Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][CH:5]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Br[CH2:31][C:32]([C:34]1[O:35][CH:36]=[CH:37][CH:38]=1)=[O:33]>O1CCCC1>[O:35]1[CH:36]=[CH:37][CH:38]=[C:34]1[C:32]([CH2:31][N:10]1[C:9]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:6][CH:5]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4]1=[O:3])=[O:33]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Reactant: O=C(CBr)c1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccco1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
60% Sodium hydride (320 mg) was suspended in tetrahydrofuran (30 ml), under ice-cooling 2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Step I of Example 89, and the mixture was stirred for 30 minutes. Bromomethyl(furan-2-yl)ketone (1.89 g) was added dropwise thereto, stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added, and separated into aqueous layer and organic layer. The aqueous layer was acidified with 1N hydrochloric acid, extracted with ethyl acetate. The extract was combined with the former organic layer. The combined extract was washed with saturated brine, dried over anhydrous magnesium sulfate, subsequently, purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 550 mg of the titled compound.
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[CH3:30][NH2:31].O1CCCC1>>[CH3:30][NH:31][C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 67 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using 2M methylamine-tetrahydrofuran solution instead of 3-fluorobenzylalcohol, the title compound (yield 67%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]>O1CCCC1>[ClH:19].[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:17])=[O:18]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Product: Cl
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 2-dimethylaminoethylamine (2.2 ml, 20 mmol) in tetrahydrofuran (25 ml) was added over 30 minutes to a stirred solution of 3-nitrobenzenesulfonyl chloride (2.2 g, 10 mmol) in tetrahydrofuran (50 ml) cooled in an ice bath. After addition was complete, the reaction mixture was stirred in the ice bath for 30 minutes, then at 20°-25° for 20 hours. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried (Na2SO4), filtered and concentrated. The residue was flash chromatographed on silica gel and eluted with 5% methanol-95% chloroform to give pure base. Further purification was effected by conversion to the HCl salt (1.75 g), m.p. 174.0°-76.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:29][CH:30]=O>>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:29][CH2:30][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:13](=[O:18])[CH2:14]1
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: O=CCc1ccc([N+](=O)[O-])cc1F
Product: O=C1CN(CCc2ccc([N+](=O)[O-])cc2F)CCN1CCc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and (2-Fluoro-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 417 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13]([OH:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH2:16](N(CC)CC)C.IC>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)O
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)(C)C)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
17.4 g (0.076 mol) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfinic acid are suspended in 120 ml of acetone, and 13.3 ml (0.095 mol) of triethylamine and 8.5 ml (0.12 mol) of iodomethane are added. The mixture is stirred at room temperature for 2 hours and then poured onto ice-water. The precipitate which separates out is filtered off with suction and recrystallized from N-butanol.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:7]=[CH:6][C:5]=1[C:21](=[O:23])[CH3:22]>O1CCOCC1>[Br:1][CH2:22][C:21]([C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:9]([Cl:10])[C:4]=1[Cl:3])=[O:23]
Reactant: CC(=O)c1ccc(Sc2ccccc2C(C)C)c(Cl)c1Cl
Reactant: BrBr
Solvent: C1COCCO1
Product: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Reaction time: 0.17 h

Procedure:
Then 2-bromo-1-(2,3-dichloro-4-(2-isopropyl-phenylsulfanyl)-phenyl)-ethanone 41 was prepared as follows. A solution of Br2 (50 mg) in dioxane (1.0 ml) was added to a solution of compound 40 (100 mg, 0.3 mmole) in 2 ml of dioxane. The solution was then stirred for another 10 minutes and concentrated. The residue was dissolved in EtOAc and purified on a 5-g silica gel cartridge, giving the desired product 41 as a white solid. 136 mg, ˜100%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 3.43 (heptet, J=8.5 Hz, 1H), 4.45 (s, 2H), 6.42 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.25-7.31 (m, 1H), 7.49-7.54 (m, 3H); MS (DCI/NH3) m/z 436 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]12[O:38][CH2:37][CH2:36][N:35]1[C:33](=[O:34])[C:5]1[C:6]([OH:32])=[C:7]3[C:13]4[C:14]([C:16]5[C:27](=[O:28])[C:26]6[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([OH:29])[CH:25]=6)[O:20][C:17]=5[C:18](=[O:19])[C:12]=4[CH:11]=[CH:10][C:8]3=[CH:9][C:4]=1[CH2:3]2)=[O:15].N[C:40]1C=CC=CN=1.CN(C1C=CC=CN=1)C.CC1(O)C2CC3CC(CC1C3)C2>C(OCC)(=O)C.O.O1CCCC1>[CH3:1][C:2]12[O:38][CH2:37][CH2:36][N:35]1[C:33](=[O:34])[C:5]1[C:6]([OH:32])=[C:7]3[C:13]4[C:14]([C:16]5[C:27](=[O:28])[C:26]6[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([O:29][CH3:40])[CH:25]=6)[O:20][C:17]=5[C:18](=[O:19])[C:12]=4[CH:11]=[CH:10][C:8]3=[CH:9][C:4]=1[CH2:3]2)=[O:15]
Reactant: COc1cc2oc3c(c(=O)c2cc1O)C(=O)c1c(ccc2cc4c(c(O)c12)C(=O)N1CCOC1(C)C4)C3=O
Reactant: Nc1ccccn1
Agent: CC1(O)C2CC3CC(C2)CC1C3
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2oc3c(c(=O)c2cc1OC)C(=O)c1c(ccc2cc4c(c(O)c12)C(=O)N1CCOC1(C)C4)C3=O
Temperature: 23 °C

Procedure:
16.42 parts of the compound (II-167-a) (5-norbornene-2,3-dicariboxylic acid anhydride, Wako Pure Chemical Industries, Ltd.) and 53.29 parts of tetrahydrofuran were charged, stirred at 23° C. to dissolved. To the obtained mixture, 2.44 parts of amino pyridine was added at 23° C., and stirred. To the obtained mixture, 2.44 parts of dimethylamino pyridine was added at 23° C., and stirred for 30 minutes at 50° C. To the obtained mixture, a mixture of 16.63 parts of 2-methyl-2-adamantanol and 53.29 parts of tetrahydrofuran was added in the form of drops over 1 hour, and stirred for 10 hours at 50° C. To the obtained mixture, 30 past of ion-exchanged water and 60 parts of ethyl acetate were added to wash, and separated to collect an organic layer. To the obtained organic layer, 30 past of ion-exchanged was added to wash, and separated to collect an organic layer. This washing with water operation was repeated three times. The obtained organic layer was concentrated to obtain a concentrate. The concentrate was column-fractionated under the condition below, whereby giving 25.2 parts of the compound (II-167-b).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].Cl[C:20](OCC)=[O:21]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:16]=[CH:15][C:14]2[O:17][C:20](=[O:21])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:6])[C:4]=2[C:3]=1[CH3:18]
Reactant: Cc1c(Br)ccc(O)c1C(=O)Nc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(Br)ccc2oc(=O)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
Step 1 A solution of 3-bromo-6-hydroxy-2-methyl-N-phenylbenzamide (Intermediate 16-1, 40 mg, 0.131 mmol) in pyridine (1 mL) was treated with ethyl chloroformate (0.015 mL, 0.157 mmol) at rt and the mixture was heated to 100° C. for 2 h. Additional ethyl chloroformate (0.015 mL, 0.157 mmol) was added and the mixture was stirred at 100° C. for 15 h. The mixture was cooled and diluted with EtOAc (80 mL), and the solution was washed with NaHCO3 (aq) (10 mL), water (2×10 mL) and brine (10 mL), and dried and concentrated. The residue was purified by column chromatogaphy (eluting with a gradient from 95:5 to 70:30 hexane-EtOAc) to give 6-bromo-5-methyl-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (19 mg, 44%). 1H NMR (400 MHz, chloroform-d) δ 7.90 (1 H, d, J=9.02 Hz), 7.43-7.68 (3 H, m), 7.27-7.40 (2 H, m), 7.12 (1 H, d, J=8.80 Hz), 2.90 (3H, s). Mass spectrum m/z 332, 334 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1.CO>[CH2:8]([OH:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCCCC#CCCCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCC#CCCCCCCCCCO
Reaction time: 3 h

Procedure:
25.6 g (0.048 mol) of 1-tetrahydropyranyloxyhentriacont-10-yne of Example 8 were dissolved in a mixture of 100 ml of THF and 50 ml of methanol, and a catalytic amount (spatula tipful) of p-toluenesulfonic acid monohydrate was added at room temperature. After 3 h at room temperature, the reaction mixture was poured into 1.5 1 of water and stirred for 30 min. The product was filtered off with suction, washed with water and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([OH:15])=O)=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:22]1([C:28]([NH2:33])([CH2:31][CH3:32])[CH2:29][NH2:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O.CCOC(C)=O>[NH2:33][C:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:31][CH3:32])[CH2:29][NH:30][C:13]([C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[O:2][CH3:1])=[O:15]
Reactant: CCC(N)(CN)c1ccccc1
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(N)(CNC(=O)c1c(OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1

Procedure:
A mixture of 3-methoxy-2-phenylquinoline-4-carboxylic acid (3.0 g), and the compound of step 2 (3.0 g), BOP (5.7 g) and TEA (2.0 g) in 25 mL of anhydrous DMF is stirred at ambient temperature overnight. The mixture is diluted with water and EtOAc. The organic layer is separated, washed with water and concentrated under vacuum. The residue is purified on a silica gel column, eluting with EtOAc and Hexane (1:1) to afford the title compound as white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][CH:17]1[O:19][CH2:18]1>CN(C)C=O>[Br:15][CH2:16][CH:17]([OH:19])[CH2:18][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: BrCC1CO1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CC(O)CBr
Temperature: 80 °C

Procedure:
A stirred suspension of 5-chloropyrimidin-2-one (2.610 g), potassium carbonate (55 mg) and 1-bromo-2,3-epoxypropane (3.42 ml) in dry N,N-dimethylformamide (40 ml) was heated at 80° C. After 23/4 h the reaction mixture was evaporated and the residue was subjected to column chromatography on silica developing and eluting with chloroform-ethanol, 19:1. This gave an off white solid which was triturated with ethyl acetate to give white crystals of the title pyrimidinone (1.483 g), m.p. 166°-170° C., λmax (EtOH) 227 nm (ε 9,740).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[CH3:18][N:19]=[C:20]=[O:21].C(N(CC)CC)C>CCOCC>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:20](=[O:21])[NH:19][CH3:18])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CN=C=O
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (12 parts) in ether (46 parts) was added methyl isocyanate (4.5 parts) and triethylamine (0.3 parts). The solution was left at room temperature for 2 hours and the solvent evaporated off. The crude product was recrystallised from a mixture of benzene and light petroleum to give 2-methylcarbamoyloxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate, melting point 126°-127°C.
Reaction SMILES: P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:20]Br.[C:22]([CH:28]([O:39][SiH:40]([CH3:42])[CH3:41])[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35]O)=[CH:32][CH:31]=1)([CH:25]([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:22]([CH:28]([O:39][SiH:40]([CH3:42])[CH3:41])[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][Br:20])=[CH:32][CH:31]=1)([CH:25]([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)C(C)(C)C(Cc1ccc(CCO)cc1)O[SiH](C)C
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)C(C)(C)C(Cc1ccc(CCBr)cc1)O[SiH](C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a stirred solution of (C6H5)3P (9.03 g, 34.4 mmol) in 220 ml of toluene at 0° C. was added bromine (1.76 ml, 34.4 mmol) over 10 minutes. To this stirred slurry was then added a solution of p-(2-thexyldimethylsilyloxyethyl)phenethyl alcohol (10.6 g, 34.4 mmol) and pyridine (2.78 ml, 34.4 mmol) in 50 ml of toluene over 10 minutes. This mixture was stirred at room temperature for 4 hours and diluted with 300 ml of saturated NaHCO3 solution. The resulting mixture was extracted with ether (4×300 ml). The combined ether extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated in 200 ml of hexane-ether 4:1 and filtered. The filtrate was concentrated and distilled under vacuum to give 9.9 g of p-(2-thexyldimethylsilyloxyethyl)phenethyl bromide (78%) as an oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18](Cl)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Solvent: ClCCl
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
To a solution of 3-benzyloxy-7-chloro-1-ethyl-6-fluoro-1H-pyrido[2,3-d]-pyrimidine-2,4-dione (Example N-2, 146 mg, 0.42 mmol) in dichloromethane (3 mL) was added pyrrolidine (0.070 mL, 0.84 mmol) and the mixture was stirred at room temperature for 10 minutes. The reaction was diluted with dichloromethane (10 mL). The organic phase was washed with saturated aqueous sodium bicarbonate, dried on MgSO4, and concentrated. Washing the solid residue with hexane afforded 120 mg of the title compound as a solid, mp 189-190° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>CN1C(=O)CCC1>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C#N)c2)CC1
Temperature: 100 °C

Procedure:
5-Fluoro-2-nitrobenzenecarbonitrile (1.02 eq) and N-methylpiperazine (1.0 eq) were dissolved in NMP. Triethylamine (2.1 eq) was added, and the resulting solution heated at 100° C. for 1 hour. The solution was cooled to room temperature and poured into H2O. A precipitate formed which was filtered to yield the desired product as a green solid. LC/MS m/z 247.3 (MH+), Rt 1.46 minutes.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8]Br)[N:6]=1.[OH:11][CH2:12][CH2:13][NH:14][CH:15]([CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](OC)=[O:26])=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[OH:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]([N:14]([CH2:13][CH2:12][OH:11])[CH2:8][CH:7]([OH:10])[C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)[CH3:29])=[CH:18][CH:19]=1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc(OCCO)cc1)N(CCO)CC(O)c1csc(Cl)n1

Procedure:
Prepared by analogy to Example 30 by reaction of 2-chloro-4-bromoacetyl-thiazole with N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed by reduction in methanol with sodium borohydride at room temperature. The crude product is purified on a silica gel column using chloroform/ethyl acetate/methanol=10:9:1 as eluant.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OCC)OCC)[C:13](=[O:25])[CH:12]2[C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.Cl.[OH-].[Na+]>CO.O>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:25])[CH:12]2[C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH2:39][CH2:40][CH2:41][N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1
Reactant: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2cc(OCc3ccccc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(C3C(=O)Nc4ccc(O)cc43)ncnc2cc1OCCCN1CCOCC1

Procedure:
A mixture of 4-(5-benzyloxy-1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (240 mg, 0.38 mmol) and TFA (8 ml) was heated at reflux for 30 minutes. The TFA was removed by evaporation, the residue was triturated with ether, the solid was collected by filtration, washed with ether and dried under vacuum. The orange solid thus obtained was dissolved in a 1M hydrochloric acid solution (5 ml, 5 mmol) and heated at reflux for 40 minutes. After cooling, the reaction mixture was adjusted to pH2.3 with 6M sodium hydroxide and subjected to column chromatography on reverse phase silica gel (C18 10μ) with a gradient of methanol in water (30 to 100%) as eluent The fractions containing the compound were combined, the solution was adjusted to pH1.5 with concentrated hydrochloric acid and the solvents removed by evaporation The residue was triturated with methanol/ether, the solid was collected by filtration, washed with ether and dried under vacuum at 40° C. to give 4-(5-hydroxyoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline as a hydrochloride salt (90 mg, 45%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]2)[CH2:37][CH2:36]1.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.N>ClCCl>[NH:43]1[CH2:44][CH:41]([N:38]2[CH2:39][CH2:40][N:35]([C:3]3[C:2]([Cl:1])=[C:7]([NH:8][C:9]4[N:14]=[C:13]([N:15]([CH:25]5[CH2:26][CH2:27]5)[CH2:16][C:17]5[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=5)[C:12]5=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]5[N:10]=4)[CH:6]=[C:5]([C:33]#[N:34])[CH:4]=3)[CH2:36][CH2:37]2)[CH2:42]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CN(C(=O)OC(C)(C)C)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CNC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 3-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperazin-1-yl)azetidine-1-carboxylate (400 mg, 0.563 mmol) in dichloromethane (4.0 mL) at 0° C., was added 2,6-lutidine (0.197 mL, 1.690 mmol). After that TMS-OTf (0.305 mL, 1.690 mmol) was added drop wise. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction mixture was diluted with dichloromethane (50 mL) and poured into a separating funnel containing liquor ammonia (5 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layer were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was washed with pentane (3×10 ml) and diethyl ether (3×5 mL). After the washing the resultant solid was dried under vacuum to get 2-((3-(4-(azetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (250 mg) as a off white solid.