Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)[C@@H:13]1[C:24]1[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:44]#[CH:45].C([O-])([O-])=O.[K+].[K+].Cl>O.CC#N.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.[Cu]I.CCOC(C)=O>[Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:45]#[C:44][CH2:43][NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:19][CH:18]=2)[C@@H:13]1[C:24]1[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Reactant: C#CCNS(C)(=O)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Methyl {4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-iodophenyl)-4-oxoazetidin-2-yl]phenoxy}acetate (500 mg, 0.69 mmol) and N-prop-2-yn-1-ylmethanesulfonamide (150 mg, 1.13 mmol) were mixed in 15 ml water and 4 ml MeCN. K2CO3 (220 mg, 1.59 mmol), Pd(PPh3)4 (40 mg, 5 mol %) and CuI (13 mg, 10 mol %) were added. The solution was stirred at 50° C. for 2 h and at ambient temperature over night. EtOAc (20 ml) and 2 M HCl (1 ml) were added. The mixture was stirred for 5 min and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with 2% NaHCO3, brine (2×), dried with MgSO4 and concentrated to yield the title compound. M/z: 725.3 (M−1). 1H-NMR (400 MHz, DMSO-d6) δ: −0.18 (s, 3H), −0.04 (s, 3H), 0.77 (s, 9H), 2.85-3.02 (m, 5H), 3.69 (s, 3H), 3.80 (dd, 1H), 4.01 (d, 2H), 4.29 (d, 1H), 4.79 (s, 2H), 4.91 (dd, 1H), 5.11 (d, 1H), 6.95 (d, 2H), 7.09-7.18 (m, 2H), 7.18-7.25 (d, 2H), 7.32-7.42 (m, 6H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[NH:14][CH:13]=[CH:12]2)C)(C)(C)C>CO.Cl.O=[Pt]=O>[F:19][C:18]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][C:15]2=[O:20])=[CH:10][C:9]=1[NH:7][CH3:6]
Reactant: CN(C(=O)OC(C)(C)C)c1cc2cc[nH]c(=O)c2cc1F
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CNc1cc2c(cc1F)C(=O)NCC2
Reaction time: 8 h
Yield: 30.5 %

Procedure:
A mixture of tert-butyl 7-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl(methyl)carbamate (Example 45, 700 mg, 2.40 mmol) and PtO2 (470 mg) in MeOH (30 mL) containing concentrated HCl (8 drops) was hydrogenated under 300 psi in a high pressure vessel overnight. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was treated with TFA (10 mL) and stirred for 1 hr, after which, the TFA solution was concentrated in vacuo. The residue was purified by RP-HPLC to give the noted intermediate compound (142 mg). ES-MS (M+H)+=195.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH2:9]([CH2:11][CH2:12][CH2:13][C:14](CC([O-])=O)=[O:15])[CH3:10]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:14](=[O:15])[CH2:13][C:12]([CH2:11][CH2:9][CH3:10])=[N:8]1
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: NNc1ccccn1
Product: CCCC1=NN(c2ccccn2)C(=O)C1

Procedure:
From the reaction of 2-pyridylhydrazine and ethylbutyrylacetate, 2,4-dihydro-2-(2-pyridyl)-5-propyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-2-(2-pyridyl)-5-propyl-3H-pyrazol-3-one, Mp 151° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[C@H:3]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C:4](=[O:30])[N:5]1[C@H:10]([C:11]2[NH:15][C:14]3[CH:16]=[C:17](B4OC(C)(C)C(C)(C)O4)[CH:18]=[CH:19][C:13]=3[N:12]=2)[C@@H:9]2[CH2:29][C@H:6]1[CH2:7][CH2:8]2.Br[C:38]1[CH:50]=[C:49]2[C:41]([C:42]3[CH:43]=[CH:44][C:45]([C:53]4[NH:57][C:56]([C@@H:58]5[CH2:62][CH2:61][CH2:60][N:59]5[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[N:55][CH:54]=4)=[CH:46][C:47]=3[C:48]2([F:52])[F:51])=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[F:52][C:48]1([F:51])[C:47]2[CH:46]=[C:45]([C:53]3[NH:57][C:56]([C@@H:58]4[CH2:62][CH2:61][CH2:60][N:59]4[C:63]([O:65][C:66]([CH3:68])([CH3:67])[CH3:69])=[O:64])=[N:55][CH:54]=3)[CH:44]=[CH:43][C:42]=2[C:41]2[C:49]1=[CH:50][C:38]([C:17]1[CH:18]=[CH:19][C:13]3[N:12]=[C:11]([C@@H:10]4[C@@H:9]5[CH2:29][C@@H:6]([CH2:7][CH2:8]5)[N:5]4[C:4](=[O:30])[C@@H:3]([NH:31][C:32]([O:33][CH3:34])=[O:35])[CH:2]([CH3:36])[CH3:1])[NH:15][C:14]=3[CH:16]=1)=[CH:39][CH:40]=2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc3-4)cc2[nH]1)C(C)C
Temperature: 95 °C
Reaction time: 4 h
Yield: 52.6 %

Procedure:
A mixture of methyl (S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate (122 mg, 0.25 mmol), (S)-tert-butyl 2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (127 mg, 0.25 mmol), 1M aqueous sodium bicarbonate solution (0.93 mL, 0.93 mmol), triphenylphosphine (13 mg, 0.05 mmol), palladium(II) acetate (5.5 mg, 0.02 mmol) and dimethoxyethane (2.5 mL) was degassed with a stream of argon for twenty minutes. The reaction was heated to 95° C. After four hours, the reaction was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-tert-butyl 2-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (106 mg, 54%).
Reaction SMILES: S(=O)(=O)(O)O.[N+]([C:9]1[CH:10]=C(S([O-])(=O)=O)C=C[CH:14]=1)([O-])=O.[Na+].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1.[OH-].[NH4+]>O.OCC(CO)O>[Cl:20][C:21]1[CH:27]=[C:26]2[C:24](=[C:23]([F:28])[CH:22]=1)[N:25]=[CH:10][CH:9]=[CH:14]2
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: OCC(O)CO
Solvent: O
Product: Fc1cc(Cl)cc2cccnc12
Temperature: 110 °C

Procedure:
A solution of concentrated sulphuric acid (16 ml, 300 mmol) in water (12 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially available, for example, from Aldrich) (11.3 g, 50 mmol) and glycerol (commercially available, for example, from Fisher and/or Aldrich) (12 ml, 160 mmol) to give a suspension. This was heated to 110° C. with stirring, and 4-chloro-2-fluoroaniline (commercially available, for example, from Aldrich) (5.6 ml, 50 mmol) was added. The reaction was heated to 140° C. and stirred overnight. The reaction mixture was cooled and then poured into water (400 ml) and basified to pH 11 with aqueous ammonium hydroxide (0.88 s.g., 60 ml). The brown precipitate that formed was collected by filtration and dried under suction. EtOAc was then added to the sinter funnel, dissolving most of the material to give a brown solution. This filtrate was concentrated in vacuo to give a brown solid (7.7 g). This was purified by chromatography on silica (2×100 g, eluting with 0-50% EtOAc-cyclohexane over 60 min). The relevant fractions were concentrated in vacuo to give the title compound as a yellow solid (6.5 g, 70%) LCMS RT=2.78 min, ES+ve m/z 182/184 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH2:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17][CH2:16]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Clc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3s2)CC1
Temperature: 180 °C
Yield: 73.7 %

Procedure:
A mixture of 2-chloro-benzothiazole (2.00 g, 12.0 mmol, 1.0 equiv), ethyl 4-amino-1-piperidine carboxylate (2.44 g, 14.0 mmol, 1.2 equiv) and triethylamine (1.79 g, 18.0 mmol, 1.5 equiv) was heated by microwave irradiation to 180° C. for 5 min. To the crude reaction mixture was added dichloromethane (10 mL) and the suspension quickly poured onto tert-butyl methylether (200 mL). The hydrochloric salts of remaining ethyl 4-amino-1-piperidine carboxylate and triethylamine precipitated out and were removed by filtration. The filtrate was evaporated to dryness and the residue purified with column chromatography on silica eluting with dichloromethane/methanol (95:5) to yield 2.7 g (75%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO): δ 1.19 (t, J=7.1 Hz, 3H), 1.31-1.44 (m, 2H), 1.96-2.01 (m, 2H), 2.98-3.06 (m, 2H), 3.88-3.98 (m, 3H), 4.04 (q, J=7.1 Hz, 2H), 7.01 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H). MS (ISP): 306.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.FC1C(C2=CCOCCC2)=CC=CN=1>C1COCC1.[Pd]>[F:1][C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1C1=CCCOCC1
Agent: [Pd]
Agent: Fc1ncccc1C1=CCOCCC1
Solvent: C1CCOC1
Product: Fc1ncccc1C1CCCOCC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Palladium (0.20 g, 0.0188 mmol, 10% wt. on activated carbon) was added to a stirred solution of an approximately 7:3 mixture of (E)-2-fluoro-3-(2,3,6,7-tetrahydrooxepin-4-yl)pyridine:(E)-2-fluoro-3-(2,5,6,7-tetrahydrooxepin-4-yl)pyridine (0.75 g, 3.88 mmol) in THF (15 mL). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 4.5 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give 2-fluoro-3-(oxepan-4-yl)pyridine. [M+1]=196.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:21])[CH:10](C([O-])=O)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C@H:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][C:11](=[O:21])[CH2:10][C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])C1C(=O)CC(Cc2ccccc2)N(Cc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1CC(=O)N(Cc2ccccc2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 106.1 g (0.301 mol of methyl (6R(-1,6-dibenzyl-2,4-dioxo3-piperidine carboxylate in 298 ml of toluene and 445 ml of 10% strength (vol/vol) acetic acid is heated at 80° for 21/2 hours. The reaction mixture is cooled to room temperature, neutralised by adding 48 g of solid sodium carbonate while cooling in ice-water, the phases are separated, and the aqueous phase is extracted once more with 300 ml of ethyl acetate. The combined organic phases are washed with water, then with brine dried over sodium sulfate and evaporated to dryness. The resulting oil is crystallised from ether, resulting in the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2O.[Cl:25]CCl.C(Cl)(C(Cl)=O)=O>CN(C)C=O>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[N:6]=1
Reactant: COc1cc(-c2nc(O)c3cc(F)ccc3n2)cc(OC)c1OC
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(Cl)c3cc(F)ccc3n2)cc(OC)c1OC

Procedure:
Into a 500-mL round-bottom flask, was placed 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol (8.0 g, 24.22 mmol, 1.00 equiv), dichloromethane (200 mL) and N,N-dimethylformamide (0.5 mL). This was followed by the addition of (COCl)2 (23.74 g) dropwise with stirring. The resulting solution was stirred for 1 h at 40° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of dichloromethane. The resulting mixture was washed with 2×100 mL of NaHCO3 (sat.) and 1×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by ethyl acetate:petroleum ether in ratio of (1:5). This resulted in 5 g (59%) of 4-chloro-6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline as a white solid. MS (ESI) m/z 349 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:35][CH:34]=[N:33][CH:32]=1)CCC.O1CCOCC1>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>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:31]1[S:35][CH:34]=[N:33][CH:32]=1)[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-c1cncs1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.2000 g, 0.5388 mmol), 5-(tributylstannyl)thiazole (0.4032 g, 1.078 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.06226 g, 0.05388 mmol) in 1,4-dioxane (4.490 mL, 0.5388 mmol) was stirred at 100° C. After 94 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 7 min as eluent to give 2-((S)-1-(8-chloro-2-(thiazol-5-yl)-quinolin-3-yl)ethyl)isoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (1H, s), 8.83 (1H, s), 8.30 (1H, d, J=0.8 Hz), 8.13 (1H, dd, J=8.2, 1.2 Hz), 7.99 (1H, dd, J=7.6, 1.4 Hz), 7.71-7.82 (4H, m), 7.60-7.69 (1H, m), 6.03 (1H, q, J=7.2 Hz), 1.88 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 420.1 [M+H]+.
Reaction SMILES: CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:28][CH:29]1[CH2:36][CH:35]2[CH2:37][C:31]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=3)([CH:32]([CH3:47])[CH2:33][N:34]2[CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:30]1.Cl.[CH3:56][N:57]([CH3:64])[CH2:58][CH2:59][CH2:60][C:61](O)=[O:62].C(N(CC)CC)C>C1COCC1.CCOCC>[CH3:56][N:57]([CH3:64])[CH2:58][CH2:59][CH2:60][C:61]([NH:28][C@H:29]1[CH2:36][C@H:35]2[CH2:37][C@:31]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=3)([C@H:32]([CH3:47])[CH2:33][N:34]2[CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30]1)=[O:62]
Reactant: CN(C)CCCC(=O)O
Reactant: CC1CN(CCCc2ccccc2)C2CC(N)CC1(c1cccc(O)c1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CCCc2ccccc2)[C@H]2C[C@H](NC(=O)CCCN(C)C)C[C@]1(c1cccc(O)c1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
BOP reagent (27 mg, 0.060 mmol) was added to a solution of (+)-7-amino-4-methyl-5-(3 -hydroxyphenyl)-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]nonane (23, 20 mg, 0.055 mmol), 4-(dimethylamino)butyric acid hydrochloride (18 mg, 0.11 mmol) and triethylamine (0.038 mL, 0.27 mmol) in dry THF (5 mL). The reaction mixture was stirred under N2 at room temperature for 4 h. The mixture was diluted with Et2O (20 mL), washed with saturated NaHCO3, followed by water, organic layer collected, dried (Na2SO4) and solvent removed under reduced pressure yielding crude product. This was purified by flash chromatography (33% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3) to afford 4-(dimethylamino)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]butanamide (13) (23 mg, 89%) as an off-white foam. 1H-NMR (CDCl3) δ7.28-7.09 (m, 6H), 6.89 (d, 1H, J=7.0 Hz), 6.64-6.59 (m, 3H), 6.31 (m, 1H), 4.65 (br., 1H), 3.16 (br., 1H), 3.02 (d, 1H, J=7.8 Hz), 2.69-2.14 (m, 16H), 1.91 (m, 1H), 1.86-1.75 (m, 4H), 1.58 (m 1H), 1.36-0.83 (m, 3H), 0.71 (d, 3H, J=6.5 Hz); LRMS (ES) m/z 478.7 (M+H)+.
Reaction SMILES: [CH2:1]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[O:10][CH2:9][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:11][O:12]2)=[CH:16][CH:15]=1
Reactant: CCCCCCCC(CO)CO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCC1COC(c2ccc(Br)cc2)OC1

Procedure:
Quantities: compound from Example 8 (44 g, 0.25 mol), 4-bromobenzaldehyde (42.8 g, 0.23 mol) and 4-toluenesulphonic acid (150 mg). The experimental procedure was as described in Example 11.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 6-phenylhexanoic acid (19.8 mmoles) in sieve dried tetrahydrofuran (5 ml) and reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmoles) at 0° C. for 4 hours to give 6-phenylhexanol. To an ice cold solution of the hexanol (ca. 19.8 mmoles) and carbon tetrabromide (21.98 mmoles) in methylene chloride (50 ml) was added triphenylphospine (22.30 mmoles) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 6-phenylhexyl bromide as an oil. A mixture of the bromide (8.00 mmoles), salicylaldehyde (8.19 mmoles) and potassium carbonate (9.33 mmoles) in dimethylformamide (10 ml) was heated to 100° C. and maintained at that temperature for one hour. The cooled reaction mixture was taken up in hexane (50 ml) and washed with 5% sodium hydroxide (50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation yielded a colorless oil which was purified by flash chromatography over silica gel with 5% ethyl acetate in hexane as eluant to afford the desired product as an oil.
Reaction SMILES: Br[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.[CH3:13]B(O)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][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: CB(O)O
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CCCC2=O
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 19 (1.4 g, 6.1 mmol), methyl boronic acid (0.6 g, 9.3 mmol), Pd(OAc)2 (0.07 g, 0.31 mmol), PPh3 (0.16 g, 0.61 mmol), and K3PO4 (5.2 g, 24 mmol) in dry THF were stirred at reflux under N2 atm overnight. After cooling at room temperature, crude was filtered through celite, concentrated by rotary evaporation, and purified by column chromatography to give 6-methyl-3,4-dihydronaphthalen-1(2H)-one (20) (88%). 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J=12.0 Hz, 1H), 7.11 (d, J=12.0 Hz, 1H), 7.06 (s, 1H), 2.92 (t, J=6.0 Hz, 2H), 2.63 (t, J=12.0 Hz, 2H), 2.37 (s, 3H), 2.13-2.10 (m, 2H). GC-MS (ES) for C11H12O [M]+ 160.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([S:14]([Cl:13])(=[O:16])=[O:15])=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Yield: 19.9 %

Procedure:
Synthesized as described for 1 using 1-tert-butyl-3,5-dimethylbenzene (5.76 mL; 30.81 mmol), chlorosulfonic acid (2.46 mL; 36.96 mmol) and anhydrous dichloromethane (200 mL). The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 25% v/v gradient elution over 400 mL) to give the title compound as a white solid (1.60 g).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Cl:11][C:12]1[C:13]([NH2:21])=[C:14]([NH2:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]>Cl>[Cl:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]2[C:13]=1[NH:21][C:2](=[O:4])[C:1](=[O:8])[NH:20]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)c(F)c(Cl)c1N
Agent: Cl
Product: O=c1[nH]c2cc(F)c(F)c(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (981 mg, 6.72 mmol) and 3-chloro-4,5-difluoro-1,2-diaminobenzene (120 mg, 0.670 mmol) was heated to reflux under N2 for 15 h. The reaction was allowed to cool to room temperature and the gray solid collected by vacuum filtration and rinsed with ice-cold EtOH (10 mL) and air dried. The solid was taken and dissolved in 5 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 1N HCl (pH=1). A white powder formed in the solution at pH=6, but a few drops 1N NaOH cleared the solution and upon addition of a few drops 1N HCl white needles slowly formed in the solution. These were collected by vacuum filtration, rinsed with 20 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 24.9 (16%) of pale yellow needles. 1H NMR (d6 -DMSO) δ7.05 (dd, 1H, J=10.5, H-8), 11.6 (br s, 1H, NH), 12.0 (br s, 1H, NH). There was 13% 6,7-difluoro-1,4-dihydro-2,3-quinoxalinedione present by NMR.