Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:9][CH:8]([CH3:10])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:39])=[O:5]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4ccccc4o3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (S)-3-methyl-2-{4′-[(benzoxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester was added 4 mL of TFA/CH2Cl2 (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 90 mg of (S)-3-methyl-2-{4′-[(benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.6, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 7.6 (m, 1 H) 7.6 (m, 1 H) 7.8 (m, 6 H) 8.0 (m, 2 H) 8.1 (m, 3 H) 11.4 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O.C(OCC)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CNC(=O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CNC(=O)CCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 70.8 %

Procedure:
A solution of 6.1 g (0.020 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 3.7 g (0.025 mole) of 5-chloro-N-methylpentanamide, 8.5 g (0.080 mole) of anhydrous sodium carbonate and 0.4 g (0.002 mole) of potassium iodide in 100 mL of N,N-dimethylformamide was heated on a steam bath for 24 h. The mixture was poured into 1.5 L of water and extracted twice with 500 ml portions of ethyl acetate. The ethyl acetate portions were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a golden oil. The oil was dissolved in ethyl ether and allowed to stand, whereupon a white solid precipitated. The solid was collected by filtration, and recrystallized from ethyl ether to yield 5.9 g (71%) of white solid, mp 130°-131° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-])=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>C1(C)C=CC=CC=1.[Pt]>[NH2:26][C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: CN(CCOCCNc1c([N+](=O)[O-])cnc2ccccc12)C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CN(CCOCCNc1c(N)cnc2ccccc12)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 112.3 %

Procedure:
A solution of tert-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate (6.56 g, 16.8 mmol) in 75 mL of toluene was treated with 0.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.8 g of crude tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate as an orange syrup which was carried on without further purification.
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](N1C=CN=C1)=[C:6]2[CH3:17].[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>CN(C)C=O.O>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([CH3:17])=[CH:7]1)([OH:28])=[O:27]
Reactant: COc1ccc2[nH]c(-n3ccnc3)c(C)c2c1
Reactant: O=C(O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C)cn2CCCCCC(=O)O

Procedure:
A solution of 5-methoxy-3-methyl-2-(1-imidazolyl)indole (0.57 g) in dimethylformamide (4 ml) is added dropwise to a suspension of sodium hydride (50% dispersion in mineral oil), 0.27 g in dimethylformamide (5 ml) while stirring under N2 at 0°-5°. The mixture is stirred at 5° for 1/2 hour. A solution of 6-bromohexanoic acid (0.55 g) in dimethylformamide (4 ml) is added dropwise to the reaction mixture while stirring at 0°-5°. The mixture is stirred at 0°-5° for 1/2 hour and then overnight at room temperature. The thick suspension is diluted with water (50 ml) and the mixture is washed with ether (2×25 ml). The aqueous layer is acidified to pH 5.6 with 1N hydrochloric acid and extracted with ethyl acetate (3×30 ml). The organic extract is dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil which becomes partially crystalline. This material is triturated with ether and the solid is collected to give 1-(5-carboxypentyl)-5-methoxy-3-methylindole, m.p. 134°-137°.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:43][C:44](=[O:52])[C@H:45]([CH2:47][C:48]([O:50]C)=[O:49])[NH2:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:46][C@H:45]([C:44]([OH:43])=[O:52])[CH2:47][C:48]([OH:50])=[O:49])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](CC(=O)O)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and L-Aspartic acid dimethyl ester hydrochloride (40 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.46-13.35 (br.s, 2 H), 8.95 (s, 1 H), 8.13 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.03 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.54 (m, 1 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 2.91 (s, 3 H), 2.69 (m, 1 H), 2.55 (m, 3 H), 2.39 (s, 3 H), 2.12 (t, 2 H), 1.76 (m, 2 H); MS (APCI+) m/z 674 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CNS(=O)(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: O
Product: CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-fluoro-N-methylbenzenesulfonamide (189 mg, 0.999 mmol) and piperazine (430 mg, 4.99 mmol) were combined and the reaction mixture was stirred at 120° C. for 2 h. It was diluted with water (5 mL) and stirred until a fine suspension resulted. The precipitate was filtered, washed with water (5×3 mL) and dried in vacuum to afford N-methyl-4-(piperazin-1-yl)benzenesulfonamide (222 mg, 0.869 mmol, 87% yield) as a white solid. ESI-MS: m/z 256 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=O)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([NH:6][C:7]([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[S:24])=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)NC(=O)C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=S)C1CCNCC1

Procedure:
N-Ethoxycarbonylpiperidine-4-carboxamide (6 g 30 mmol) in toluene (300 ml) is treated with Lawesson's reagent (6.1 g 15 mmol) at room teperature for 18 h. The reaction mixture is evaporated and purified by SiO2 chromatography (acetone/cyclohexane 20/80) to yield the title compound, which is recrystallised from hexanes (3.6 g 52.5%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[O:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)=[CH:24][CH:25]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1cnccc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: c1ccc(COc2ccc(-c3nc4cnccc4o3)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of commercially available 4-hydroxy-3-amino-pyridine (14, 19.3 g, 175 mmol) in acetonitril (1500 ml) was added 4-benzyloxy-benzoic acid (24, Ra=Rb=H, 40 g, 175 mmol), triphenylphosphine (142.5 g, 543 mmol, 3.1 eq) and trichloroactonitril (54.5 ml, 543 mmol, 3.1 eq). The reaction mixture was allowed to reach room temperature and the mixture was stirred for 16 hrs at 80° C. The mixture was concentrated in vacuo and the residues was dissolved in DCM and washed with 2N NaOH (3×). The combined water layers were extracted with DCM and the organic layers dried (Na2SO4) to give crude 25 (Ra=Rb=H) as oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12]Br)=[CH:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([C:21]2([O:29][CH3:30])[CH2:26][CH:25]([CH3:27])[O:24][CH:23]([CH3:28])[CH2:22]2)[CH:18]=[CH:19][CH:20]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:14][C:15]3[CH:16]=[C:17]([C:21]4([O:29][CH3:30])[CH2:26][CH:25]([CH3:27])[O:24][CH:23]([CH3:28])[CH2:22]4)[CH:18]=[CH:19][CH:20]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2ccc(CBr)cc2c1
Reactant: COC1(c2cccc(O)c2)CC(C)OC(C)C1
Product: COC1(c2cccc(OCc3ccc4ccc(F)cc4c3)c2)CC(C)OC(C)C1
Yield: 77 %

Procedure:
Using the procedure described in Example 5, 7-fluoro-2-bromomethylnaphthalene (0.5 g) was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,6-dimethyltetrahydropyran (0.45 g, more polar isomer) to give 4-[3-(7-fluoronaphth-2-ylmethoxy)phenyl]-4-methoxy-2,6-dimethyltetrahydropyran (0.74 g, 77%), as an oil which crystallised on standing, m.p. 77° C.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([N:16]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.Cl>CO>[NH2:16][CH:7]([CH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:30])=[O:5]
Reactant: CC(C)(C)OC(=O)C(CC1CCCCCC1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: NC(CC1CCCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.7 %

Procedure:
To a solution of 2-(Benzhydrylidene-amino)-3-cycloheptyl-propionic acid tert-butyl ester (1.34 g; 3.31 mmol) in methanol (5 mL) was added 10N HCl solution (15 mL) and the mixture heated to reflux. After 15 h, the mixture was allowed to cool to room temperature and transferred to a separatory funnel and washed with ethyl acetate. The aqueous layer was then neutralized with concentrated ammonium hydroxide solution and the white solid was filtered off and air dried to give 329 mg of 2-Amino-3-cycloheptyl-propionic acid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][N:6]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH3:5][N:6]([CH:17]1[CH2:18][CH2:19][N:20]([C:3](=[S:4])[NH:2][CH3:1])[CH2:21][CH2:22]1)[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN=C=S
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Solvent: ClCCl
Product: CNC(=S)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
A solution of methyl isothiocyanate (500 mg, 6.8493 mmol, 1 eq) in dichloromethane (4 ml) was added dropwise over a period of 5 min to a solution of benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (1.7 g, 6.8493 mmol, 1 eq). When the addition was complete, the reaction mixture was stirred for 20 hours at room temperature. Concentration under reduced pressure was then carried out and the crude product was purified by column chromatography (silica gel, 2% methanol in dichloromethane). Yield: 45% (1 g, 3.115 mmol)
Reaction SMILES: N[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(I)[I:20].N(OCCC(C)C)=O>[Cu]I>[Br:18][C:8]1[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]2[NH:12][C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][CH:3]=[C:2]([I:20])[CH:14]=3
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(I)ccc12
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 7-amino-3-bromo-9H-carbazole-1-carboxamide 470B (1 g, 2.79 mmol) and CH2I2 (15 mL) was slowly added isopentyl nitrite (1 mL, 7.48 mmol). The mixture was heated in microwave at 60° C. for 45 mins copper(I) iodide (0.266 g, 1.397 mmol) was added to the reaction mixture and heated in microwave at 55° C. for additional 30 mins The mixture was concentrated. EtOAc(50 ml) was added and stirred for 10 mins and filtered. The collected solid was washed with H2O 2×50 ml. The remaining solid was purified using preparative HPLC to give titled product. MS (ESI) m/z 412.82 (M−H)−.
Reaction SMILES: C[Mg+].[Br-].C1([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH:13]([CH2:20][CH2:21][CH:22]2[CH2:30][C:29]4[C:24](=[CH:25]C=CC=4C4C=CC=CC=4)[C:23]2=O)[C:14]3=O)C=CC=CC=1.Cl.[CH2:39]1[CH2:43]O[CH2:41][CH2:40]1>CCOCC>[CH3:41][C:40]1([CH:12]2[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:14]=[C:13]2[CH2:20][CH2:21][C:22]2[CH:30]([C:11]3([CH3:12])[CH:10]=[CH:18][CH:17]=[CH:16][CH2:15]3)[C:29]3[C:24]([CH:23]=2)=[CH:25][CH:14]=[CH:13][CH:20]=3)[CH:21]=[CH:22][CH:23]=[CH:43][CH2:39]1
Reactant: O=C1c2cccc(-c3ccccc3)c2CC1CCC1Cc2c(cccc2-c2ccccc2)C1=O
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: CC1(C2C(CCC3=Cc4ccccc4C3C3(C)C=CC=CC3)=Cc3ccccc32)C=CC=CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 67.8 mL MeMgBr (3M in ether) in 100 mL Et2O was added a solution of 15 g (33.9 mmol) of 1,2-bis(4-phenyl-indanonyl)ethane, prepared as described in the above synthesis 8(a), in 150 mL THF, over a period of 45 minutes, at 0° C. The formation of a white/beige precipitate was observed. The reaction mixture was allowed to warm to 20° C. and was maintained under stirring for 2 hours. The reaction mixture was then poured into ice and acidified to pH 1, with 37% HCl, and finally extracted with Et2O. The organic layer was extracted with a saturated solution of NaCl and the solvent was removed in vacuum. The formed diol was dissolved in CH2Cl2 and ptoluene-sulfonic acid was added. The mixture was stirred overnight at 20° C. The solution was dried over MgSO4, filtered and the solvent was removed in vacuum, thus yielding 9.0 g of the ligand 1,2-bis(l-methyl-phenyl-2-indenyl)ethane (69% yield).
Reaction SMILES: BrC1C=CC(Br)=CN=1.NN.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18]N)=[N:16][CH:17]=1.N(C1C=CC=CN=1)N.[CH3:28][CH:29]([CH3:33])[C:30](=O)[CH3:31]>COCCO.C1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]2[C:29]([CH3:33])([CH3:28])[C:30]([CH3:31])=[N:18][C:15]2=[N:16][CH:17]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CC(=O)C(C)C
Agent: Brc1ccc(Br)nc1
Agent: NN
Agent: NNc1ccccn1
Solvent: COCCO
Solvent: c1ccccc1
Product: CC1=Nc2ncc(Br)cc2C1(C)C
Temperature: 110 °C

Procedure:
To 40 g of 2,5-dibromopyridine in 200 mL of 2-methoxyethanol is added 53 mL of anhydrous hydrazine and the mixture is heated at 110° C. for 3 hours to generate the 5-bromo-2-hydrazinopyridine. A mixture of 10 g of this hydrazinopyridine is heated at reflux overnight with 11 mL of 3-methyl-2-butanone in 40 mL of benzene equipped, using a condenser equipped with a Dean-Stark trap. All of the volatile components are removed under reduced pressure and the resulting residue is heated in 62 g of polyphosphoric acid at 140° C. for 45 minutes. The reaction mixture is poured into water, neutralized with sodium hydroxide and extracted with ethyl acetate. The resulting crude residue is purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexanes, to yield 1.44 g of the product.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[C:12](=[O:30])[N:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:14]=[CH:15][C:16]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:8][CH:7]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.ClCCl>[Br:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[C:12](=[O:30])[N:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:14]=[CH:15][C:16]=2[N:17]2[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][OH:4])[CH2:19][CH2:18]2)=[CH:8][CH:7]=1
Reactant: O=c1c(Oc2ccc(Br)cc2)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1c(Oc2ccc(Br)cc2)c(N2CCN(CCO)CC2)cnn1-c1ccc(Cl)cc1

Procedure:
1.35 ml (18.11 mmol) of 2-bromoethanol are added dropwise to a mixture of 4.18 (9.05 mmol) of 4-(4-bromophenoxy)-2-(4-chlorophenyl)-5-(1-piperazinyl)-3(2H)-pyridazinone (Example 57A), 0.15 g of potassium iodide 3.75 g (27.2 mmol) of potassium carbonate in 25 ml of 1,4-dioxane. Stirring under reflux overnight is followed by dilution with dichloromethane and washing twice with water, drying and concentration. Purification is by flash chromatography on silica gel (gradient: dichloromethane/methanol from 99:1 to 97:3).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:22])[CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>C(Cl)Cl>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][C@@H:3]([NH:2][C:23](=[O:26])[CH:24]=[CH2:25])[CH3:22])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: C=CC(=O)Cl
Reactant: C[C@H](N)COc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Agent: Cl
Solvent: ClCCl
Product: C=CC(=O)N[C@@H](C)COc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To an ice-cooled mixture of 107c (390 mg, 1.0 mmol) and TEA (0.53 ml, 3.0 mmol) in DCM (20 mL) was added acryloyl chloride (0.23 ml, 2.0 mmol) dropwise. The reaction mixture was stirred at rt for 2 h and quenched with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=10/1) to give 107d (284 mg, 70%) as brown solid. MS-ESI: [M+H]+ 409.0
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[C:19]1([CH:25]2[N:29]([C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=3)[N:28]=[C:27]([C:38]3[C:51]4[C:52]5=[C:53]6[C:48](=[CH:49][CH:50]=4)[CH:47]=[CH:46][CH:45]=[C:44]6[CH:43]=[CH:42][C:41]5=[CH:40][CH:39]=3)[CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[C:13]1([C:4]2[O:3][C:2]([CH:1]=[CH:34][C:33]3[CH:36]=[CH:37][C:30]([N:29]4[CH:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:26][C:27]([C:38]5[C:51]6[C:52]7=[C:53]8[C:48](=[CH:49][CH:50]=6)[CH:47]=[CH:46][CH:45]=[C:44]8[CH:43]=[CH:42][C:41]7=[CH:40][CH:39]=5)=[N:28]4)=[CH:31][CH:32]=3)=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(N2N=C(c3ccc4ccc5cccc6ccc3c4c56)CC2c2ccccc2)cc1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(C#N)=C1C=C(C=Cc2ccc(N3N=C(c4ccc5ccc6cccc7ccc4c5c67)CC3c3ccccc3)cc2)OC(c2ccccc2)=C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 8, 0.24 g (1.0 mmol) of 2-(2-methyl-6-phenyl-pyran-4-ylidene)-malononitrile and 0.46 g (1.0 mmol) of 4-(5-phenyl-3-pyren-1-yl-4,5-dihydro-pyrazol-1-yl)benzaldehyde were added into 20 ml of ethanol, and 0.13 g (1.53 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[C:3]=1[CH2:21][CH2:22][CH3:23].Cl[CH2:25][CH:26]=O>CN(C=O)C>[F:20][C:16]1[N:15]=[C:14]([C:10]2[N:9]([CH2:8][C:4]3[N:5]=[CH:6][N:7]4[CH:25]=[CH:26][N:1]=[C:2]4[C:3]=3[CH2:21][CH2:22][CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1c(N)ncnc1Cn1ccnc1-c1cccc(F)n1
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2ccnc12

Procedure:
A solution of 105 (1.2 mmol) and chloroacetaldehyde (1 mL) in DMF (10 ml) is heated overnight at 70° C. in a sealed tube. The solvent is removed in vacuo and EtOAc (15 ml) and water (15 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (15 ml). The combined extracts are washed with brine (15 ml), dried (Na2SO4) and evaporated. PTLC separation of the residue with 10% MeOH in CH2Cl2 provides the title compound as a white solid (106). 1H-NMR (CDCl3) δ: 8.78 (s, 1H), 8.11 (dd, 1H), 7.83 (q, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 7.18 (d, 1H), 7.15 (d, 1H), 6.83 (dd, 1H), 6.04 (s, 2H), 3.07–3.13 (m, 2H), 1.62–1.72 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:12]([F:23])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[H-].[Na+].[CH3:27]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:11]2[C:12]([F:23])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1
Reactant: CN1C(=O)COc2cc(F)c(C(=O)Cc3ccc(Br)cc3Cl)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C(=O)c1cc2c(cc1F)OCC(=O)N2C)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-acetyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as a light brown foam. MS (m/e, ISP neg. ion)=426.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[NH:5][C:6]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][CH2:22]O)=[C:15]([CH3:24])[CH:14]=1)=[N:7]2.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:27][CH2:22][CH2:21][O:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([C:6]2[NH:5][C:4](=[O:25])[C:3]3[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=3[Cl:1])[N:7]=2)=[CH:14][C:15]=1[CH3:24]
Reactant: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-3H-quinazolin-4-one (1.14 g, 3.00 mmol) in anhydrous DMF (15 mL) was added carbon tetrabromide (1.10 g, 3.30 mmol). Then, triphenylphosphine (0.86 g, 3.30 mmol) was added in small portions. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. Solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate (50 mL) and dried under vacuum to give 2-[4-(2-bromo-ethoxy)-3,5-dimethylphenyl]-5,7-dichloro-3H-quinazolin-4-one as a white solid. Yield: 0.46 g (35%).