Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:14]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[CH:19]=O)=[O:15])=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26].CC(C)([O-])C.[K+]>C1COCC1.CCOCC>[CH:1]([C:4]1[C:5]([C:14]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:27][C:25]#[N:26])[CH:21]=[C:22]([CH3:24])[CH:23]=2)=[O:15])=[N:6][C:7]([O:12][CH3:13])=[N:8][C:9]=1[O:10][CH3:11])([CH3:2])[CH3:3]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=O)c2)n1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=CC#N)c2)n1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-benzaldehyde (2.26 g, 6.89 mmol) and diethyl cyanomethylphosphonate (1.14 ml, 7.03 mmol) in anhydrous THF (15 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (0.85 g, 7.58 mmol). After stirring for 1 hr., the mixture was further stirred for 4 hr. at room temperature. The reaction mixture was diluted with ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 1.56 g (65%) of a white solid. m.p. 144-145° C.; 1H NMR (300 MHz, CDCl3) δ 1.19 (6H, d, J=6.9 Hz), 2.42 (3H, s), 2.83 (1H, m), 3.94 (3H, s), 4.08 (3H, s), 5.92 (1H, d, J=16.8 Hz), 3.39 (1H, d, J=16.8 Hz), 7.49 (1H, s), 7.69 (1H, s), 7.75 (1H, s).
Reaction SMILES: [I-].[Na+].[CH2:3]([NH2:5])[CH3:4].[Br:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:18][CH2:17][CH:16](OS(C)(=O)=O)[C:15]2=[O:24])[CH:10]=[CH:11][C:12]=1[F:13].O>O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:18][CH2:17][CH:16]([NH:5][CH2:3][CH3:4])[C:15]2=[O:24])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CCN
Reactant: CS(=O)(=O)OC1CCN(c2ccc(F)c(Br)c2)C1=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC1CCN(c2ccc(F)c(Br)c2)C1=O
Reaction time: 2 h

Procedure:
Sodium iodide (1.1 g), followed by ethylamine (1.92 ml) was added to a solution in tetrahydrofuran (60 ml) of the ethylamino compound prepared in Step 2 (2.6 g). The solution was stirred for two hours and then left to stand overnight. The reaction mixture was then poured into water and extracted with ethyl acetate three times. The extracts were combined, washed twice with water and once with brine, dried (magnesium sulphate), and concentrated to yield a dark brown oil. This was chromatographed on a silica column using a mixture of triethylamine and ethyl acetate (1:9) as the eluent. The title compound was obtained as a yellow solid. The NMR spectrum was consistent with the expected structure.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:8]=1)=[O:5].[N:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Cu]I>[N:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:8]=2)=[O:5])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Oc1ccccc1N1CCCCC1
Reactant: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccc(NC(=O)c2ccccc2Oc2ccccc2N2CCCCC2)c1
Temperature: 150 °C

Procedure:
A suspension of 2-bromo-N-(3-(aminosulfonyl)phenyl)benzamide (0.10 g, 0.28 mmol), 2-(piperidin-1-yl)phenol (74 mg, 0.28 mmol), K3PO4 (0.12 g, 0.56 mmol), and CuI (53 mg, 0.28 mmol) in DMF (1 mL) and water (20 μL) was sealed in a glass tube and heated in a microwave oven at 150° C. for 15 min. The reaction was filtered and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(2-(piperidin-1-yl)phenoxy)-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 452.0 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[C:26]([O:36][CH3:37])=[C:27]([C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:28](=[O:29])[C:27]3[C:31]([O:34][CH3:35])=[CH:32][CH:33]=[C:25]([Br:24])[C:26]=3[O:36][CH3:37])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Br)c(OC)c1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg), 3-bromo-2,6-dimethoxybenzoic acid (23 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (68 mg) and N,N-diisopropylethylamine (32 μl) in dichloromethane (4 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: [O:1]1[C@@H:6]2[CH2:7][NH:8][CH2:9][C@H:5]2[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:40][CH3:41])=[C:32]([O:35][CH2:36][CH2:37][CH2:38]Cl)[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:20]=[CH:21][C:22]=1[F:23]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:40][CH3:41])=[C:32]([O:35][CH2:36][CH2:37][CH2:38][N:8]4[CH2:7][C@@H:6]5[O:1][CH2:2][CH2:3][O:4][C@H:5]5[CH2:9]4)[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: C1CO[C@@H]2CNC[C@H]2O1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1C[C@@H]2OCCO[C@H]2C1
Temperature: 60 °C
Reaction time: 9 h
Yield: 24.5 %

Procedure:
A mixture of (4aR,7aR)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (129.0 mg, 1.0 mmol), K2CO3 (217.0 mg, 1.56 mmol), tetrabutylammoniumiodide (44.0 mg, 0.12 mmol) and N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (475.0 mg, 1.20 mmol) in 15 mL of DMF was stirred for 9 h at 60° C., then poured into 10 mL of ice-water and extracted with CH2Cl2. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (120 mg, 24.50%), HPLC: 94.43%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.04 (m, 2H), 2.6 (br, 1H), 2.72 (m, 2H), 2.82 (m, 2H), 3.04 (m, 2H), 3.64 (t, J=6.08 Hz, 2H), 3.80 (m, 4H), 3.98 (s, 3H), 4.16 (t, J=6.48 Hz, 2H), 7.14 (t, J=8.76 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.58 (m, 2H), 7.90 (dd, J1=6.48 Hz, J2=2.56 Hz, 1H), 8.65 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]([C:16]([OH:18])=O)=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C1(C)C=CC=CC=1.C(Cl)Cl.CN(C=O)C>[CH2:23]([NH:30][C:16]([C:13]1[C:14](=[O:15])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCn1cc2c(c(C(=O)O)c1=O)CCCC2
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCn1cc2c(c(C(=O)NCc3ccccc3)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
2-Butyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxylic acid (4-501-05) (5 mg, 0.02 mmol) was dissolved in toluene (1 mL), and to the reaction mixture were added thionyl chloride (4.4 μL, 0.06 mmol) and catalytic amount of DMF, and the reaction mixture was reacted at 75° C. for 30 min. After concentration of the reaction mixture under reduced pressure, the residue was dissolved in methylene chloride (1 mL), and then benzylamine (6.2 μL, 0.06 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 10 min. To the reaction mixture was added diluted hydrochloric acid (1 mol/L, 3 mL), and the reaction mixture was extracted with ethyl acetate (8 mL), washed with brine (4 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 2-butyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carboxylic acid benzylamide (4-501) (5 mg, 74%) as a white crystal.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH3:16])[CH2:5][O:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:9]([O:8][CH2:7][O:6][CH2:5][C@H:4]([CH3:16])[CH2:3][OH:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@H](C)COCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)COCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of ester 2 (0.5 g, 2.1 mmol) in anhydrous THF (4 mL) was added dropwise to a suspension of lithium aluminum hydride (0.16 g, 4.2 mmol) in anhydrous THF (10 mL) at 0° C. The cooling bath was removed, and the reaction was stirred at room temperature overnight, quenched with cold water, and extracted with EtOAc. The solvents were removed in vacuum and the crude oil was purified by silica gel chromatography using hexane/EtOAc (8:2) as an eluent to afford oily diol 3 (0.29 g, 66%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][CH2:13]1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C@H:13]2[C:12](=[O:11])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]2)=[CH:32][CH:31]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@@H](Cc2ccc(F)cc2)C(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 39.3 %

Procedure:
Step (b) 1M LiHMDS (27.5 mL, 27.5 mmol) was added to a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (6.4 g, 25 mmol) in THF (20 mL) at −78° C. The mixture was stirred for 50 minutes and then 4-fluorobenzyl bromide (3.25 mL, 26.5 mmol) in THF (2 mL) was added dropwise. The mixture was stirred for 1 hour and 40 minutes and quenched with excess saturated ammonium chloride. The mixture was warmed to ambient temperature and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate, filtered and concentrated. The solid residue was dissolved in a 3:1 hexane/methyl tert-butyl ether solvent mixture (100 mL) and slow crystallization was allowed at ambient temperature. The mixture was cooled to 0° C. and the solid was collected by filtration, washed with a 3:1 hexane/methyl tert-butyl ether solvent mixture (50 mL) and dried to give (2S,4R)-1-tert-butyl 2-ethyl 4-(4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (3.59 g, 39%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.15-7.12 (m, 2H), 7.01-6.96 (m, 2H), 4.47 (dd, J=2.0, 9.2, 1H), 4.22-4.17 (m, 2H), 3.22 (dd, J=4.4, 14.4, 1H), 2.94-2.85 (m, 1H), 2.71-2.65 (m, 1H), 2.08-1.94 (m, 2H), 1.50 (s, 9H), 1.26 (t, 3H).
Reaction SMILES: [NH:1]1[C@:9]2([CH2:11][OH:12])[O:10][C@:2]1([C@H:5]([C@@H:7]2[OH:8])[OH:6])[CH2:3][OH:4].[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(OCC)C>CN(C)C=O>[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][N:1]2[C@:9]3([CH2:11][OH:12])[O:10][C@:2]2([C@H:5]([C@@H:7]3[OH:8])[OH:6])[CH2:3][OH:4])=[CH:16][CH:15]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: OC[C@]12N[C@](CO)(O1)[C@@H](O)[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2CCOc1ccc(F)cc1

Procedure:
A solution of a compound Formula XIV (2.60 g, 0.0159 mol), 2-(4-fluorophenoxy)ethyl bromide (3.70 g, 0.0169 mol), and Na2CO3 (1.86 g, 0.0175 mol) in 11 mL of dimethylformamide was heated at 85° C. for 8 h. The solution was cooled, then treated with 250 mL of ethyl ether portion wise, and the solvent was removed. The resultant residue was diluted with chloroform, filtered, and concentrated. This crude material was chromatographed on a Waters Prep-500 HPLC (88:11:1, CHCl3 /MEOH/NH4OH) to give the product, which was recrystallized from EtOAc/hexane (3.49 g, 73%), mp 96°-98° C. (corrected). 1H NMR supported the assigned structure.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](OC)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[S:25][CH3:26]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([C:21]2[CH:22]=[CH:23][C:24]([S:25][CH3:26])=[C:19]([F:18])[CH:20]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Cl
Reactant: CSc1ccc(B(O)O)cc1F
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1F

Procedure:
2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579–1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-trifluoromethylsulfonyloxy-analog following the method of Example 8. Subsequent coupling to 3-fluoro-4-(methylthio)phenylboronic acid, according to the method of Example 9, provided 2-benzyl-4-chloro-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled in the 4-position with 4-fluorophenylboronic acid following the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-arylated with 4-fluoroiodobenzene according to the method of Example 62. The resulting sulfide was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide final product according to the method of Example 68 (yield: 500 mg, 75%). mp 222–224° C. 1H NMR (300 MHz, CDCl3) δ 5.06 (s, 2H), 7.01 (t, J=9 Hz, 2H), 7.06 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.18 (t, J=9 Hz, 2H), 7.69 (dd, J=9 Hz, 3 Hz, 2H), 7.88 (t, J=9 Hz, 1H), 7.95 (s, 1H). MS (DCI/NH3) m/z 458 (M+H)+. Anal. calc. for C22H14F3N3O3S: C, 57.76; H, 3.08; N, 9.18. Found: C, 57.5; H, 3.15; N, 8.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH:14]([O:17][C:18]1[CH:19]=[C:20]([CH2:24][NH2:25])[CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:25][CH2:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH:14]([CH3:16])[CH3:15])[CH:19]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: CC(C)Oc1cccc(CN)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)Oc1cccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Yield: 21.8 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (156 mg, 0.601 mmol), 1-(3-isopropoxyphenyl)methanamine (116 mg, 0.702 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (113 mg, 0.181 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (6 mL) was heated at 85° C. for 2 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-isopropoxy-benzylamino)-2H-phthalazin-1-one (45 mg) as an off white solid, 1H (400 MHz, d6-DMSO) δ: 1.22 (d, 6H), 4.40 (d, 2H), 4.57 (quintet, 1H), 6.80 (m, 2H), 6.91 (m, 2H), 7.16 (dd, 1H), 7.22 (t, 1H), 7.64 (t, 1H), 7.92 (d, 1H), 12.34 (s, 1H) ppm; m/z (M+1) 344.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-])=O)=[CH:6]2>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([NH2:13])=[CH:6]2
Reactant: COc1ccc2ncc([N+](=O)[O-])cc2c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(N)cc2c1
Temperature: 4 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
21.2 g (0.104 mole) of the nitroquinoline 14 was added portionwise to a 1.0 L beaker containing 320 mL conc. HCI at 50° C., with vigorous stirring. Then the heating bath was removed and 71.0 g of SnCl2 ·2H2O (0.312 mole, finely ground) was added portionwise over 2-3 min (the temperature of the mixture reached 80° C.). The mixture was stirred vigorously for 10 min, and diluted with water to 1.0 L. The pH was adjusted to 9 using 5M NaOH (900-950 mL) and the aqueous layer (2.0 L) was cooled to 4° C., and extracted with EtOAc (3×500 mL). The combined organic layers were washed with ice-cold water (200 mL), brine (400 mL) and dried over anhydrous MgSO4. Filtration and removal of the solvent in vacuo gave 17.6 g of crude 15. The crude product was vigorously stirred with 50 mL CHCl3 and the tan microcrystalline solid forming was filtered on a sintered glass funnel. The precipitate was washed with CHCl3 (2×25 mL) and then air dried. Removal of the last traces of solvent in vacuo gave 8.1 g of product. The washings were combined with the filtrate, concentrated by rotovap and placed in the freezer. Two more crops of 15 were thus obtained (3.8 and 2.3 g). The mother liquor concentrate was purified by column chromatography on silica gel (EtOAc -hexanes 1:1) and a further 1.3 g of product 15 was obtained (overall yield 15.5 g, 86%). A small amount of 4-chloro-6-methoxy-3-aminoquinoline (5%) was also obtained as a less polar byproduct.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH2:19][C:20]2[N:21]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:22]=[C:23]([CH2:25][C:26]4([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]4)[N:24]=2)([OH:18])[CH2:13][CH2:12]3)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][N:61]=1>CO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:66][C:63]1[CH:64]=[CH:65][C:60]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH2:19][C:20]2[N:21]([C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:22]=[C:23]([CH2:25][C:26]4([C:29]([F:31])([F:30])[F:32])[CH2:28][CH2:27]4)[N:24]=2)([OH:18])[CH2:13][CH2:12]3)=[N:61][CH:62]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3(O)Cc2nc(CC3(C(F)(F)F)CC3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: OC1(Cc2nc(CC3(C(F)(F)F)CC3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2cc(-c3ccc(F)cn3)ccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Pd(PPh3)4 (264 mg, 0.23 mmol) was added to a degassed solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazol-2-yl)methyl]indan-1-ol (1.61 g, 2.29 mmol), potassium carbonate (411 mg, 2.97 mmol), and 2-bromo-5-fluoropyridine (483 mg, 2.74 mmol) in methanol/toluene (5 mL/50 mL). The solution was stirred at 90° C. for 2 h. The solvent was removed in vacuo and the residue was redissolved in EtOAc (200 mL). The solution was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography eluting with 0-100% EtOAc/hexanes to give 5-(5-fluoropyridin-2-yl)-1-[(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazol-2-yl)methyl]indan-1-ol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[OH-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: BrCCCBr
Reactant: c1ccc2[nH]nnc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCn1nnc2ccccc21
Reaction time: 20 h
Yield: 58.7 %

Procedure:
To a solution of 1,3-dibromopropane (510 μl, 5.0 mmol) in dimethylformamide (10 ml) was added benzotriazole (600 mg, 5.0 mmol) and KOH (430 mg, 7.7 mmol). After stirring for 20 h at room temp., water (15 ml) and ethyl acetate (15 ml) were added. The phases were separated and the aqueous phase was re-extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over MgSO4 and concentrated, giving 1.44 g of the crude product. The crude product was purified by flash chromatography (0-10% methanol in DCM) yielding 705 mg (59%) of the title compound 64. TLC (5% methanol in DCM): Rf=0.4. HPLC-MS (Method A): M+=239.9 (UV/MS(%)=52/58).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.Cl>COCCOCCOC.C(OCC)(=O)C>[ClH:12].[ClH:14].[C:1]([C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[N:7]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Cl)ccc1N
Reactant: ClCCNCCCl
Agent: Cl
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Cl)ccc1N1CCNCC1
Temperature: 170 °C
Reaction time: 72 h
Yield: 14.7 %

Procedure:
A mixture of 2-tert-butyl-4-chloroaniline (Reference Example 19, 16.7 g, 90.8 mmol) and bis(2-chloroethyl)amine hydrochloride (17.8 g, 99.9 mmol) in diglyme (170 mL) was stirred at 170° C. for 3 days under nitrogen atmosphere. After this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 M NaOH. The organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil and a brown solid. The solid was dissolved in ethyl acetate and the solution was treated with 4 M HCl in ethyl acetate to give the title compound (2.17 g) as a brown solid. The impure brown oil was partitioned between ethyl acetate and 1 M HCl and the resulting white precipitate was collected by filtration, and washed with diethyl ether to give the title compound (2.98 g) as a white solid.