(C)(=O)=O)C3)c(-c3ccccc3)c2c1

Procedure:
To a methylene chloride (0.100 mL) solution of (±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one (30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol) was added methanesulfonyl chloride (0.007 mL, 0.095 mmol). After 24 hours saturated sodium bicarbonate and additional methylene chloride were added. The layers were separated and the organic phase dried with anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by trituration with ether-EtOAc gave a white solid which was isolated by vacuum filtration to give the titled product. ESI+MS: 427.1 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>>[N:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=Nc1cc(F)ccc1C(=O)O
Product: [N-]=[N+]=Nc1cc(F)ccc1C(=O)Cl
Temperature: 80 °C

Procedure:
2-Azido-4-fluoro-benzoic acid (3.01 g, 17 mmol; Barral, Karine; Moorhouse, Adam D.; Moses, John E. Organic Letters (2007), 9(9), 1809-1811) was dissolved at ambient temperature in thionyl chloride (27.3 ml) under an argon atmosphere. The reaction mixture was heated to 80° C. for 1.5 h and brought to dryness under reduced pressure to give 2-azido-4-fluoro-benzoyl chloride as orange oil. 2-Azido-4-fluoro-benzoyl chloride was dissolved at ambient temperature in CH2Cl2 (23 ml) under an argon atmosphere. 4-Chloro-phenylamine (2.12 g, 17 mmol; [106-47-8]) was added and the reaction mixture was stirred at ambient temperature for 14 h. Saturated aqueous NaHCO3 solution was added until a pH of 8 was adjusted, the layers were separated and the aqueous layer was extracted two more times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from heptane/CH2Cl2 to give the title compound (3.08 g, 11 mmol; 64%) as off-white crystals. MS: m/e=291.0 [M+H+].
Reaction SMILES: I[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].[CH3:19][O:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:25]=1[CH3:32].[H-].[Na+]>CN(C=O)C>[CH3:19][O:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[CH:26][C:25]=1[CH3:32]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CI
Reactant: COC(=O)CCc1ccc(CO)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(COCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.3 %

Procedure:
To a solution of 5-Iodomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.14 g, 0.37 mmol) and 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (0.064 g, 0.31 mmol) in DMF (1 mL) is added sodium hydride (60% dispersion, 0.036 g, 1.50 mmol). The mixture is stirred at RT for 3 h. The reaction is quenched with water, and the mixture is extracted with EtOAc. The organics are dried with MgSO4 and concentrated. The crude material is purified by flash chromatography to yield the title compound (0.022 g, 16%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: C[Si](C)(C)C#Cc1cc2c(O)c(C#N)cnc2cn1
Reactant: O=P(Cl)(Cl)Cl
Product: C[Si](C)(C)C#Cc1cc2c(Cl)c(C#N)cnc2cn1

Procedure:
To 500 mg of 4-hydroxy-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 10 mL of phosphorous oxychloride. After two hours at reflux, the excess phosphorous oxychloride was removed in vacuo and ice-water, chloroform, a tract of methanol, and aqueous saturated sodium bicarbonate were added. The chloroform layer was washed with brine, dried with sodium sulfate, and evaporated to give 626 mg of crude 4-chloro-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile as a yellowish solid, which was used in the following step.
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH3:3].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[CH3:1][CH:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH3:3]
Reactant: CC(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 9.9 %

Procedure:
The title compound (9.4 mg, 8%) was prepared from (4-{[(1-methylethyl)amino]sulfonyl}phenyl)boronic acid (49 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 2H, J=8.6 Hz), 7.66 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.9 Hz), 6.98 (d, 2H, J=8.8 Hz), 4.97-4.87 (m, 1H), 4.28-4.18 (m, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.58-3.45 (m, 1H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.37-1.27 (m, 3H), 1.25 (d, 6H, J=6.4 Hz), 1.11 (d, 6H, J=6.5 Hz); LRMS (ESI), m/z 475 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=O.[NH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH:16]=2)[O:11][C:10]([CH3:30])([CH3:29])[CH:9]1[OH:31].[BH3-]C#N.[Na+].O>CO>[CH2:22]([NH:21][C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:29])([CH3:30])[CH:9]([OH:31])[CH:8]2[NH:7][CH2:1][C:2]([CH3:6])([CH3:5])[CH3:3])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C(N)C1O
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)CNC1c2cc(CC(=O)NCc3ccccc3)ccc2OC(C)(C)C1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4 ml of trimethylacetaldehyde was added to a solution of 11 g of the 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-benzylacetamide obtained above in 200 ml methanol. 2.44 g of NaBH3CN was added in several portions, and the resulting suspension was stirred for 2 hours at 50° C. After cooling to room temperature, the reaction mixture was poured into 200 ml water. The aqueous phase was extracted once with 150 ml EA, the combined organic phases were dried over sodium sulfate, and the solvent was largely evaporated at reduced pressure. Chromatography of the remaining residue on silica gel (mobile phase: ethyl acetate/cyclohexane 1:1 v/v) and drying of the product fractions on a rotary evaporator yielded 10.8 g N-benzyl-2-[3-hydroxy-2,2-dimethyl-4-(neopentylamino)-3,4-dihydro-2H-chromen-6-yl]acetamide as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:28](=[O:30])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:28]([OH:30])=[O:29]
Reactant: Clc1cccnc1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A solution of 3-chloropyridine (1.00 mL, 10.5 mmol) in THF at −78° C. was treated dropwise with a solution of lithium diisopropylamide in THF [freshly prepared by addition of butyllithium (7.21 mL, 11.5 mmol) to diisopropylamine (11.5 mmol)]. After 0.25 h, the mixture was treated with carbon dioxide (g) and slowly warmed to ambient temperature. The mixture was concentrated, partitioned between EtOAc and water, and the aqueous layer was washed with EtOAc (2×). The pH of the aqueous layer was adjusted (˜3) by addition of 1 N HCl and then washed with EtOAc (3×). The combined extracts were dried with magnesium sulfate and concentrated. The residue was recrystallized from EtOAC yielding 200 mg (12%) of 3-chloroisonicotinic acid.
Reaction SMILES: [CH3:1][C:2]([C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1)([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:2]([CH3:1])([N:4]5[CH2:8][CH2:7][CH2:6][CH2:5]5)[CH3:3])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)N1CCCC1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(C(C)(C)N5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
To a solution of Intermediate 80c (180 mg, 0.46 mmol) in 1,4-dioxane (5.00 mL) was added DIPEA (160 μL, 0.92 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 185 mg, 0.46 mmol). The reaction was heated to 60° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM. Further purification by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (58 mg, 20%). LCMS (Method 5): Rt 3.84 min, m/z 647.2 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.60 (6H, s), 1.70-1.76 (4H, m), 1.86-2.06 (2H, m), 2.11 (1H, m), 2.20 (1H, m), 2.38 (3H, s), 2.45-2.52 (2H, m), 2.55-2.62 (2H, m), 4.89 (1H, dd, J 5.6, 8.9), 5.29 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.62 (1H, d, J 9.9), 8.77 (1H, d, J 2.0).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.C(N(CC)CC)C.[Cl:14][C:15]1[N:20]=[C:19]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:18]=[C:17]2[N:36]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:37]=[C:38]([CH2:39][CH:40]=[O:41])[C:16]=12>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[N:18]=[C:17]2[N:36]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:37]=[C:38]([CH2:39][CH:40]([C:5]#[N:6])[OH:41])[C:16]=12
Reactant: C[Si](C)(C)C#N
Reactant: COc1c(C)cnc(Cn2nc(CC=O)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc(CC(O)C#N)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reaction time: 16 h
Yield: 94 %

Procedure:
Trimethylsilyl cyanide (0.219 mL) and triethylamine (0.198 mL) were added to a mixture composed of the above di-tert-butyl {4-chloro-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (796 mg) and dichloromethane (10 mL) under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred for 16 hours. Chloroform (80 mL) and a 0.5 N hydrochloric acid solution (100 mL) were added to the reaction mixture, followed by separation. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (20 mL). A 1 N hydrochloric acid solution (10 mL) was added and the mixture was stirred at room temperature for 30 minutes. A saturated sodium bicarbonate solution (80 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (788 mg, 94%). The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[F:37][C:33]1[CH:32]=[C:31]([CH:23]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1cccc(F)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2cccc(F)c2)c1
Yield: 26.4 %

Procedure:
The procedure is as in Example 1, but using 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.02 g of tert-butyl (RS)-2-anilino-2-(3-fluorophenyl)acetate and 0.72 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: methanol/dichloromethane (1/99 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 10 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from cyclohexane. 1.3 g of tert-buty (RS)-2-(3-fluorophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 107° C. are then obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:3]=1.[CH3:17][N:18]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:10]([O:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:17]#[N:18])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccn1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)[Si](C)(C)OCc1cc(C#N)ccn1
Temperature: 95 °C
Yield: 26 %

Procedure:
To a stirring solution of 4-bromo-2-((tert-butyldimethylsilyloxy)methyl)pyridine INT-70 (0.800 g, 2.6 mmol) in 3 mL of 1-methy-2-pyrrolidine (NMP) was added zinc cyanide (0.610 g, 5.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol). The solution was degassed with N2 and the reaction mixture heated at 95° C. for 12 h. Upon cooling, the reaction mixture was diluted with saturated NaHCO3 and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (MeOH/DCM) to produce 0.170 g (26%) of 2-((tert-butyldimethylsilyloxy)methyl)isonicotinonitrile INT-71 as a light yellow solid. LCMS-ESI (m/z) calculated for C13H20N2OSi: 248.4; found 249.1 [M+H]+, tR=4.21 min (Method 1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH2:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[N:31]=4)=[CH:26][CH:25]=3)=[O:37])[CH:18]=2)[NH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CNCCCC(=O)O
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(CNCCCC(=O)O)n4)cc3)cc12

Procedure:
Using 4-(methylamino)-butyric acid and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 483 (M+H)+.