Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2][O:3][CH2:4][C:5]#N.[Cl:7][C:8]1[CH:9]=[C:10]([Mg:15][Br:16])[CH:11]=[CH:12][C:13]=1[Cl:14].C([O:19]CC)C>BrC1C=CC(Cl)=C(Cl)C=1>[Cl:7][C:8]1[CH:9]=[C:10]([Mg:15][Br:16])[CH:11]=[CH:12][C:13]=1[Cl:14].[Cl:7][C:8]1[CH:9]=[C:10]([C:5](=[O:19])[CH2:4][O:3][CH3:2])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: COCC#N
Reactant: CCOCC
Agent: Clc1ccc(Br)cc1Cl
Agent: Clc1ccc([Mg]Br)cc1Cl
Agent: [Mg]
Product: COCC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution (about 100 mL) of 3,4-dichlorophenylmagnesium bromide in diethyl ether was prepared from a mixture of magnesium (flakes) (2.07 g) in diethyl ether (100 mL) and 1-bromo-3,4-dichlorobenzene (17.5 g). A solution of methoxyacetonitrile (5.0 g) in diethyl ether (10 mL) was added dropwise to a solution of 3,4-dichlorophenylmagnesium bromide in diethyl ether under ice-cooling, and the resulting mixture was stirred under ice-cooling for 20 min. The reaction mixture was quenched with water, the mixture was acidified with 1 N hydrochloric acid, and the mixture was stirred under ice-cooling for 15 min. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a pale-yellow oil. The oil was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (19:1-1:1)) to give the title compound (10.5 g).
Reaction SMILES: O([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])=[O:9])C1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][NH:27][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[O:9])=[CH:20][CH:19]=1
Reactant: O=C1CCCN1C(=O)Oc1ccccc1
Reactant: COc1ccc(NCCN)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(NCCNC(=O)N2CCCC2=O)cc1
Yield: 91.4 %

Procedure:
A mixture of 4.0 g (19.5 mmol) of 1-phenoxycarbonyl-2-oxopyrrolidine and 3.4 g (20.4 mmol) of 2-(4-methoxyphenylamino)ethylamine was heated at 115°-120° C. for 4 hr. The reaction solution was refined by silica gel column chromatography, whereby 4.94 g (87.0%) of the objective product (I a-1) was obtained from the eluate with toluene-ethyl acetate (3/1 v/v). The needles melting at 83.5°-84.5° C. were obtained by recrystallizing from ethanol.
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:34][CH3:35])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([O:32]C)=[O:31])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([O:34][CH3:35])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-methoxypyrrolidine-2-carboxylate (166 mg, 0.294 mmol) in THF (2 mL) and MeOH (2 mL) was added a pre-made solution of lithium hydroxide monohydrate (37 mg, 0.882 mmol) in water (2 mL). This cloudy solution was stirred at rt for 18 h, and then concentrated in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH 2. This aqueous solution was extracted with EtOAc. The organic phase was washed with 5% citric acid and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 148 mg (91%) of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-methoxypyrrolidine-2-carboxylic acid as a white solid. No further purification was undertaken.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:21]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:29][CH2:28]1
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NCC1CC1
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NCC1CC1
Yield: 85 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (68 mg, 85%) which was obtained as an off white solid. MS: m/e=401.1 [M+H]+.
Reaction SMILES: [N:1]([C:4]1([CH2:19][OH:20])[O:8][CH:7]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]([OH:17])[CH:5]1[OH:18])=[N+:2]=[N-:3].CO[C:23](OC)([CH3:25])[CH3:24].S(O)(C)(=O)=O.C(N(CC)CC)C>CC(C)=O>[N:1]([C:4]1([CH2:19][OH:20])[CH:5]2[O:18][C:23]([CH3:25])([CH3:24])[O:17][CH:6]2[CH:7]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[O:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1(CO)OC(n2ccc(=O)[nH]c2=O)C(O)C1O
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1(C)OC2C(n3ccc(=O)[nH]c3=O)OC(CO)(N=[N+]=[N-])C2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Compound 48.2 (1.81 g, 6.35 mmol) was dissolved in 60 mL acetone, treated with 2,2-dimethoxypropane (60 mL) and MsOH (1.23 mL, 19.09 mmol). The mixture was stirred at rt for overnight. Triethylamine was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was partitioned between CHCl3 and water; the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in EtOAc to give compound 48.3 (2.12 g, 100% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].I[CH2:16][CH3:17].C(N(CC)CC)C>O1CCOCC1>[N+:10]([C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:14][CH2:16][CH3:17])=[CH:6][C:7]=1[CH3:13])([O-:12])=[O:11]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCI
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOc1cc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
2.5 g (12.5 mmol) of 2,4-dinitro-5-methylphenol (I. R. Gibbs and P. W. Robertson, J. Chem. Soc. (London) 105, 1885) are dissolved in 12.5 ml of dioxane, added to 1.5 ml (19 mmol) of 2-iodoethane and 3.5 ml (25 mmol) of triethylamine and heated for 24 hours to 80° C. The reaction mixture is then poured over ice. The yellow crystals that precipitate out are isolated by suction. 2.2 g (77% of theoretical) of the ethoxy compound, having a melting point of 92° to 93° C., are obtained.
Reaction SMILES: C1N(CCO)CCN([CH2:10][CH2:11]S(O)(=O)=O)C1.[F-].[K+].[CH2:18](S)[C@@H:19](O)[C@H:20](O)[CH2:21]S>>[CH3:18][C:19](=[CH:20][CH2:21][CH2:18]/[C:19](=[CH:20]/[CH2:21][CH2:10]/[C:11](=[CH:10]/[CH2:11][CH2:18]/[CH:19]=[C:20](/[CH2:21][CH2:18]/[CH:19]=[C:20](/[CH2:10][CH2:11][CH:10]=[C:10]([CH3:11])[CH3:11])\[CH3:21])\[CH3:21])/[CH3:20])/[CH3:19])[CH3:18]
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: O[C@H](CS)[C@H](O)CS
Agent: [F-]
Agent: [K+]
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C

Procedure:
Buffer mixture contains 270 mM HEPES, pH 7.5, 20 mM Potassium fluoride and 5.4 mM Dithiothreitol(DTT). 55 μl of this mixture was used per assay. The final concentrations of HEPES, KF and DTT in the assay are 150 mM, 11 mM and 3 mM respectively.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]([C:14]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[C:7]([Br:6])[CH:15]=1)=[O:17]
Reactant: O=C(O)c1cc(Br)c2cc[nH]c2c1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCO)c1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
3-Aminopropanol (1.36 g, 18.1 mmol) was added to a solution of 4-bromo-1H-indole-6-carboxylic acid (4.35 g, 18.1 mmol), triethylamine (4.60 mL, 45.3 mmol), and O-benzotriazol-1-yl-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (6.87 g, 18.1 mmol) in DMF (40 mL) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (10% methanol in dichloromethane) to yield 3.0 g (56%) of 4-bromo-1H-indole-6-carboxylic acid (3-hydroxy-propyl)-amide. Mass spectrum (LCMS, ESI pos.): Calcd for C12H13BrN2O2 296.02. Found 296.9; (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)CO.COC.O.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37].C(=O)(O)[O-].[Na+]>>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([C:32]3[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=3)[N:11]=2)=[CH:14][CH:15]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Cc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Agent: COC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: COc1cc(-c2nc(Nc3ccc(C)cc3)c3ccccc3n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-p-tolyl-amine, 3.76 g, 0.014 mol), ethylene-glycol-dimethyl-ether/water (1 l/120 ml), 3,4,5-trimethoxyphenylboronic acid (2.714 g, 0.014 mol) and sodium bicarbonate (3.6 g) was degassed with argon for 15 minutes. Pd(dppf)Cl2 (0.84 g) was added, and the mixture was heated to reflux overnight. After cooling to room temperature CH2Cl2 (1 l) and H2O (500 ml) were added. The organic and aqueous layers were separated, the aqueous layer was extracted with CH2Cl2 (2×500 ml), and the combined organic layers were dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure. The crude product was purified by methanol. Filtration in a Büchner apparatus afforded p-tolyl-[2-(3,4,5-trimethoxy-phenyl)-quinazolin-4-yl]-amine, 2 (3.15 g, 0.0078 mol 56%). m.p.: >250° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.33 (s, 3H), 3.74 (s, 3H), 3.91 (s, 6H), 6.81 (s, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.33 (d, J=7.3 Hz, 2H), 7.58 (t, J=8.2 Hz, 1H), 7.83 (t, J=7.2 Hz, 2H), 8.54 (d, J=7.5 Hz, 1H). Anal. (C24H23N3O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9](Cl)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([S:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=1
Reactant: Cc1cc(Br)ncc1C(Cl)c1c(F)ccc(F)c1F
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of 2-bromo-5-[chloro(2,3,6-trifluorophenyl)methyl]-4-methylpyridine (4.65 g, 13.3 mmol) in N,N-dimethylformamide (70 ml), 4-fluorobenzenethiol (1.41 ml, 13.3 mmol) and then potassium carbonate (2.02 g, 14.6 mmol) were added in an argon atmosphere at 0° C., and the resulting mixture was stirred for 4 hours at room temperature. Ethyl acetate and water were added to the reaction mixture at 0° C., the organic layer was separated, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=19:1 was concentrated under reduced pressure, and the resulting residue was washed with hexane, and then was collected by filtration, to obtain the title compound (5.17 g, 11.7 mmol, 88%) as a white solid.
Reaction SMILES: [C:1]([C:5]1([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][C:8]2=[CH:9][O:10][CH:11]=[C:7]2[CH2:6]1)([O:3]C)=[O:2].[OH-].[K+]>C(O)C.O.O1CCCC1>[C:1]([C:5]1([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][C:8]2=[CH:9][O:10][CH:11]=[C:7]2[CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(SCc2ccc(OC)cc2)Cc2cocc2C1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(CSC2(C(=O)O)Cc3cocc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 5-(carbomethoxy)-5-(4-methoxybenzylthio)-2,4,5,6-tetrahydro-cyclopenta[c]furan (1.08 g, 3.55 mmol) in 95% ethanol (25 mL), water (12 mL) and tetrahydrofuran (15 mL). Treat with potassium hydroxide (1.3 g, 23 mmol) and stir at room temperature for 1 hour. Filter and evaporate the solvent in vacuo. Partition between water (125 mL) and ether (75 mL). Separate the aqueous phase and acidify with cold concentrated hydrochloric acid. Extract with methylene chloride (75 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give 5-(carboxy)-5-(4-methoxybenzylthio)-2,4,5,6-tetrahydrocyclopenta[c]furan.
Reaction SMILES: C(O[C:5]([C:7]1[N:8]([NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1)=[O:6])C=C.[CH3:18][S:19]([N:22]([CH3:39])[C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[CH:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].[O-]CC.[Na+].C(O)C>ClCCl.CN(C)C=O>[OH:6][C:5]1[C:7]2[N:8]([CH:9]=[CH:10][CH:11]=2)[N:12]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:34](=[O:35])[C:33]=1[C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([N:22]([CH3:39])[S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[CH:29]=1
Reactant: CN(c1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2)S(C)(=O)=O
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)c(C2=CS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)c(O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.112 g, 0.473 mmol) and [7-(methanesulfonyl-methyl-amino)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl]-acetic acid (Example 7e, 0.164 g, 0.473 mmol) were dissolved in a 3:1 mixture of dichloromethane and N,N-dimethylformamide (4 mL) at 25° C. A solution of N,N-dicyclohexylcarbodiimide (0.473 mL, 1.0 M in dichloromethane, 0.473 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h then filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethanol (4 mL) at 25° C. A 21% solution of sodium ethoxide in ethanol (0.368 mL, 1.14 mmol) was added and the reaction mixture was heated at 80° C. for 6 h. After cooling to 25° C., the mixture was partitioned between 0.5 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Sequential purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5{tilde over (0)}→100% ethyl acetate in hexanes) and preparative HPLC [column=Luna 5μ C18(2) 100 Å Axia 50×21.2 mm Id; eluent=0→100% acetonitrile in water (both containing 0.05% trifluoroacetic acid) over 7.0 min, flow=30 mL/min] afforded the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-N-methyl-methanesulfonamide (0.060 g, 0.119 mmol, 25% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.94 (6H, d, J=6.4 Hz), 1.50-1.54 (2H, m), 1.64-1.70 (1H, m), 2.99 (3H, bs), 3.28 (3H, bs), 4.29-4.32 (2H, m), 5.74 (1H, s), 6.12 (1H, bs), 6.49 (1H, bs), 6.90 (1H, bs), 7.30 (1H, bs), 7.60 (1H, bs), 7.82 (1H, bs). LC-MS (ESI) calcd for C22H26N4O6S2 506.13, found 507.25 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH2:9][CH:10]=O.[NH2:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O>CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:9]1[CH:10]=[N:13][C:14]2[C:15]([C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[O:12]
Reactant: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Reactant: O=CCC(=O)c1ccccc1F
Solvent: CC(=O)O
Product: O=C(c1ccccc1F)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 91.5 %

Procedure:
3-(2-Fluorophenyl)-3-oxopropionaldehyde (0.451 g, 2.70 mmol) and [2-amino-3-(trifluoromethyl)phenyl](phenyl)methanone (0.119 g, 0.448 mmol) in AcOH (5 mL) is treated with 0.1 mL of 1:20H2SO4/AcOH solution and heated at reflux for 20 min. The cooled reaction is quenched with water and extracted with ethyl acetate twice. The combined organic layers are washed with saturated aq sodium bicarbonate and dried over MgSO4. The product is purified by chromatography (5:95 ethyl acetate:hexane) to afford the title compound as a yellow solid (0.162 g, 91.5%). MS (ESI) m/z 396.1009; HRMS: calcd for C23H13F4NO+H, 396.10115; found (ESI, [M+H]+), 396.1009.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH:13]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2].[F:21][C:22]1[N:27]=[C:26]([CH2:28]Br)[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[N:27]=3)[C:7]3[CH2:12][CH:13]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)C(=O)NC1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: Fc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1Cc2c(n(Cc3cccc(F)n3)c3ccc(C#N)cc23)C1
Yield: 56.5 %

Procedure:
Mix (±)-N-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-isobutyramide (6.28 g, 18.8 mmol), 6-fluoro-2-bromomethylpyridine (3.93 g, 20.7 mmol), and Cs2CO3 (12.25 g, 37.6 mmol) in DMF (25 mL). Heat the reaction at 50° C. for 18 h. Cool, dilute with EtOAc, and wash with water (3×200 mL). Dry the organic layer (MgSO4) and concentrate to give 7.1 g crude material. Purify by silica gel chromatography (5-20% EtOAc/CH2Cl2). Obtain 4.0 g (56%) yellow-tan solid. MS (m/z): 377 (M+1), 375 (M−1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[NH2:23][CH2:24][CH:25]([C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1)[OH:26]>CN(C=O)C>[C:25]([OH:26])(=[O:8])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[OH:38][C:30]1[CH:29]=[CH:28][C:27]([CH:25]([OH:26])[CH2:24][NH:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:32][C:31]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35]
Reactant: BrCCCCCCOCCCCc1ccc2ccccc2n1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(C(O)CNCCCCCCOCCCCc2ccc3ccccc3n2)ccc1O
Product: O=C(O)c1ccccc1
Yield: 31.1 %

Procedure:
A mixture of 2-[4-[(6-bromohexyl)oxy]butyl]quinoline (900 mg), N-[5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl]methanesulphonamide (800 mg) and DEA (0.52 ml) in DMF (50 ml) was heated at 100° for 4 h, cooled, and the solvent evaporated in vacuo. The residue was purified by FCC eluting with System A (39:10:1) and (34:15:1). A solution of the resulting product in methanol (10 ml) was treated with benzoic acid (61.3 mg), the solution evaporated in vacuo and triturated with dry ether (×2) to afford the title compound as a fawn powder (250 mg) m.p. 155°-157°.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16].CCCCCC.C([Li])CCC.[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>O1CCCC1>[Cl:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=1[F:28])[OH:32]
Reactant: O=Cc1ccc(F)cc1F
Reactant: Cc1nn(C)c(Br)c1-c1ccc(F)cc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nn(C)c(C(O)c2ccc(F)cc2F)c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Synthesis Example 1, Step B) (0.25 g, 0.82 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL), and the mixture was cooled in a dry ice/acetone bath under a nitrogen atmosphere. A hexane solution of n-butyllithium (2.0 M, 0.49 mL, 0.98 mmol) was added dropwise over 5 minutes. After 15 minutes, a solution of 2,4-difluorobenzaldehyde (0.09 mL, 0.82 mmol) in anhydrous tetrahydrofuran (3 mL) was added slowly dropwise, causing the dark red-colored solution to lighten to a yellow color. After 45 minutes, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (˜20 mL) and allowed to warm to ambient temperature. This mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous NH4Cl solution (25 mL) and with brine, dried over Na2SO4, and concentrated to leave a viscous residue. This residue was purified by column chromatography through silica gel eluted with a gradient of ethyl acetate in hexane (7% to 10%) to give the title compound as a white semi-solid (109 mg).
Reaction SMILES: [C:1]1(=[O:10])[O:9][C:6]([CH3:8])([CH3:7])[O:5][C:3](=[O:4])[CH2:2]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].Cl>CS(C)=O.O>[CH3:7][C:6]1([CH3:8])[O:9][C:1](=[O:10])[C:2]([C:27](=[O:28])[NH:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)=[C:3]([OH:4])[O:5]1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)OC(=O)C(C(=O)Nc2ccc(Cl)c(Cl)c2)=C(O)O1

Procedure:
To a solution of 14.4 g of isopropylidene malonate in 150 ml of dimethyl sulphoxide were added dropwise, at room temperature, 10.1 g of triethylamine and thereafter, at 20° to 30° C, 18.8 g of 3,4-dichlorophenylisocyanate in 30 ml of dimethyl sulphoxide. The mixture was reacted for 12 to 15 hours at room temperature and the resultant solution was poured into a solution of 20 ml of concentrated hydrochloric acid in 200 ml of water. The precipitate which formed was collected with suction. Recrystallisation from 130 ml of acetone yielded the product of the formula ##STR5## with a melting point of 132°-134° C.