Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:25])=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(Cl)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of (R)-tert-butyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (1.17 g, 3.22 mmol) in 50 mL of dichloromethane was added 10 mL of trifluoroacetic acid in portions. The reaction was stirred at RT for 1 hour. The solvent was evaporated, and the residue was dissolved in 20 mL of dichloromethane, cooled to 0° C., and quenched with 1M NaOH until basic. After partitioning between CH2Cl2 and H2O, the mixture was separated and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (800 mg, 94% yield). LC/MS: m/z 262.9 (M+H)+ at 0.79 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[Si:2]([Cl:16])([Cl:15])[CH2:3][CH:4]([CH3:14])[CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.C1COCC1>[Cl:16][Si:2]([Cl:15])([CH2:3][CH:4]([CH3:14])[CH2:5][C:6]([CH3:12])([CH3:13])[CH2:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)[Mg]Cl
Reactant: CC(CC(C)(C)CC(C)(C)C)C[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(CC(C)(C)CC(C)(C)C)C[Si](Cl)(Cl)C(C)C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
137.8 g trichloro(2,4,4,6,6-pentamethylheptyl)silane, prepared according to example 7, were dissolved in toluene and heated to 100° C. under argon. By means of a dropping funnel were added 220 ml isopropylmagnesium chloride as a 2 molar solution in THF were added to this solution within 1 h. Subsequently the THF was distilled off by means of a column and the reaction mixture was stirred at 100° C. for 20 h. Filtration was carried out for separating the precipitated solid and the product was isolated by vacuum distillation.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1(=[O:18])=[O:17].[CH2:19]([CH2:21][NH2:22])[OH:20]>C1COCC1>[OH:20][CH2:19][CH2:21][NH:22][C:8](=[O:9])[C:7]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:6]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:18])=[O:17]
Reactant: O=C1c2c([N+](=O)[O-])cccc2S(=O)(=O)N1CCO
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NCCO)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 72 h
Yield: 90.8 %

Procedure:
A solution of 2-(2-hydroxyethyl)-4-nitro-2H-1,2-benzisothiazol-3-one 1,1-dioxide (100 mg, 0.37 mmol) and ethanolamine (24 mg, 0.39 mmol) in THF (5 ml) was allowed to stand at 20-25° for 3 days. After removal of THF under reduced pressure, the residue was recrystallized from MeOH-EtOAc-hexane to give 112 mg (91%) of product, m.p. 176.5-177.5°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:15][C@@H:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=3[C@@H:5]2[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CC(C)=O>[OH:1][CH:2]1[CH2:15][CH:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:24][CH:23]=[CH2:22])=[CH:10][C:9]=3[CH:5]2[CH2:4][CH2:3]1
Reactant: Oc1ccc2c(c1)[C@@H]1CC[C@H](O)C[C@@H]1O2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)C1CCC(O)CC1O2
Yield: 61 %

Procedure:
A mixture of 1.40 g (6.86 mmol) of the product of Example 5, Step A, 2.5 g (mmol) of K2CO3 and 2.4 g (mmol) of allyl bromide in 10 mL of dry acetone was heated under reflux for 18 h. The solution was partitioned between ether and water and the aqueous layer was extracted with ether. The organic extractes were washed with saturated Na2CO3 solution and brine, and the combined extracts were dried over MgSO4 and concentrated to an oil. This crystallized from ethyl acetate-hexane to afford 1.03 g of white prisms that was a single C3-diastereomer (75% based on a 4:1 mixture of starting epimers).
Reaction SMILES: [F:1][C:2]1([CH2:26]O)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:34])CC>COCCOCCOC>[F:1][C:2]1([CH2:26][F:34])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CO)CC3)c(F)c2)C(=O)O1
Solvent: COCCOCCOC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CF)CC3)c(F)c2)C(=O)O1
Yield: 24 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-fluoro-4-hydroxymethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with DAST (1.25 mmol) in diglyme (10 ml) at a temperature 0° C. for two hours and by purifying the compound by silica gel column chromatography in 24% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[C:5]2[C:14]([OH:16])=O.[NH2:17][C@@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:19]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:12])[CH3:13])[N:6]=[C:5]2[C:14]([NH:17][C@@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:20]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:19]1)=[O:16]
Reactant: CC(C)n1nc(C(=O)O)c2cc(F)ccc21
Reactant: COC(=O)C[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Product: COC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccc(F)cc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from 5-fluoro-1-isopropyl-1H-indazole-3-carboxylic acid (step 2 of Example 11) and tert-butyl (2S,4S)-4-amino-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (step 4 of Example 9).
Reaction SMILES: CN.Cl.Cl.[CH2:5]([N:7]([CH2:30][CH3:31])[CH2:8][CH2:9][NH:10][C:11](=[O:29])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)[CH3:6].[C:32]([BH3-])#[N:33].[Na+]>CO>[ClH:20].[CH2:5]([N:7]([CH2:30][CH3:31])[CH2:8][CH2:9][NH:10][C:11]([C:12]1[N:33]([CH3:32])[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]2[C:14]=1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16]2)=[O:29])[CH3:6]
Reactant: CCN(CC)CCNC(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.45 g. of methylamine in 120 ml. of methanol is treated with 12 ml. of 6.65-N methanolic hydrochloric acid. Thereafter, there are successively added under an atmosphere of argon at 20°-25° C. 17.0 g. of o-benzoyl-p-chlorophenylglyoxylic acid [2-(diethylamino)ethyl]amide hydrochloride and 1.6 g. of sodium cyanoborohydride and the mixture is stirred at room temperature for an additional 2 hours. The mixture is made acidic with concentrated hydrochloric acid while cooling with ice, stirred at room temperature for an additional 0.5 hour and evaporated to dryness under reduced pressure. The residue is made alkaline with 2-N ammonium hydroxide with the addition of ice and extracted with diethyl ether. After drying over sodium sulfate, the extract is concentrated to dryness and the oily residue triturated with hexane to crystallize the product. The product is removed by filtration, dissolved in 30 ml. of methanol and the solution treated with excess ethereal hydrochloric acid. After dilution with diethyl ether to a ten-fold volume, the hydrochloride which crystallizes out is removed by filtration and washed with diethyl ether. Recrystallization from methanol/diethyl ether yields 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [2-(diethylamino)ethyl]amide hydrochloride in the form of almost colorless crystals having a melting point of 211°-214° C. (decomposition).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH2:21][CH2:20]1>O1CCCC1>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12](=[CH:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[N:22]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: O=C1CNC(=O)N1Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccccc2C=C2NC(=O)N(Cc3ccc(Cl)cc3)C2=O)CC1

Procedure:
Under a nitrogen atmosphere in a flame-dried flask, sodium hydride (43 mg, 1.07 mmol, 60% oil dispersion) was washed with hexanes and then treated with tetrahydrofuran (THF) (8 mL), followed by 3-(4-chlorobenzyl)-imidazolidine-2,4-dione (235 mg, 1.04 mmol) and 2-(4-methylpiperazin-1-yl)-benzaldehyde (209 mg, 1.02 mmol), and an additional 2 mL of THF. After refluxing the mixture overnight, the solvent was removed and the residue was treated with aqueous ammonium chloride and aqueous sodium bicarbonate to a pH of 8, then extracted with methylene chloride. The organic extracts were washed with aqueous sodium chloride, dried and concentrated in vacuo to a yellow foam. The foam was crystallized from hot ethyl acetate: hexanes to give a solid, 240 mg (57%).
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([CH:5]([CH2:8][CH3:9])[CH:6]=O)[CH3:4]>>[CH2:3]([C:5](=[CH:6][N:2]=[CH:6][CH:5]([CH2:8][CH3:9])[CH2:3][CH3:4])[CH2:8][CH3:9])[CH3:4]
Reactant: [NH4+]
Reactant: CCC(C=O)CC
Agent: [OH-]
Product: CCC(=CN=CC(CC)CC)CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a sample of 250 grams of 28% ammonium hydroxide was added 215 grams of 2-ethylbutyraldehyde and the heterogeneous mixture was stirred for 18 hours at ambient temperature. The resulting organic layer was separated, and after drying, slowly distilled at atmospheric pressure to yield 148.8 grams of 3,7-diethyl-5-azanona-3,5-diene. Mass spectrum m/e=181. 13C nuclear magnetic resonance spectrum, solvent CDCl3, ref. TMS. ##STR7##
Reaction SMILES: C([Li:5])C[CH2:3][CH3:4].[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[CH3:13][C:14](C)([O-:16])C.[K+].C(=O)CCCCC>CCCCCC.CCOCC>[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[Li+:5].[CH3:13][CH2:14][O:16][CH2:3][CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: [Li]CCCC
Agent: CC(C)[N-]C(C)C
Agent: CCCCCC=O
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li+]
Reaction time: 0.5 h

Procedure:
67 ml (0.11 M) of a 1.6 N solution of butyllithium in hexane were treated at 0° with 11.1 g (0.11 M) of diisopropylamide, and the reaction mixture was kept at 0° under stirring during 30 min. To this reaction mixture there was then added 1 g of potassium ter-butoxide followed by 24.5 g (0.05 M) of 4-bromo-pent-2trans-en-1-yl triphenylphosphonium bromide and the mixture obtained was kept under stirring during 18 h at 23°, whereupon a solution of 5 g (0.05 M) of hexanal in 35 ml of anhydrous ether at 8°-15° was added thereto.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (108 mg, 27%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][C:6]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[CH:5]2.NC1C=CC=C2C=1N=CC(S(C1C=CC=CC=1)(=O)=O)=C2>>[NH2:12][C:10]1[CH:11]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][C:6]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[CH:5]2
Reactant: Cc1cc([N+](=O)[O-])c2ncc(S(=O)(=O)c3ccccc3)cc2c1
Agent: Nc1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Product: Cc1cc(N)c2ncc(S(=O)(=O)c3ccccc3)cc2c1

Procedure:
Prepared from 6-methyl-8-nitro-3-phenylsulfonylquinoline (D24) in an analogous process to that described in Description 5 (D5);
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@H:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[C:5]([CH3:20])([CH3:19])[CH2:4][CH2:3]1.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:1][C@H:2]2[CH2:3][CH2:4][C:5]([CH3:20])([CH3:19])[C@H:6]([N:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])[CH2:7]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CC[C@H](O)C[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1N1C(=O)c2ccccc2C1=O
Yield: 114.8 %

Procedure:
To a solution of the cis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (500 mg, 1.83 mmol) obtained in Example 590 in tetrahydrofuran (10 ml) were added 4-nitrobenzoic acid (321 mg, 1.05 mmol), triphenylphosphine (576 mg, 2.20 mmol) and a 40%-diethyl azodicarboxylate/toluene solution (1.00 ml, 2.20 mmol) at 3° C., and stirred overnight at room temperature. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain trans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4-dimethylcyclohexyl 4-nitrobenzoate (509 mg, 66%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>>[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CNc1ccc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc1

Procedure:
[2-(4-Methylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine following general procedures as described in these Examples. MP 273-275° C., M+H=349.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][C@@H:15]([CH2:19][O:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[CH:28]=[CH:29][C:30](O)=[O:31])#[N:24].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:30](=[O:31])[CH:29]=[CH:28][C:27]4[CH:26]=[C:25]([CH:35]=[CH:34][CH:33]=4)[C:23]#[N:24])[C@@H:15]([CH2:19][O:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccc(C=CC(=O)O)c1
Reactant: COC[C@@H]1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)C=Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-amino-quinazoline-7-ylmethyl)-3-(S)-methoxymethyl-piperazine-2-one, EXAMPLE 75, (50 mg, 0.16 mmol) and 3-cyanocinnamic acid (29 mg, 0.17 mmol, prepared from 3-cyanobenzaldehyde) in 1 mL of DMF is added N,N-diisopropylethylamine (0.07 mL, 0.38 mmol), followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (59 mg, 0.18 mmol). The resulting mixture is stirred at room temperature for 16 h and the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) over 30 min and the appropriate product fractions are combined and lyopholized to provide the title compound (73 mg, 0.13 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.72 (bs, 2H), 8.78 (s, 1H), 8.40 (s, 1H), 8.35 (d, 1H), 8.04 (m, 1H), 7.83 (d, 1H), 7.60 (m, 4H), 7.46 (d, 1H), 5.25-4.44 (m, 4H, rotamers), 4.02 (m, 1H), 3.66 (m, 1H), 3.51-3.40 (m, 3H), 3.27 (s, 3H). ISP MS, [M+H]+=457.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([CH:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)C#N)=[CH:5][CH:4]=1.CC(C)([O-:21])C.[K+].OO>C(#N)C>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C#N)c2cccnc2)nn1
Reactant: CC(C)(C)[O-]
Agent: OO
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)c2cccnc2)nn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
(6-Methoxypyridazin-3-yl)pyridin-3-ylacetonitrile (7.7 g, 0.034 mol) were dissolved in acetonitrile (200 ml) at 23° C. under a nitrogen atmosphere, and potassium tert-butoxide (4.16 g, 0.037 mol) was added. The suspension was stirred at 23° C. for 30 minutes, cooled to −4° C., and hydrogen peroxide (30% solution, 11.34 ml, 0.11 mol) was slowly added dropwise. The reaction mixture was stirred at 0° C. for a further 30 minutes and subsequently at room temperature for 2 hours. Conventional work-up gave 3.46 g (48% yield) of (6-methoxypyridazin-3-yl)pyrdin-3-ylmethanone;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28]C)=[O:27].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: COCCOCOc1c(C/C=C(\C)CCC(=O)OC)c(OC)c(C)c2c1C(=O)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCOc1c(C/C=C(\C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To methyl (E)-6-(1,3-dihydro-6-methoxy -4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (76.0 g) in methanol (300 ml) was added 1N aqueous sodium hydroxide (300 ml). After 11/2 hours the solution was diluted with water, washed twice with ether, then acidified with dilute hydrochloric acid. The acidified solution was extracted with ether, and the extract was dried and evaporated to give (E)-6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy -7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 77°-82° C. (etherhexane).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:41])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:35]([CH3:41])=[CH:36][CH:37]=[CH:38][C:39]=4[CH3:40])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1
Reactant: COc1cc2c(NC(=O)Nc3c(C)cccc3C)ncnc2cc1OCCCN1CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(NC(=O)Nc3c(C)cccc3C)ncnc2cc1OCCCN1CCC(CN)CC1

Procedure:
Using an analogous procedure to that described in Example 21, 1-{7-[3-(4 tert-butoxycarbonylaminomethylpiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}-3-(2,6-dimethylphenyl)urea was reacted with trifluoroacetic acid to give the title compound; NMR Spectrum: (DMSOd6) 1.0-2.0 (m, 9H), 2.23 (s, 6H), 2.4 (m, 2H), 2.7-2.9 (m, 4H), 3.1-3.5 (partially obscured by a water signal), 3.93 (s, 3H), 4.18 (t, 2H), 6.9-7.15 (m, 4H), 7.23 (s, 1H), 8.03 (s, 1H), 8.62 (s, 1H), 11.7 (s, 1H); Mass Spectrum: M+H+ 493.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:18][C:2]2[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]3=[N:10][CH:11]=[CH:12][C:3]=23)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCC1
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Product: CSc1nc(NC2CCCC2)c2ccnc-2[nH]1

Procedure:
To 100 mg of 4-chloro-2-methylthiopyrrolo[2,3-d]pyrimidine was added 2 ml of cyclopentylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford tan crystals of product, yield 50 mg (40%), m.p. 190°-191° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]3[N:15]([CH3:28])[C:16](=[O:27])[N:17]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[C:9]=23)[CH2:3]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(OCC)(=O)C>ClCCl>[C:21]([C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[CH2:18][N:17]1[C:9]2[C:10](=[N:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:36](=[O:38])[CH3:37])[CH2:3]2)[N:15]([CH3:28])[C:16]1=[O:27])#[N:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N2CCC[C@@H](N)C2)c2c(n1)n(C)c(=O)n2Cc1ccccc1C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H]1CCCN(c2cc(C)nc3c2n(Cc2ccccc2C#N)c(=O)n3C)C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
430 mg (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile (1.14 mmol) was dissolved in 5 mL dichloromethane at 0° C. 0.35 mL (2.5 mmol) triethylamine and 123 mg (1.2 mmol) acetic anhydride were added dropwise. After the reaction was continued for 1 h at 0° C., ethyl acetate was added until turbidity appeared. It was cooled at −5° C., and a lot of solid was precipitated. 270 mg white powder was obtained after filtration, with a yield of 56.6%.