Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH2:26])[N:20]=4)=[CH:14][C:13]=3[F:27])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:34][NH:35][CH2:36][C@H:29]12.C(N(C(C)C)CC)(C)C>C(C(CCCC)CO)C>[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:34][N:35]([C:23]3[CH:24]=[C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([O:11][C:7]5[C:6]6[C:2]([NH2:1])=[N:3][O:4][C:5]=6[CH:10]=[CH:9][CH:8]=5)=[C:13]([F:27])[CH:14]=4)[N:20]=[C:21]([NH2:26])[N:22]=3)[CH2:36][C@H:29]12
Reactant: C1CN[C@H]2CNC[C@H]2C1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3cccc4onc(N)c34)c(F)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCC(CC)CO
Product: Nc1nc(Nc2ccc(Oc3cccc4onc(N)c34)c(F)c2)cc(N2C[C@H]3CCCN[C@H]3C2)n1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
88 mg (0.23 mmol) of N-{4-[(3-amino-1,2-benzisoxazol-4-yl)oxy]-3-fluorophenyl}-N-(2-amino-6-chloro-4-pyrimidinyl)amine (from example 3) and 114.8 mg (0.91 mmol) of [(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridine together with 294.1 mg (2.28 mmol) of diisopropylethylamine are dissolved in 4 ml of 2-ethylhexanol, and the mixture is stirred at 150° C. for 3 h. After cooling, the reaction mixture is filtered and water is added. The mixture is extracted repeatedly with ethyl acetate, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:17]2[N:22]=[C:21]([Br:23])[CH:20]=[CH:19][CH:18]=2)([C:10]2[N:15]=[C:14]([Br:16])[CH:13]=[CH:12][CH:11]=2)O)[N:3]=1.C(N(S(F)(F)[F:30])CC)C.[OH-].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:17]2[N:22]=[C:21]([Br:23])[CH:20]=[CH:19][CH:18]=2)([C:10]2[N:15]=[C:14]([Br:16])[CH:13]=[CH:12][CH:11]=2)[F:30])[N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(c1cccc(Br)n1)(c1cccc(Br)n1)c1cccc(Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: FC(c1cccc(Br)n1)(c1cccc(Br)n1)c1cccc(Br)n1
Temperature: 5 °C

Procedure:
A solution of 50.0 g (100 mmol) of tris(2-bromo-6-pyridyl)methanol in 750 ml of dichloromethane was admixed with good stirring dropwise with 47.3 ml (400 mmol) of diethylaminosulfur trifluoride. Subsequently, the reaction mixture was heated under reflux for 30 min, then cooled to 5° C., and admixed with good stirring (highly exothermic!!!) with 300 ml of water and then with a solution of 64.0 g (1600 mmol) of sodium hydroxide in 600 ml of water (highly exothermic!!!). The organic phase was removed, the aqueous phase was washed twice with 200 ml of dichloromethane, and the combined organic phases were dried over calcium chloride and subsequently freed of dichloromethane. The remaining red-brown crystal slurry was taken up in 100 ml of methanol and filtered off. After washing with methanol, the colorless to beige crystals were dried under reduced pressure. The yield was 47.4 g (91.3%) at a purity of greater than 99.0% by 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].P([O-])([O-])[O-]>>[CH2:12]([O:11][P:10]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cccc(Br)c1
Agent: [O-]P([O-])[O-]
Product: CCOP(=O)(Cc1cccc(Br)c1)OCC
Temperature: 130 °C
Yield: 98.3 %

Procedure:
To 1-bromo-3-(bromomethyl)benzene (100 g, 400 mmol) in a 500 mL round-bottom flask under nitrogen was added triethyl phosphite (69.6 mL, 400 mmol) and the solution was heated to 130° C. The apparatus was set up ready for distillation. As the heating block reached 130° C. the mixture began to reflux and a large volume of colourless liquid was allowed to distil off. Analysis of the reaction by hplc after 40 min showed some starting material so another 0.5 eq of the phosphite was added and heating with distillation continued. The reaction was then heated under vacuum: the excess phosphite was distilled off under vacuum (130° C. heater and 15 mbar, gradually going down to 0.5 mbar). This gave a colorless oil 120.8 g. HPLC 2.20 min (ret time), 97%; LC-MS m/z 307, 309 (M+H)+, 1.01 min (ret time).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH:30]1[O:32][CH2:31]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CO>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH:30]([OH:32])[CH2:31][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CSc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 77 %

Procedure:
4-Nitrothiophenol (1.21 g) and triethylamine (0.91 ml) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)-pyrrolidine (1.39 g) as obtained in Example 1-A) in methanol (50 ml), and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate : hexane-ethyl acetate) to give 1.85 g of the title compound. B) (2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(4-nitrophenylthio)ethyl]pyrrolidine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:27](=[O:28])[C:11]2=[CH:12][N:13]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C(N(CC)CC)C.[CH3:36][N:37]=[C:38]=[O:39]>ClCCl.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:27](=[O:28])[C:11]2=[CH:12][N:13]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:38]([NH:37][CH3:36])=[O:39])[CH2:25][CH2:26]3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: CN=C=O
Reactant: O=c1c2cn(CC3CCNCC3)c3ccccc3c-2nn1-c1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCC(Cn2cc3c(=O)n(-c4ccccc4F)nc-3c3ccccc32)CC1
Reaction time: 0.17 h

Procedure:
2-(2-Fluorophenyl)-5-(piperidin-4-ylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (30 mg, 0.080 mmol) was dissolved in dichloromethane (2 ml) and tetrahydrofuran (1 ml), treated with triethylamine (0.011 ml, 0.080 mmol, 1 equiv) and methylimino(oxo)methane (4.55 mg, 0.080 mmol) were added. After 10 minutes, the mixture was concentrated in vacuo and the residue was purified by silica gel gradient chromatography (80:20 to 70:30; dichlormethane:methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.85 (1H, s), 8.21 (1H, dd, J=, 7.9, 1.6 Hz), 7.98 (1H, d, J=8.7 Hz), 7.61-7.56 (2H, m), 7.47-7.30 (4H, m), 6.37 (1H, q, J=4.2 Hz), 5.70 (2H, br s), 4.35 (2H, d, J=6.8 Hz), 3.94 (2H, br d, J=13.6 Hz), 2.52 (3H, d, J=4.9 Hz), 2.13-2.02 (1H, m), 1.49 (2H, br d, J=12.3 Hz), 1.25-1.13 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 434.1998 [(M+H)+; calculated for C24H25FN5O2: 434.1987].
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][C:18](=[O:23])[NH:19][C:20]([CH3:22])([CH3:21])[C:13]2=[N:12][C:11]=1[C:24]([O:26]CC)=O)(=O)C1C=CC=CC=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:24]([C:11]2[N:12]=[C:13]3[C:20]([CH3:21])([CH3:22])[NH:19][C:18](=[O:23])[CH2:17][N:14]3[C:15](=[O:16])[C:10]=2[OH:9])=[O:26])=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC(=O)NC2(C)C
Reactant: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)Cn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Intermediate 30, ethyl 3-(benzoyloxy)-9,9-dimethyl-4,7-dioxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxylate, (1 mmol), was dissolved in 4 mL of DMF. To this was added 4-fluorobenzylamine (0.457 mL, 4 mmol) and triethylamine (0.139 mL, 1 mmol). The mixture was warmed to 80° C. and allowed to stir overnight, after which it was allowed to cool to room temperature and transferred to a seperatory funnel. The mixture was diluted with ethyl acetate, washed with 1N HCl, dried over Na2SO4 then concentrated in vacuo. Methanol and ether were added to the residue and the resulting precipitate isolated by filtration. 1H NMR (500 MHz, DMSO) δ: 1.56 (s, 3H), 4.50 (m, 4H), 7.17 (m, 2H), 7.38 (m, 2H), 8.72 (brs, 1H), 9.37 (brm, 1H), 12.37 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[H][H]>CO.[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc2c(N(C)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cnc2c(N(C)c3ccc(N)cc3)ccnc2c1
Reaction time: 4 h

Procedure:
To a mixture of 7-methoxy-N-methyl-N-(4-nitrophenyl)-1,5-naphthyridin-4-amine (0.233 g, 0.751 mmol) in MeOH (10 mL) at RT was added a suspension of 10% palladium on carbon (0.0799 g, 0.751 mmol) in EtOAc (10 mL). The mixture was exposed to an atmosphere of hydrogen (balloon). After 4 h, the mixture was filtered over celite and concentrated in vacuo. The crude yellow foam, N1-(7-methoxy-1,5-naphthyridin-4-yl)-N1-methylbenzene-1,4-diamine, was advanced without further purification. MH+=281.2@1.21 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.CO>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(CBr)cc1Br
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(CBr)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
The compound of Step 1 (23.8 g, 81 mmol, 1 eq) was dissolved in THF under nitrogen at 0° C. A 1M borane solution in THF (242 ml, 242 mmol, 3 eq) was then added dropwise and the mixture was stirred at r.t. for 1 h. under nitrogen. The solution was cooled in an ice bath and 125 ml of methanol was then added slowly. The solvents were removed and the mixture partitioned between 400 ml of water and 400 ml of 20% THF/EtOAc. The aqueous layer was washed 3 times with 400 ml of 20% THF/EtOAc and the combined organic layer was dried with sodium sulfate. The solvent was removed and 19.7 g (87%) of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1>>[CH3:20][C:18]1[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:11]2[NH:12][C:13](=[O:15])[CH2:14][C:8]([C:4]3[CH:3]=[C:2]([C:33]4[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=4)[CH:7]=[CH:6][CH:5]=3)=[N:9][C:10]=2[CH:19]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(N)(=O)=O)cc3)c1)=N2

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.1) (200 mg, 0.50 mmol) and commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonamide [CAS-no. 214360-51-7] (170 mg, 0.60 mmol) according to the general procedure II. Obtained as a white solid (165 mg, 69%). MS (ISP) 473.9 [(M+H)+]; mp>260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13]C1C=CC(C(F)(F)F)=CC=1N.CN1C(=O)CCC1.S(Cl)(Cl)(=O)=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: Clc1ccccc1
Product: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 94 %

Procedure:
A mixture (276 g) of 2-chloro-4-trifluoromethylaniline, 2-chloro-5-trifluoromethylaniline and NMP (0.73 m/m) was mixed with 500 ml chlorobenzene. Sulfuryl chloride (135 g) was added to the mixture at 55-60° C. liquid temperature over a period of 4 hours and the reaction temperature was maintained for further 2 hours. Additional 20.2. g of sulfuryl chloride was added for completion of reaction. Reaction medium on treatment and fractionation gave 2,6-dichloro-4-trifluoromethylaniline, in 94% yield on 2-chloro-4-trifluoromethylaniline.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:20])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:22][O:23][C:24](=[O:29])[NH:25][C:26](=[O:28])[CH3:27])[CH3:21])=[O:11])=CC=1)([O-])=O.[H][H]>[Pd].O>[C:26]([NH:25][C:24]([O:23][CH2:22][C@@:13]1([CH3:21])[C@H:12]([C:10]([OH:11])=[O:9])[N:16]2[C:17](=[O:20])[C@@H:18]([NH2:19])[C@H:15]2[S:14]1)=[O:29])(=[O:28])[CH3:27]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Yield: 65.1 %

Procedure:
To a prehydrogenated suspension of 10% palladium on carbon (0.83 gm), water-washed ethyl acetate (8.3 ml) and water (4.1 ml) was added (2R,3S,5R,6R)2-(N-acetyl)carbamoyloxymethyl-6-amino-2-methylpenam-3-carboxylic acid p-nitrobenzyl ester (0.83 gm, 1.84 mmol). The mixture was shaken at 50 psi hydrogen pressure for 80 minutes and filtered through Dicalite-coated paper. The aqueous phase was separated, concentrated at reduced pressure to remove volatile solvent and gases, frozen and lyophilized. There was obtained 0.38 gm of the title compound as a white amorphous solid. Its nmr spectrum was consistent with the desired product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCc1ccccc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A stirred solution of 25.0 grams (0.152 mole) of 5-phenylpentanol and 23.3 mL (0.167 mole) of triethylamine in 250 mL of methylene chloride was cooled to 0° C., and a solution of 13.0 mL (0.167 mole) of methanesulfonyl chloride in 50 mL of methylene chloride was added dropwise at a rate to maintain the reaction mixture temperature at 0° C. to 5° C. The complete addition required about 45 minutes. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature. After this time the reaction mixture was washed with two 200 mL portions of an aqueous 5% sodium bicarbonate solution and then with 200 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 36.8 grams of 1-methylsulfonyloxy-5-phenylpentane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].[C:23]1(C)C=CC(S(OCC)(=O)=O)=C[CH:24]=1>CN(C)C=O>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1)[CH3:24]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A solution of 5-hydroxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine (500 mg, 1.78 mmol, from step 120f) in dimethylformamide (15 mL) was treated with ground KOH (170 mg, 1.7 mmol) and stirred for 30 minutes at room temperature. To this mixture was rapidly added ethyl p-toluenesulfonate (430 mg, 2.14 mmol), and the resultant was stirred at 80° C. overnight. The mixture was concentrated to remove the dimethylformamide, and the residue was diluted with water and extracted with EtOAc. The organic extracts were combined, dried (MgSO4), filtered and concentrated under vacuum to give 1.0 g of unpurified product. This material was purified by chromatography (silica gel: hexane/EtOAc, 1:1) to give 537 mg (98%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ: 1.40 (s, 9H), 1.42 (t, J=6 Hz, 3H), 2.30 (m, 2H), 3.92 (t, J=9 Hz, 2H), 4.05 (q, J=6 Hz, 2H), 4.30 (m, 1H), 4.54 (m, 1H), 6.80 (m, 1H), 7.95 (m, 2H). MS (CI/NH3) m/e: 309 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1SC.[C:25]([C:28]1[CH:29]=[CH:30][C:31]([NH:48][CH2:49][CH3:50])=[C:32]([N:34]=[C:35]2[N:39]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:38](=[O:47])[CH2:37][S:36]2)[CH:33]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:29]=[CH:30][C:31]([NH:48][CH2:49][CH3:50])=[C:32]([N:34]=[C:35]2[N:39]([CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:38](=[O:47])[C:37](=[C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]3[CH3:12])[S:36]2)[CH:33]=1)(=[O:27])[CH3:26]
Reactant: CSc1ccc2ccccc2[n+]1C
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2C=Cc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 102, 1-methyl-2-methylthioquinolinium p-toluenesulfonate was condensed with 2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one to afford the title compound. 1H-NMR (CDCl3): δ 7.66–7.71 (2H, m), 7.43–7.56 (4H, m), 7.20–7.38 (7H, m), 6.53 (1H, d), 5.20 (2H, s), 3.78 (3H, br s), 3.07 (2H, q), 2.51 (3H, s), 1.06 (3H, t); MS(ESI): 509 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:14](#N)[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17].Cl.C1C[O:27]CC1>C(OCC)(=O)C>[NH2:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[C:14]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)=[O:27]
Reactant: N#Cc1ccccc1N
Reactant: Fc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromofluorobenzene (1 eq.) in THF was cooled to −78° C. under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 M solution in pentane) at a rate of 40 mL/h. The internal temperature did not rise above −74° C. The orange solution was stirred at −78° C. for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as a solution in THF. The reaction was warmed to 0° C. and stirred for 2 hours. 3N HCl was added to the mixture and stirring continued for 30 minutes. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted thrice with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 93:7 hexanes/ethyl acetate.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH:17]([C:20]1[N:24]2[N:25]=[CH:26][C:27]3[C:32]([C:23]2=[C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]=1/[CH:39]=[CH:40]/[CH:41]=[O:42])=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH3:19])[CH3:18]>O1CCCC1.CCCCCC>[OH:42][CH:41](/[CH:40]=[CH:39]/[C:21]1[C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[N:25][N:24]2[C:20]=1[CH:17]([CH3:19])[CH3:18])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)c1c(/C=C/C=O)c(-c2ccccc2)c2c3ccccc3cnn12
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
A stirred suspension of sodium hydride (80% dispersion in oil, 112 mg; 3.7 mmol) in dry tetrahydrofuran (15 ml) was treated with ethyl acetoacetate (0.43 g) under an atmosphere of argon, maintaining the temperature at -10° C. The mixture was stirred for 30 minutes and then it was treated with a solution of butyl lithium in hexane (2.5M; 1.38 ml), still maintaining the temperature at -10° C. The mixture was stirred for a further period of 20 minutes and then it was treated dropwise with a solution of (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)propenal (0.56 g) in tetrahydrofuran (5 ml) at -10° C., and the resulting mixture was stirred at -10° C. for 1 hour. The reaction mixture was then quenched at -10° C. by treatment with saturated aqueous ammonium chloride solution (15 ml). The mixture was allowed to warm to the ambient temperature and then it was partitioned between water (20 ml) and diethyl ether (50 ml). The organic layer was separated and the aqueous layer was extracted with diethyl ether (50 ml). The combined organic layers were dried over magnesium sulphate, evaporated and subjected to flash chromatography on silica gel, using as eluant a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (3:1 v/v), to give ethyl (E)-5-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)-3-oxohept-6-enoate (0.33 g) in the form of an orange oil. [NMR (in a mixture of CDCl3 and D2O): 1.27 (3H, t, J=7 Hz), 1.54 (6H, d, J=7 Hz), 2.52-2.62 (2H, m), 3.44 (2H, s), 3.78 (1H, septet, J=7 Hz), 4.21 (2H, q, J= 7 Hz), 4.50-4.62 (1H, m), 5.3 (1H, dd, J=16 Hz, 7 Hz), 6.65 (1H, dd, J=16 Hz, 1 Hz), 7.22-7.62 (9H, m), 8.24 (1H, s)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)Cl.C1(C)C=CC([Mg]Br)=CC=1.COC(C(=O)C1C=CC=CC=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:47]1[CH:51]=[CH:50][N:49]=[CH:48]1>C(#N)C>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:48]1[NH:47][CH:51]=[CH:50][N:49]=1
Reactant: COC(=O)C(Cl)(c1ccccc1)c1ccc(C)cc1
Reactant: c1c[nH]cn1
Agent: COC(=O)C(=O)c1ccccc1
Agent: Cc1ccc([Mg]Br)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)(c1ccc(C)cc1)c1ncc[nH]1

Procedure:
13.7 g phenyl-p-tolyl-chloroacetic acid methyl ester (prepared from p-tolyl-magnesium bromide and benzoyl-formic acid methyl ester and treatment with PCl5 ; (b.p. 150°C./0.3 mm Hg) are heated with 10 g imidazole in 100 ml acetonitrile at boiling temperature for 16 hours. The acetonitrile is distilled off in a vacuum. The residue is treated with 50 ml of water and then extracted with methylene chloride. The methylene chloride solution is distilled off in a vacuum and the residue recrystallized from a little ethyl acetate. The phenyl-p-tolyl-imidazolyl-acetic acid methyl ester i.e. phenyl-4-methylphenyl-imidazolyl-acetic acid methyl ester of m.p. 146°C. is thus obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cn1cccc1
Product: CCOC(=O)Cc1cccn1C
Reaction time: 0.02 h

Procedure:
In a flask is placed 9.72 grams (120 mmol) N-methyl pyrrole and 158 mg (.016 mmole; 1.5 mol%) Cu(acetylacetonate)2, abbreviated herein as "Cu(acac)2 ". The mixture is heated to 50° C. after which a few drops of the 4.56 grams (40 mmol) ethyl diazoacetate are added with stirring. Nitrogen gas is evolved after about 1 minute and the mixture darkens, whereupon the remainder of the ethyl diazoacetate is added drop by drop over a period of 15 minutes. The reaction mixture is then heated and stirred for a further 45 minutes to insure completion of the reaction.