Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17]C(=O)C.O.[C:23]1(C)C=CC(S(O)(=O)=O)=C[CH:24]=1.CCOC(C)=O>CCO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([O:12][CH2:23][CH3:24])[CH3:11])[C:7]([C:13]([F:14])([F:15])[F:16])=[CH:6][C:5]=1[NH2:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(C)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 179 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-ethyl)-4-trifluoromethyl-benzoic acid methyl ester (500 mg, 1.64 mmol) in EtOH (5 mL) was treated with p-toluenesulfonic acid monohydrate (100 mg, 0.518 mmol) and stirred at r.t. for 5 d. The reaction mixture was taken into EtOAc and washed with sat. aq NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes/EtOAc) to give title product (270 mg, 57%) as colorless crystals. m.p.: 100-103° C., API-ES: m/z 292 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH2:13][Cl:14])[N:3]=1.O.[NH2:16][NH2:17].C(=O)([O-])O.[Na+]>O1CCCC1.O>[Cl:14][CH2:13][C:4]1[N:3]=[C:2]([NH:16][NH2:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=1
Reactant: Cc1ccc2nc(CCl)nc(Cl)c2c1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nc(CCl)nc(NN)c2c1
Temperature: 10 °C
Reaction time: 0.13 h

Procedure:
3. 63.5 g of 4-chloro-2-(chloromethyl)-6-methylquinazoline are dissolved in 630 ml of absolute tetrahydrofuran at room temperature and then cooled to 10° C. 27.2 ml of hydrazine hydrate are added dropwise thereto within 8 min., whereby a solution results and the temperature rises to 15° C. The reaction mixture is stirred at 5° to 15° C. for 4 h. and then poured into a solution of 40 g of sodium hydrogen carbonate in 5 l of water. The mixture is extracted five times with 1.5 l of dichloromethane each time. The combined organic phases are washed with water, dried and concentrated (T<40° C.) in a vacuum to a volume of 0.5 l. 0.5 l of ethyl acetate is added thereto and the dichloromethane is evaporated completely in a vacuum, whereby the product crystallizes out. The mixture is left to stand at -25° C. overnight and the crystals are filtered off, washed with diethyl ether and dried at room temperature in a vacuum. There are obtained 38 g of 2-(chloromethyl)-4-hydrazino-6-methylquinazoline of m.p. above 140° C. (dec.).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]1[C:18](=[O:19])[CH2:17][C@:16]([CH:23]([CH3:25])[CH3:24])([C:20]([OH:22])=O)[CH2:15]1.C(N(CC)C(C)C)(C)C.[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40].Cl>C1COCC1.C(Cl)Cl>[F:35][C:36]([F:48])([F:49])[C:37]1[CH:38]=[C:39]([NH:40][C:20]([C@@:16]2([CH:23]([CH3:24])[CH3:25])[CH2:17][C:18](=[O:19])[N:14]([C:8]3[C:7]([CH3:6])=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:13])[CH2:15]2)=[O:22])[CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Methanesulfonyl chloride (167 mg, 1.45 mmol) was added dropwise to a solution of enantiopure (3R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxo-pyrrolidine-3-carboxylic acid (182 mg, 0.661 mmol, prepared in step a above), N,N-diisopropylethylamine (374 mg, 2.90 mmol) and 3,5-bis(trifluoromethyl)aniline (331 mg, 1.45 mmol) in THF (4 mL). Stirring at room temperature for 1 h allowed the reaction to reach completion, whereupon 5 mL of 0.3 M aqueous hydrochloric acid and 10 mL of DCM were added and the mixture was stirred vigorously for 5 min. The separated organic phase was concentrated in vacuo on silica gel and purified by flash chromatography (SiO2, 25-60% EtOAc/hexanes) to give an off-white residue, which was recrystallized from a mixture of hot ethyl acetate (2 mL) and hexanes (7 mL) to give 203 mg of the desired compound (63% yield) as colorless crystals. 1H NMR (400 MHz, CDCl3) 1.09 (d, J=7.4, 3H), 1.11 (d, J=7.4, 3H), 2.13 (s, 3H), 2.23 (s, 3H), 2.26 (qq, J=7.4, 7.4, 1H), 2.81 (d, J=17.2, 1H), 3.09 (d, J=17.2, 1H), 3.61 (d, J=10.4, 1H), 4.17 (d, J=10.4, 1H), 7.02-7.18 (m, 3H), 7.64 (s, 1H), 7.86 (s, 1H), 8.05 (s, 2H). LC-MS: Rt (retention time)=3.10 min, MS: (ES) m/z 487 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:19]Br>O1CCCC1.ClCCl>[Br:19][C:4]([CH3:3])([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: BrBr
Reactant: CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of sodium hydride (1.7 g, 80% dispersion in oil) in tetrahydrofuran (60 ml) under an atmosphere of nitrogen was added di-t-butyl methylmalonate (11.52 g). The mixture was stiirred at 60°-70° for 1.5 hours to give a clear solution. This solution was cooled to -25°, and to it was rapidly added a solution of bromine (2.6 ml) in dichloromethane (30 ml). The solution was allowed to warm to ambient temperature, then concentrated. The residue in ether was washed with water, dried, and fractionally distilled under reduced pressure to give the title compound b.p. 78°-86°/1.0 mm Hg, (7.56 g, 49%); νmax (CHBr3) 1730cm-1 (CO2But); τ (CDCl3) values include 8.05 (s, C(CH3)3) and 8.53 (2s, CH3 and C(CH3)3).
Reaction SMILES: C(OC([C:6]1[N:7]=[C:8]([CH:12]2[CH2:14][CH2:13]2)S[C:10]=1N)=O)C.C(O[C:18]([C:20]1[N:21]=[C:22]([CH:32]2[CH2:34][CH2:33]2)[S:23][C:24]=1[NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:19])C.C1(C2SC(NC3C=NC=CC=3)=C(C(O)=O)[N:42]=2)CC1>>[CH3:10][C:6]1[N:7]=[C:8]([NH:42][C:18]([C:20]2[N:21]=[C:22]([CH:32]3[CH2:33][CH2:34]3)[S:23][C:24]=2[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:19])[CH:12]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1nc(C2CC2)sc1Nc1cccnc1
Reactant: CCOC(=O)c1nc(C2CC2)sc1N
Reactant: O=C(O)c1nc(C2CC2)sc1Nc1cccnc1
Product: Cc1cccc(NC(=O)c2nc(C3CC3)sc2Nc2cccnc2)n1

Procedure:
The title compound, MS (ISP): m/e=352.3 (M+H+), was prepared as for example 153, steps A to G. Step C was performed using cyclopropanecarbonyl chloride, and yielded cyano-(cyclopropanecarbonyl-amino)-acetic acid ethyl ester, which was cyclized to 5-amino-2-cyclopropyl-thiazole-4-carboxylic acid ethyl ester in step D. This was used in step E to generate 2-cyclopropyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester, which was hydrolized to 2-cyclopropyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid in step F. Coupling as described in step G generated the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[F:14][C:15]([F:23])(S(F)(=O)=O)C(O)=O>C(#N)C>[F:14][CH:15]([F:23])[O:8][C:6]1[N:7]=[C:2]([CH3:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=1
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(OC(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
To a solution of 6-methyl-5-nitropyridin-2-ol (0.5 g, 3.2 mmol) in acetonitrile (10 mL) was added NaH (0.35 g, 8.64 mmol) and the reaction mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added 2,2-difluoro-2-(fluoro-sulfonyl)acetic acid (1.1 mL, 5.5 mmol) dropwise. The reaction mixture was stirred for a further 15 minutes. The reaction mixture was then quenched by the addition of water, and diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-4%) to afford the title compound (0.5 g, 75%) as a white solid. LCMS (ES−) 202.85 (M−H)−, RT 2.75 minutes (method 1).
Reaction SMILES: SCC[OH:4].CCCCCC[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17]S([O-])(=O)=O.[Na+].C(O)[C:24]([NH2:29])([CH2:27]O)[CH2:25][OH:26].Cl>>[NH2:29][C@H:24]([C:25]([OH:26])=[O:4])[CH2:27][C:13]1[CH:12]=[CH:11][C:16]([OH:17])=[CH:15][CH:14]=1
Reactant: NC(CO)(CO)CO
Reactant: OCCS
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 4 °C
Reaction time: 0.08 h

Procedure:
The transfectants were cultured in RPMI 1640 medium supplemented with 10% FCS (GIBCO), and then centrifuged at 1000 rpm for 5 minutes to recover 2×107 cells. The cell pellets were washed with PBS, dissolved in lysis buffer (20mMTris-HCl, pH7.5, 150 mM NaCl, 2 mM EDTA, Nonidet P-40, 50 mM NaF, 10 mg/ml a protinin, 10 mg/ml leupeptin, 1 mM Na3VO4, 50 mM Na2MoO4, 1 mM phenylmethylsulfonyl fluoride (PMSF)), allowed to stand for 1 hour at 4° C., then centrifuged at 15000 rpm for 30 minutes. Rabbit anti-human FLT3 antibody (Santa Cruz Biotechnology, Santa Cruz, Calif., USA) was added to the supernatants and the mixture was stirred for 2 hours at 4° C. After adding Protein A/G Plus agarose (Santa Cruz), the resulting mixture was stirred for 2 hours at 4° C. and washed with the lysis buffer three times. The pellets were then dissolved in sample loading buffer (0.125 M Tris-HCl, pH 6.8, 10% 2-mercaptoethanol, 4% SDS), subjected to SDS-PAGE, transferred onto Immobilon PVDF membrane (Millipore), and reacted with anti-phosphorylated tyrosine antibody (4G10, Upstate Biotechnology, Lake Placid, N.Y., USA). Following the reaction, the bands were detected using the ECL system (Amersham). To confirm the presence of FLT3 protein, the same membrane was incubated in stopping buffer (100 mM 2-mercaptoethanol, 2% SDS, 62.5 mM Tris-HCl, pH 6.8) for 30 minutes at 70° C., and then reacted with rabbit anti-human FLT3 antibody.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.CCCCCC>C(OCC)(=O)C.CO.[C].[Pd]>[Cl:1][C:2]1[C:3]([CH:14]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In a mixed solvent of ethyl acetate (3 ml) and methanol (3 ml) was dissolved methyl(E)-3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]acrylate (110 mg, 0.21 mmol). To the resulting solution was added 10% palladium-carbon catalyst (60 mg). Under a hydrogen atmosphere, the resulting mixture was stirred at room temperature for 2 hours. After the catalyst was removed by Celite filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (94 mg, 0.18 mmol, 85%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:19]([NH2:22])[C:20]#[CH:21].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:22][CH2:19][C:20]#[CH:21])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCNC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (160 mg, 0.53 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). Propargylamine (Fluka) (35.0 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (44) as a pale yellow powder (83.3 mg; 49%). 1H NMR (DMSO-d6, 300 MHz) δ 2.14 (s, 3H), 2.49 (s, 3H), 3.14 (s, 1H, C—CH), 4.04 (m, 2H), 8.01 (s, 1H), 9.20 (t, J=4.5 Hz, 1H), 12.15 (s, 1H). M− (ESI): 319.05; M+ (ESI): 321.05. HPLC (method A), Rt: 2.71 min (purity: 100%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:31]=[CH:30][N:16]3[C:17](=[O:29])[C:18]([CH:27]=O)=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].FC(F)(F)COP([CH2:46][C:47]([O:49][CH3:50])=[O:48])(=O)OCC(F)(F)F.N12CCCN=C1CCCCC2>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:31]=[CH:30][N:16]3[C:17](=[O:29])[C:18](/[CH:27]=[CH:46]/[C:47]([O:49][CH3:50])=[O:48])=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/c1c(N2CCOCC2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.4 %

Procedure:
N8-[4-(tert-Butyl)-1,3-thiazol-2-yl]-3-formyl-2-morpholino-4-oxo-4H-pyrido-[1,2-a]pyrimidine-8-carboxamide (98.2 mg, 0.223 mmol) was added with tetrahydrofuran (6 ml), lithium chloride (30 mg, 0.669 mmol) and bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)-phosphonate (142 μl, 0.669 mmol), then added dropwise with 1,8-diazabicyclo[5.4.0]undec-7-ene (92 μl, 0.669 mmol) at room temperature, stirred at room temperature for 1 hour, and further added with bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)-phosphonate (75 μl) and 1,8-diazabicyclo[5.4.0]undec-7-ene (45 μl). The reaction solution was further stirred at room temperature for 30 minutes and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=40:1) to obtain 145.8 mg of the title compound in a mixture with 1,8-diazabicyclo[5.4.0]undec-7-ene.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.Cl[C:14]1[C:19]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:31])[CH:27]=3)[N:22]=[C:21]2[CH3:32])=[CH:18][CH:17]=[CH:16][N:15]=1.[C:33]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])#[N:34]>O1CCCC1>[C:33]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])#[N:34].[F:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([CH:32]=[C:37]([C:36]1[CH:41]=[CH:42][CH:43]=[CH:44][C:35]=1[C:33]#[N:34])[OH:38])[N:20]([C:19]1[C:14]([CH3:1])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:29]2=[O:30]
Reactant: CC(C)NC(C)C
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Agent: COC(=O)c1ccccc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncccc1-n1c(C=C(O)c2ccccc2C#N)nc2ccc(F)cc2c1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
Two identical reactions were run side by side. A solution of diisopropylamine (0.120 mL, 0.91 mmol) in tetrahydrofuran (5.4 mL) was chilled to -78° C. and butyllithium (0.26 mL, 0.65 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.204 g, 0.70 mmol) in tetrahydrofuran (5 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (1.02 g, 6.33 mmol) in tetrahydrofuran (15 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 1 hour at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two side by side reactions were combined and flash chromatographed on silica gel (40×220 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (250 mL), nil; 20% ethyl acetate/hexane (250 mL), nil; 30% ethyl acetate/hexane (50 mL), unweighed impurity; 40% ethyl acetate/hexane (250 mL), unweighed recovered 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 50% ethyl acetate/hexane (250 mL), nil; 60% ethyl acetate/hexane (250 mL), desired product (tlc Rf =0.3 with 50% ethyl acetate/hexane on silica gel). The product containing fractions were combined and concentrated. The residue was triturated with ether and the light yellow solid which formed was collected and dried to yield 0.093 g (17%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 217-218° C.; 1H NMR δ8.60 (dd, J=3, 5 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.81 (dd, J=2, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.58-7.42 (m, 6 H), 4.98 (s, 1 H). Analysis calculated for C21H12ClFN4O2 : C, 63.09; H, 2.89; N, 13.38. Found: C, 62.90; H, 2.81; N, 13.01.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[OH:24].C(N(CC)CC)C.Cl>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24]
Reactant: OC1CCCCC1CC1CCCCO1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCCC1CC1CCCCO1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
Neat, dry DMSO (4 equivalents) is added slowly to a CH2Cl2 solution of the oxalyl chloride (1.25 equivalents) cooled to -70° C. under N2. After stirring for about 15 min., the product of Example 193 (1 equivalent) in CH2Cl2 is added slowly. Neat triethylamine (4 equivalents) is then added and the mixture is warmed to 0° C. After 30 min., the mixture is poured into stirred ice-water and neutralized with dilute HCl. The mixture is then separated and the aqueous layer extracted with CH2Cl2. The organic extracts are then combined, washed with dilute brine, dried (MgSO4) and stripped of all solvent under reduced pressure. The crude title compound is purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6](=[O:13])[C:7]1=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 5-methoxyisatin (15.0 g, 84.7 mmol) in DMF (100 mL), sodium hydride (5.1 g, 127 mmol) and benzyl bromide (12.1 mL, 101.6 mmol) were added at 0° C., and the resulting mixture was stirred for 1 hour. Water was added thereto, and the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated ammonium chloride aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the aimed product (yield: 96%).
Reaction SMILES: C[OH:2].[CH3:3][CH:4]([NH:8][C:9]1[C:12](=[O:13])[C:11](=[O:14])[C:10]=1[NH:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)[CH:5]([CH3:7])[CH3:6].[C:24](#N)[CH3:25]>>[O:13]=[C:12]1[C:9](=[O:2])[C:10]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)=[C:11]1[O:14][CH2:24][CH3:25].[CH3:3][CH:4]([NH2:8])[CH:5]([CH3:7])[CH3:6]
Reactant: CO
Reactant: CC(C)C(C)Nc1c(Nc2ccc(C#N)cc2)c(=O)c1=O
Reactant: CC#N
Product: CC(C)C(C)N
Product: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O

Procedure:
This compound was prepared according to the procedure described in Example 11, first paragraph. 4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol) and (±)-1,2-dimethylpropylamine (5 g, 57.4 mmol) in acetonitrile (125 mL) there was obtained after trituration with methanol 0.28 g (24%) of 4-[2-(1,2-dimethyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino)-benzonitrile as a yellow solid: mp 222°-224° C.; 1HNMR (DMSO-d6): δ9.89 (br s, 1H), 7.78 (d, 2H), 7.73 (d, 1H), 7.59 (d, 2H), 3.98 (m, 1H), 1.76 (m, 1H), 1.19 (d, 3H), 0.90 (d, 3H), 0.89 (d, 3H). IR (KBr): 2980, 2240, 1799, 1660, 1600, 1565, 1525 cm-1 ; MS (m/z) 283 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH:9]=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1cccc(-c2cnc3[nH]cc(-c4ccccc4F)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Crude (3-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone from last step was dissolved in methanol (1 mL) and potassium hydroxide (50% w/v, 0.038 mL, 0.136 mmol) was added to the solution. The resulting mixture was stirred at room temperature for 30 minutes before being diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was then dissolved in DMSO and purified by mass triggered reverse phase HPLC to afford pure (3-(3-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (5.6 mg, 21% yield from (3-(3-iodo-1-tosyl-1H-pyrrolo [2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone) as light brown syrup. 1H NMR (500 MHz, DMSO-d6) δ 3.60 (m, br, 8H), 7.33 (m, 3H), 7.39 (m, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.74 (m, 1H), 7.84 (m, 3H), 8.28 (m, 1H), 8.61 (d, J=2.5 Hz, 1H), 12.17 (s, 1H). MS: m/z 402.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]#N)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:15]([Mg]Br)[CH2:16][CH3:17].C(Br)CC.[Mg].Cl.CC[O:28]CC>O.C1(C)C=CC=CC=1>[C:13]([C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH2:11][CH2:10]1)(=[O:28])[CH2:15][CH2:16][CH3:17]
Reactant: CCC[Mg]Br
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCCBr
Solvent: Cc1ccccc1
Product: CCCC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-cyclobutanecarbonitrile prepared as described in Example 1 (35.2 g) in ether (100 ml) was added to a solution of propyl magnesium bromide prepared by the reaction of propyl bromide (32 g) with magnesium turnings (6.36 g) in ether (100 ml). The ether was replaced by dry toluene and the mixture heated under reflux for one hour. Water (200 ml) and then concentrated hydrochloric acid (120 ml) were added and the mixture heated under reflux for one hour. The reaction mixture was extracted with ether and after washing and drying the extract yielded a residue from which 1-butyryl-1-(3,4-dichlorophenyl)cyclobutane (b.p. 120°-128° C. at 0.25 mm) was distilled.