Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[N:6]#N.[CH:8]([NH:11][CH:12](C)C)([CH3:10])C.N1C=CN=[C:16]1[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>O1CCCC1>[N:11]1([CH:20]([C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)[CH3:16])[CH:8]=[CH:10][N:6]=[CH:12]1
Reactant: CC(C)NC(C)C
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1ccc(C#N)cc1)n1ccnc1

Procedure:
A solution of n-butyl lithium (25 mL of 2.1M reagent in hexane, 0.0525 mole) is added dropwise in an N2 atmosphere to a solution of di-isopropylamine (5.6 g) in tetrahydrofuran (100 mL) which is maintained at -20°. This cold solution is then added dropwise to a solution of 4-(1-imidazolylmethyl)benzonitrile (9.15 g) in tetrahydrofuran (250 mL) which is maintained at -50° during addition and for 30 minutes subsequently. The reaction mixture is then cooled to -70° for 30 minutes and then without external cooling for 10 hours. The reaction is quenched by addition of water (300 mL) and extracted with diethyl ether (3×100 mL). The combined ether extracts are extracted with 3N hydrochloric acid (3×60 mL) and the acid extracts are made basic (pH 9) with 6N sodium hydroxide. The crude product is extracted into ether (3×60 mL), and after drying (MgSO4) and solvent evaporation, 4-[1-(1-imidazolyl)ethyl]benzonitrile is obtained. The crude material is dissolved in acetone and treated with ethereal HCl to afford the hydrochloride salt, m.p. 184°-186°.
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]1=2>CN(C=O)C.C1(C)C=CC=CC=1>[S:5]1[C:9]([C:10]([Cl:3])=[O:11])=[CH:8][C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2s1

Procedure:
The Benzo[b]thiophene-2-carbonyl chloride was prepared by adding toluene (2 mL), DMF (2 drops) and thionyl chloride (50 μL) to benzo[b]thiophene-2-carboxylic acid. Heating the mixture to reflux for 5 hours followed by removal of the solvent afforded the crude product, which was used without further purification.
Reaction SMILES: N[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]([CH2:16][CH2:17][CH:18](N(CCC)CCC)[CH3:19])[CH2:6]2.C(=O)([O-])[O-].[K+].[K+].C([C:38]1[CH:48]=[CH:47][CH:46]=[C:40]2[C:41]([NH:43][C:44](=[O:45])[C:39]=12)=[O:42])(OCC)=O.O>CN(C=O)C>[CH2:41]([N:43]([CH2:44][CH2:39][CH3:38])[CH2:19][CH2:18][CH2:17][CH2:16][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][N:43]3[C:44](=[O:45])[C:39]4[C:40](=[CH:46][CH:47]=[CH:48][CH:38]=4)[C:41]3=[O:42])[CH:4]=2)[CH:8]1[O:12][CH2:13][O:14][CH3:15])[CH2:40][CH3:46]
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: CCCN(CCC)C(C)CCC1Cc2cc(CN)ccc2C1OCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCC1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1OCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 131.4 %

Procedure:
The compound (189.7 mg) obtained in Example 127-10 was dissolved in DMF (5.69 ml) and added with potassium carbonate (108.5 mg) and carbethoxyphthalimide (172.0 mg), followed by stirring at room temperature for 3 hours. The reaction solution was added with water. Then, the solution was subjected to separation/extraction with chloroform, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (253.9 mg) as a yellow oily substance.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.F[S:9]([C:12]1[N:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10]>CN(C=O)C>[CH3:19][O:18][C:15]1[N:14]=[N:13][C:12]([S:9]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: c1cc[nH]c1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2cccc2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To an ice-cold suspension of sodium hydride (1.86 mmol, 74 mg) in DMF (1 mL) was added a solution of pyrrole (1.86 mmol, 125 mg) in DMF (2 mL). To this was added 3-fluorosulfonyl-6-methoxypyridazine (1.55 mmol, 298 mg) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with H2O (20 mL) and EtOAc (20 mL) and the EtOAc layer was collected, dried, filtered and evaporated to a residue. The residue was purified by silica gel chromatography (eluent:hexanes:EtOAc::9:1) to obtain 3-methoxy-6-(pyrrole-1-sulfonyl)-pyridazine (30%, 112 mg).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[H][H].[ClH:18]>C(O)C.O.[Pd]=O>[ClH:18].[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)Cc1ccc(N)cc1

Procedure:
A suspension of N-methyl-4-nitrobenzenemethanesulphonamide (30 g) in ethanol (150 ml), water (300 ml) and hydrochloric acid (2N, 65 ml) was hydrogenated over 10% palladium oxide on charcoal (7.5 g, 50% paste with water) until hydrogen uptake ceased (9.75 l). The catalyst was removed by filtration through "hyflo" and the filter pad was washed with water (30 ml). The filtrate was evaporated under reduced pressure to give the title compound as a pale yellow powder (28.2 g) m.p. 143°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=O)[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(O)C.O1CCCC1.[OH:32][CH:33]([C:38]1[CH:39]=[CH:40][C:41]([CH:44]=O)=[N:42][CH:43]=1)[C:34]([OH:37])([CH3:36])[CH3:35].C([N:48](CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:48][C:44]([C:41]3[N:42]=[CH:43][C:38]([CH:33]([OH:32])[C:34]([CH3:36])([OH:37])[CH3:35])=[CH:39][CH:40]=3)=[CH:15][CH:14]=2)[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CCN(CC)CC
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(O)C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)[nH]2)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.600 g) in a mixed 10 solvent of ethanol (5 mL) and tetrahydrofuran (5 mL) was deaerated, and 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (491 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (45 mg) and triethylamine (0.093 mL) were added. The reaction solution was purged with nitrogen, and stirred at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in acetic acid (15 mL) was added ammonium acetate (647 mg), and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-100:0, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (0.777 g, yield 87%) as colorless crystals. MS: 533 (MH+). melting point 138-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](I)[CH:14]=[C:15]([F:21])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1N=C(O)[C:31]2[C:26](=[C:27](I)[CH:28]=C(F)[CH:30]=2)N=1.ClC1C=C(C=CC=1Cl)N.CN1[CH2:51][CH2:50][CH2:49][C:48]1=O>>[CH3:48][C:49]1[CH:28]=[CH:27][C:26](/[CH:31]=[CH:30]/[C:13]2[CH:14]=[C:15]([F:21])[CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])=[CH:51][CH:50]=1
Reactant: Oc1nc(Cl)nc2c(I)cc(F)cc12
Reactant: Oc1nc(Nc2ccc(Cl)c(Cl)c2)nc2c(I)cc(F)cc12
Reactant: CN1CCCC1=O
Agent: Nc1ccc(Cl)c(Cl)c1
Product: Cc1ccc(/C=C/c2cc(F)cc3c(O)nc(Nc4ccc(Cl)c(Cl)c4)nc23)cc1
Temperature: 25 °C

Procedure:
2-((3,4-Dichlorophenyl)amino)-6-fluoro-8-iodoquinazolin-4-ol. A solution of 2-chloro-6-fluoro-8-iodoquinazolin-4-ol (3.0 g) and 3,4-dichloroaniline (4.49 g) in N-methylpyrrolidone (60 mL) was heated to 120° C. for 3.5 h. After cooling to room temperature, the reaction mixture was quenched into ice/water. The precipitate which formed was isolated by filtration, washed with water and dried to afford the title compound as a light yellow solid (3.32 g). 1H NMR (300 MHz, DMSO-d6): δ11.23 (brs, 1H), 9.16 (s, 1H), 8.82 (d, J=2.1 Hz, 1H), 8.20 (dd, J=3 & 8.1 Hz, 1H), 7.72 (dd, J=3 & 8.4 Hz, 1H), 7.55 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@H:10]([CH2:19][CH2:20]O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[C@H](CCO)[NH:29][C:30](OC(C)(C)C)=[O:31])C=C.[CH2:41]([O:48][CH2:49][N:50]1[CH:55]=[C:54]([CH3:56])[C:53](=[O:57])[NH:52][C:51]1=[O:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:30]1(=[O:31])[NH:29][C:1](=[O:8])[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=[C:7]12.[CH2:1]([O:8][C:9](=[O:22])[CH:10]([CH2:19][CH2:20][N:52]1[C:53](=[O:57])[C:54]([CH3:56])=[CH:55][N:50]([CH2:49][O:48][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:51]1=[O:58])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Reactant: Cc1cn(COCc2ccccc2)c(=O)[nH]c1=O
Reactant: C=CCOC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Product: Cc1cn(COCc2ccccc2)c(=O)n(CCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c1=O
Product: O=C1NC(=O)c2ccccc21
Yield: 51 %

Procedure:
In a similar manner to that described in Example 1(1), a reaction was carried out using (±)-N-(tert-butoxycarbonyl)homoserine benzyl ester, instead of (±)-N-(tert-butoxycarbonyl)homoserine allyl ester, and using 1-benzyloxymethyl-5-methyl-pyrimidine-2,4-dione, instead of phthalimide, to afford the desired compound (yield 51%) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16]>C(Cl)(Cl)Cl>[OH:16][CH2:15][CH2:14][N:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:17][CH2:18][OH:19]
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: OCCNCCO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CN(CCO)CCO)cc1
Yield: 64.4 %

Procedure:
A solution of 1.7 g (9.2 mmol) of methyl 4-chloromethylbenzoate in 25 ml of chloroform was added with 10 g (95 mmol) of diethanolamine, followed by heating under reflux for 10 hours. The resulting solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (chloroform), whereby 1.5 g of a colorless oil were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2[CH2:22][CH2:23][NH:24][CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH3:18])[CH:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:4]=2[O:3]1.[N:27]#[C:28]Br.C([O-])(=O)C.[Na+]>CO>[C:28]([N:24]1[CH2:25][C:20]2[C:5]3[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH3:18])[CH:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:4]=3[O:3][C:2]([CH3:1])([CH3:26])[C:21]=2[CH2:22][CH2:23]1)#[N:27]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A mixture of 4.6 g (0.0129 mole) of 5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1] benzopyrano[3,4-d]pyridine, 1.38 g (0.013 mole) of cyanogen bromide, 2.13 g (0.026 mole) of sodium acetate and 35 ml of methanol was stirred at 0° C for 3 hours, and then at ambient temperature for 12 hours. After removal of the solvent under reduced pressure, water was added to the residue and the mixture was extracted with diethyl ether. The organic layer was washed with 2 N HCl, followed by saturated NaCl solution. The ether layer was separated, dried over Na2SO4 and concentrated to give 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine as a yellow oil (4.9 g, 99% yield) which crystallized upon standing.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:28]([C:30]1[CH:31]=[C:32]([C:34]([CH3:37])=[CH:35][CH:36]=1)[NH2:33])#[CH:29]>CN(C=O)C>[ClH:1].[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:5]=[CH:4][N:3]=[C:2]2[NH:33][C:32]1[CH:31]=[C:30]([C:28]#[CH:29])[CH:36]=[CH:35][C:34]=1[CH3:37]
Reactant: C#Cc1ccc(C)c(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#Cc1ccc(C)c(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cl
Yield: 18.4 %

Procedure:
4-Chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (153 mg, 0.49 mmol), pyridine (40 μL) and 3-ethynyl-6-methylaniline (71 mg, 0.54 mmol) were reacted in DMF (3 mL) at 110° C. under an atmosphere of N2 for 36 hours. The solvent was removed in vacuo and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed on silica using 40% acetone/CH2Cl2 to provide 40 mg (19%) of pure product as its free base. This oil was dissolved in a minimum volume of CHCl3, diluted with several volumes of ether, and triturated with 1M HCl in ether to precipitate the title product as a white solid (M.P. 170°-185° C. (dec); LC-MS: 408 (MH+); anal. RP18-HPLC RT: 3.93 min.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoic acid (4.0 g, 14.2 mmol) in THF (100 mL) were added 4-fluorobenzoic hydrazide (2.40 g, 15.6 mmol), HOBt (1.91 g, 14.1 mmol), EDC (4.07 g, 21.2 mmol) and Et3N (3.0 mL, 21.5 mmol) at −20° C. sequentially. After addition, the mixture was stirred at −20° C. for 30 min., then room temperature overnight. The reaction was quenched by adding ice-water. After removal of the THF, the residue was extracted with EtOAc (300 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. The filtrate was concentrated and purified by flash chromatography to give the title compound (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (4.28 g, 72%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 9.61 (b, 2H), 8.00 (dd, J=5.5, 9.0 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.25 (t, J=9.0 Hz, 2H), 6.71 (d, J=8.6 Hz, 1H), 5.53 (d, J=7.4 Hz, 1H), 4.06 (d, J=7.4 Hz, 1H), 2.35 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16](=[O:30])[CH2:17][NH:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=4)[CH:12]=3)[CH2:7]2)[C:5](=[O:31])[NH:4][C:3]1=[O:32].[Cl:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([N:18]([CH2:17][C:16]([NH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@:6]1([C:5](=[O:31])[NH:4][C:3](=[O:32])[N:2]1[CH3:1])[CH2:14]2)=[O:30])[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:37]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CNCc3ccc4ccccc4c3)cc1C2
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN(Cc3ccc4ccccc4c3)C(=O)C(C)(C)CCl)cc1C2

Procedure:
To a stirred solution of N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]-2-[(2-naphthylmethyl)amino]acetamide from Step C (19 mg, 0.044 mmol), in DCM (1 mL), at 0° C. was added 3-chloro-2,2-dimethylpropanoyl chloride (10 mg, 0.067 mmol) and triethylamine (9.0 mg, 0.089 mmol). After 1 hour the reaction mixture was applied directly to a silica gel column for purification, eluting with DCM:MeOH—99:1 to 96:4. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=547 (M(35Cl)+1). HRMS: m/z=547.2103; calculated m/z=547.2107 for C30H32N4O5(35Cl)1.
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([NH:23]C(OC(C)(C)C)=O)[CH2:15][C@:16]([CH2:21][OH:22])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1.CCN(CC)CC>CC(C)=O>[C:1]([O:4][CH2:5][O:19][C:17](=[O:18])[C@@:16]([CH2:21][OH:22])([CH3:20])[CH2:15][C@H:14]([NH2:23])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: CC(=O)OCBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Bromomethyl acetate (38 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid acetoxymethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:4]([NH2:17])[N:3]=1.C1(C)C=C(C)C=C(C)C=1S([NH:29]O)(=O)=O.[CH3:32][C:33]1[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=1>>[NH2:17][C:4]1[N:3]2[N:29]=[C:38]([C:36]3[O:37][C:33]([CH3:32])=[CH:34][CH:35]=3)[N:1]=[C:2]2[CH:7]=[C:6]([CH2:8][NH:9][C:10]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:11])[CH:5]=1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Reactant: Cc1ccc(C=O)o1
Reactant: Nc1cc(CNC(=O)C2CCCC2)cc(N)n1
Product: Cc1ccc(-c2nc3cc(CNC(=O)C4CCCC4)cc(N)n3n2)o1
Yield: 27 %

Procedure:
The title compound was prepared in accordance with the general method of example 365 from cyclopentanecarboxylic acid (2,6-diamino-pyridin-4-ylmethyl)-amide, o-mesitylene-sulfonylhydroxylamine, and 5-methyl-2-furaldehyde. The purification was performed with column chromatography on silica eluting with dichloromethane/ethylacetate 1:2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:29]([NH2:31])[CH3:30]>>[CH2:29]([NH:31][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20])[CH3:30]
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (45 mg) was coupled to ethylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 10.6 mg of 170. MS (Q1) 409.2 (M)+.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1.O.[NH2:23][NH2:24]>C(O)(=O)C>[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([C:9](=[N:23][NH2:24])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CSCc1ccc(C(=NN)c2ccc(Cl)cc2)cc1

Procedure:
An ethanol solution (50 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone (9.3 g), hydrazine hydrate (6 ml) and acetic acid (3 ml) was heated for 20 hours with refluxing. The solvent was distilled off under reduced pressure, and then the obtained oily substance was diluted with dichloromethane and washed successively with an aqueous 5% sodium hydroxide solution, water and an aqueous saturated a sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off to obtain 4-chloro-4'-methylmercaptomethylbenzophenone hydrazone (7.1 g) as an isomer mixture (syn form/anti form=about 1:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:29][CH2:30][C:31]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:23][CH3:24])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=2[F:28])[CH2:18]1)=[O:32]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CCl)C1
Yield: 91.6 %

Procedure:
The 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline material was prepared as follows: —4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline (430 mg, 1.07 mmol) (Prepared as described in Example 22 under preparation of starting material), chloroacetyl chloride (126 mg, 1.12 mmol) and N,N-diisopropylethylamine (519 mg, 4.02 mmol) in methylene chloride (15 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) solvent, Removal of the solvent under vacuum gave 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline as a yellow gum (470 mg). This material was used without any further purification); Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)#[N:2].S(OC)(O[CH3:23])(=O)=O>[OH-].[Na+]>[C:1]([C:3]1[C:4](=[O:18])[N:5]([CH3:23])[C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)#[N:2]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(C)c1=O

Procedure:
To a mixture of 5-cyano-1-(2,6-dimethylphenyl)uracil (0.1 mol) and 80 ml of five percent sodium hydroxide solution, with stirring, is slowly added dimethyl sulfate (0.1 mol). The reaction mixture is stirred for about 2 hours and then filtered, washed with water and dried to yield 5-cyano-1-(2,6-dimethylphenyl)-3-methyluracil, m.p. 198.2-199.5° C.