Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([C@@:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCNC2)C(=O)O1
Yield: 98 %

Procedure:
A solution of (S)-tert-butyl 3-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (150 mg, 0.359 mmol) in 20% TFA/CH2Cl2 (5 mL) was stirred at 0° C. for 2 h. The mixture was concentrated to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (112 mg, crude), which was used for the next without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[NH:17][C:16]3[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:14]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:15]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]=3[N:17]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(S(C)(=O)=O)c2[nH]1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2c(S(C)(=O)=O)cccc2n1C1CCCC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-6-(((1S)-1-(7-(methylsulfonyl)-1H-benzimidazol-2-yl)-ethyl)amino)-5-pyrimidinecarbonitrile (110 mg, 0.31 mmol) and cesium carbonate (100 mg, 0.31 mmol) was stirred at rt for 30 min in DMF (2 mL). At this time bromocyclopentane (92 μL, 0.62 mmol) was added. The mixture was stirred at 110° C. in a sealed flask for 18 h. The mixture was cooled to rt and concentrated under reduced pressure. Purification of the residue by flash chromatography over silica gel, using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent gave 4-amino-6-(((1S)-1-(1-cyclopentyl-4-(methylsulfonyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, DMSO-d6) δ 8.09 (1H, s), 7.95 (1H, s), 7.94 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=8.0 Hz), 7.43 (1H, t, J=8.0 Hz), 7.35 (2H, br), 5.93-5.85 (1H, m), 5.03-4.95 (1H, m), 3.54 (3H, s), 2.70-2.66 (1H, m), 2.35-2.32 (1H, m), 2.18-1.94 (6H, m), 1.67 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 426.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12]CC1C=CC(OC)=CC=1)[C:6]([C:22]1(O)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[CH:5]2.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[C:6]([C:22]1[CH2:27][CH2:26][O:25][CH2:24][CH:23]=1)=[CH:5]2
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2C2(O)CCOCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc2ccc(Br)cc2cc1C1=CCOCC1
Temperature: 90 °C

Procedure:
4-(6-Bromo-2-(4-methoxybenzylamino)quinolin-3-yl)tetrahydro-2H-pyran-4-ol (0.250 g, 0.564 mmol) in a mixture of dioxane (4 mL), 5N HCl (4.00 mL, 20.00 mmol) and concentrated HCl (1.00 mL, 32.9 mmol) was heated at 90° C. for 5 h. The reaction was transferred to a microwave reaction vessel and heated in a microwave reactor at 130° C. for 40 min and was concentrated. The crude solid was partitioned between EtOAc and 10% sodium carbonate. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:30 2M NH3 in MeOH/DCM to provide 6-bromo-3-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-amine as white solid.
Reaction SMILES: C1O[C:4]2([CH2:21][C@H:20]([CH3:22])[C@@:19]3([CH2:23][OH:24])[C:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][CH2:12][C@@H:13]3[OH:25])=[CH:5]2)SC1>[Ni].CO>[CH3:22][C@@H:20]1[C@@:19]2([CH2:23][OH:24])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:25])=[CH:5][CH2:4][CH2:21]1
Reactant: C[C@H]1CC2(C=C3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31CO)OCCS2
Agent: [Ni]
Solvent: CO
Product: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO

Procedure:
Raney nickel is added to a solution of the above 17β,19-dihydroxy-1α-methyl-4-androsten-3-one 3-ethylenethioketal in methanol and the resulting suspension is refluxed for about 4 hours with rapid stirring. The suspension is cooled, filtered and the solvent evaporated. The residue is chromatographed on silica gel and eluted with methylenechloride. Recrystallization from acetonehexane yields 1α-methyl-4-androstene-17β,19-diol.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[CH:61]=[CH:62][C:63]2[S:67][C:66]([CH2:68]O)=[CH:65][C:64]=2[CH:70]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:68][C:66]2[S:67][C:63]3[CH:62]=[CH:61][C:60]([CH3:59])=[CH:70][C:64]=3[CH:65]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc2sc(CO)cc2c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc3cc(C)ccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (5-methyl-1-benzothien-2-yl)methanol (0.75 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24]O)[CH:20]=[C:21]([Cl:23])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:24][C:19]2[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: OCc1cc(Cl)cc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2cc(Cl)cc(Cl)c2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (0.5 g, 2.4 mmol), (3,5-dichloro-phenyl)-methanol (0.84 g, 4.8 mmol), and polymer-supported triphenyl phosphine (1.5 g, 4.8 mmol) in THF (30 mL) in ice-bath was slowly added diisopropyl azodicarboxylate (1.0 mL, 4.8 mmol) and stirred at r.t. overnight. The mixture was filtered and the solid was washed with ethyl acetate (10 mL). The filtrate was evaporated and the residue was purified by flash column chromatography (EtOAc/Hexane) to give 3-(3,5-dichloro-benzyloxy)-phthalic acid dimethyl ester (0.42 g, 48% yield). The product was used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]2[CH:22]=[CH:23][S:24][C:14]=12.C(N(CC)CC)C>C(O)(C)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:13]3[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]4[CH:22]=[CH:23][S:24][C:14]=34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: NC1CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccsc2c1NC1CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-amine (from J&W PharmLab, 0.40 g, 2.5 mmol), 7-chloro-6-nitrothieno[3,2-b]pyridine (0.29 g, 1.4 mmol) and triethylamine (0.38 mL, 2.7 mmol) in isopropyl alcohol (4.4 mL) was stirred at 90° C. for 2 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C15H18N3O4S (M+H)+: m/z=336.1. Found: 336.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH2:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(OCc2ccccc2)c2c1OCCO2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(OCc2ccccc2)c2c1OCCO2
Reaction time: 17 h

Procedure:
To a solution of 30 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX); code number 760 727, in 250 ml of chloroform and 21.3 ml of triethylamine, cooled to 0° C., 12.1 cm3 of propionyl chloride were slowly added. Then, it was stirred for 17 hours, washed with a solution of diluted hydrochloric acid, with water, with an aqueous solution of sodium bicarbonate, then with water, the organic phase was evaporated and the residue recrystallized in ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)[CH3:22])=[CH:9][CH:10]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:31])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[N:24]=3)[CH3:22])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1
Reactant: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CNCC3(C)C)n1

Procedure:
In a manner similar to that described in Example 127, to a solution of tert-butyl 4,4-dimethyl-7-{2-[1-(2-methylamino-pyrimidin-4-yl)-ethylamino]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylate (250 mg, 0.471 mmol) in CH2Cl2 (5 mL) was added TFA (3 mL) to give the final product. MS m/z: 431.3 (M+H). Calc'd. for C25H31N6O-431.55.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:19]=[CH:20][C:21]([F:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=1)#[CH:17]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:17]#[C:16][C:18]2[CH:19]=[CH:20][C:21]([F:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C#Cc2ccnc(Cl)n2)ccc1F)C(F)(F)F
Yield: 49.3 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (520 mg, 3.49 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)-palladium(II) (62 mg, 0.09 mmol), copper(I) iodide (10 mg, 0.05 mmol), and triethylamine (718 mg, 7.10 mmol). After heating the reaction at 60° C. for 30 min, N-(5-ethynyl-2-fluorophenyl)-2,2,2-trifluoroacetamide (410 mg, 1.77 mmol) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (5-50% EtOAc in hexanes) to afford the desired product (300 mg, 49%) as an off white solid. ESIMS (M+H)+=344.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[Br:13]Br>CC(O)=O>[Br:13][C:11]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.5 %

Procedure:
To a solution of 5-nitroindoline (from Aldrich, 2.0 g, 12.2 mmol) in 15 mL of AcOH was added Br2 (1.0 mL, 19.4 mmol) in a portion and the resulting solution was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid (3.9 g, >95%) of the desired product as a HBr salt, which was subjected to the following reaction without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.O.NN>C1COCC1>[CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2nnnn2C)c1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
To a stirred solution of 2-(6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (5.22 g, 11 mmol) in dry THF (130 mL) was added hydrazine hydrate (2.63 mL, 54 mmol). The reaction mixture was stirred at room temperature for 6 h, then insolubles were removed by filtration and washed with ethyl acetate. The filtrates were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate (250 mL), washed with water (2×100 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo to afford 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine as an orange solid [3.56 g, yield 89%; HPLC/MS:m/z=353 (M+H); log P(HCOOH)=1.19].
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:21])[CH2:8][CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27].Cl>ClC(Cl)C>[C:1]([C:6]1[C:7](=[O:21])[CH2:8][CH2:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([C:26](=[O:28])[CH3:27])[CH:18]=2)[C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCCC(=O)C1=C(O)C(c2ccc(O)c(C(C)=O)c2)CCC1=O
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
2-Butyryl-3-hydroxy-4-(4-methoxyphenyl)cyclohex-2-ene-1-one (7.1 g) in dichloroethane (35 ml) was added to a suspension of aluminium chloride (10.5 g) in dichloroethane (50 ml) at 0° C. After stirring for 1/2 hour, a solution of acetyl chloride (2.2 g) in dichloroethane (25 ml) was added dropwise. After stirring a further 1/2 hour at 0° C., the reaction mixture was allowed to come to room temperature and poured into cold 5N hydrochloric acid (50 ml). The aqueous solution was then extracted with dichloromethane. The extracts were dried over magnesium sulphate and evaporated in vacuo to give a red oil. Purification on a silica gel column using 5% (v/v) diethylether-dichloromethane as eluant gave the title compound (1.3 g) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12](O)=[O:13])=[C:4]([F:31])[CH:3]=1.S(Cl)([Cl:34])=O.Cl>C1CCCCC1>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:9][N:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[Cl:24])[C:11]=2[C:12]([Cl:34])=[O:13])=[C:4]([F:31])[CH:3]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)O)c1Cc1ccc(Br)cc1F
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1CCCCC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)Cl)c1Cc1ccc(Br)cc1F

Procedure:
A mixture of 672 mg (1.32 mmol) of 4-(4-bromo-2-fluorobenzyl)-3-n-butyl-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carboxylic acid (from Step C), 2.3 mL of thionyl chloride, and 6 mL of cyclohexane was stirred at reflux under N2 for 4 hours, during which time HCl gas was evolved. The cooled solution was concentrated in vacuo to yield an orange oil, which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1([F:23])[C:15]([F:17])([F:16])[C:14]2[CH2:13][CH:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:7]=2.[CH2:24]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>[Pd]>[CH2:24]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:7]=4)[C:2]([F:23])([F:1])[C:15]([F:17])([F:16])[C:14]=3[CH:13]=2)=[CH:39][CH:40]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCOc1ccc(B(O)O)cc1
Reactant: CCCCc1ccc2c(c1)C(F)(F)C(F)(F)C1=C2C=CC(Br)C1
Agent: [Pd]
Product: CCCCCCCCCCOc1ccc(-c2ccc3c(c2)C(F)(F)C(F)(F)c2cc(CCCC)ccc2-3)cc1

Procedure:
From 9,9,10,10-tetrafluoro-2-bromo-7-butyldihydrophenanthrene and 4-decyloxyphenylboronic acid by means of palladium-catalyzed Suzuki coupling (in analogy to Acc. Chem. Res. 1982, 15, 178). The crude product is purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41].[NH2:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[NH:46][C:45]([CH3:52])([CH3:51])[CH2:44]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH:43]3[CH2:44][C:45]([CH3:52])([CH3:51])[NH:46][C:47]([CH3:50])([CH3:49])[CH2:48]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(NC4CC(C)(C)NC(C)(C)C4)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Temperature: 25 °C

Procedure:
The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide (0.070 g, 0.107 mmol) was dissolved in DMF (1.5 mL) and treated with 4-amino-2,2,6,6-tetramethylpiperidine (62 ul, 0.361 mmol). Stirring at room temperature and heating to 70° C. under argon produced no reaction so the mixture was microwaved at 200° C. for 15 min. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel, eluting with CH2C2—10% MeOH/CH2C2. The product was repurified by the same method to afford the title compound as a white solid. mp (dec) 220° C.; LC-MS m/z 659 (M+H)+, 1.94 min (ret. time).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.O>CN(C=O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2cc(OCc3ccc4ccccc4n3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 6-hydroxytetralone, prepared as in step 1, (2.43 g, 15 mmol) and potassium carbonate (2.76 g, 20 mmol) in DMF (65 mL) was added chloromethylquinoline hydrochloride (3.42 g, 16 mmol), and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (100 mL). The extract was dried with MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5:1 methylene chloride-ethyl acetate to provide 2.3 g 3,4-Dihydro-6-(2-quinolylmethoxy)-1(2H)-naphthalenone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CC(C)=O.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[CH3:32]
Reactant: O=[N+]([O-])c1ccc(O)c(-n2cccc2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1-n1cccc1
Temperature: 60 °C

Procedure:
4-Nitro-2-pyrrol-1-yl-phenol (13.39 g, 0.066 mol), K2CO3 (10.9 g, 0.08 mol), Acetone (400 mL, 5 mol), and Ethyl bromoacetate (8.00 mL, 0.07 mol) were stirred at rt for 5 hours. The reaction mixture was filtered and concentrated to a yellow oil which solidified. The resulting residue was heated to 60° C. under high vacuum rotavap to remove residual ethyl bromo acetate. Recovered 15.36 g (81%) yellow solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:27][CH2:28]2)=[O:21])[CH2:17][CH2:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (Example 182(A), 0.30 g, 0.67 mmol) and methanesulfonyl chloride (0.10 g, 0.88 mmol) in pyridine (3 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 35:65) to give the title compound (0.13 g, 41%) as a white powder.