Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([O-:13])=O.[Na+].C=O.C(O)/[CH:18]=[CH:19]/[CH2:20][OH:21]>CCO>[CH2:1]([N:8]1[CH2:18][C@@H:19]([CH2:20][OH:21])[C@H:10]([CH2:11][OH:13])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: ONCc1ccccc1
Reactant: OC/C=C/CO
Agent: C=O
Agent: [Na+]
Solvent: CCO
Product: OC[C@@H]1CN(Cc2ccccc2)O[C@H]1CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-benzylhydroxylamine (4.4 g, 27.7 mmol) and anhydrous NaOAc (3.0 g, 36.7 mmol) in 35 ml EtOH was stirred at ambient temperature for 15 min, after which time formaldehyde (4.1 ml, 55.1 mmol) was added and the mixture stirred for another 30 min. A solution of (E)-but-2-ene-1,4-diol (1.63 g, 18.50 mmol) in ethanol (20 ml) was then introduced to the mixture in a single slug and the resulting solution refluxed for 18 hours. The mixture was cooled, concentrated and taken up in DCM and the solution washed sodium bicarbonate solution, dried and concentrated to an immobile oil (5.25 g). The crude product was fractionated by chromatography over silica eluting firstly with EtOAc and then with 5% MeOH/EtOAc and the title compound was isolated as an immobile syrup (1.95 g). The chromatography was repeated with only EtOAc as eluant and the compound isolated (1.46 g, 35%) as an homogeneous syrup. 1H NMR (CDCl3) δ 7.41-7.22 (m, 5H), 4.10-3.82 (m, 2H), 3.80-3.60 (m, 4H), 3.5-2.3 (m, 5H). 13C NMR 137.0, 129.3, 128.8, 128.0, 81.6, 64.1, 63.0, 58.7, 47.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19](=O)[O:20]C4C=CC([N+]([O-])=O)=CC=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ncc2c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)N3CCN(C)CC3)ncc2c1
Temperature: 90 °C
Yield: 3.8 %

Procedure:
4-nitrophenyl 7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylcarbamate (0.156 g, 0.374 mmol) was dissolved in N,N-dimethylformamide (2.0 mL, 26 mmol) and 1-methyl-piperazine (0.20 mL, 1.8 mmol) was added. The reaction mixture was heated at 90° C. for 1 hour. The reaction mixture was then diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-20% methanol in dichloromethane with 2% triethylamine) followed by reverse phase HPLC and lyophilization to yield 5.4 mg (4%) of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)-4-methylpiperazine-1-carboxamide. LCMS (ESI): RT (min)=4.017, M+H=379.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.12 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.38 (s, 1H), 7.16 (t, J=8.3 Hz, 2H), 3.52 (s, 4H), 2.33 (s, 4H), 2.25 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[F:9][CH:8]([F:10])[C:7]1[C:2]([O:29][C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]=[C:19]3[NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)c1cccnc1Cl
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncccc4C(F)F)cc23)n1

Procedure:
The compound of Example 122 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloro-3-(difluoromethyl)pyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:53])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH3:39])[CH:37]=2)[C:32]([Sn](CCCC)(CCCC)CCCC)=[N:31]1>CN(C=O)C.O.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)I>[Si:17]([O:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[C:33]4[C:38](=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[N:30]([CH2:29][CH2:28][N:27]([CH3:26])[CH3:53])[N:31]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:12])([CH3:25])[CH3:24])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCN(C)C)c2cc(C)ccc12
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)nn(CCN(C)C)c2c1
Temperature: 85 °C

Procedure:
A mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (210 mg, 0.5 mmol) and N,N-dimethyl-2-(6-methyl-3-(tributylstannyl)-1H-indazol-1-yl)ethanamine (1.4 g, 2.85 mmol) with tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), copper iodide (10 mg, 0.52 mmol) in 15 mL of dry DMF was heated to 85° C. overnight under N2. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, extracted with dichloromethane (8×50 mL), combined organics dried with sodium sulfate and concentrated. The crude product was used into the next step without further purification. LCMS: (M+H)+=550.
Reaction SMILES: Cl.Cl.[CH2:3]1[O:18][C:17]2[CH:16]=[CH:15][C:7]([CH2:8][CH:9]3[CH2:14][NH:13][CH2:12][CH2:11][NH:10]3)=[CH:6][C:5]=2[O:4]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]#[C:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][C:32]1([CH3:38])[CH3:37].[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:44](Cl)=[O:45]>CN(C)C=O>[F:39][C:40]([F:54])([F:55])[C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([C:50]([F:53])([F:51])[F:52])[CH:49]=1)[C:44]([N:10]1[CH2:11][CH2:12][N:13]([CH2:27][C:28]#[C:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][C:32]2([CH3:38])[CH3:37])[CH2:14][CH:9]1[CH2:8][C:7]1[CH:15]=[CH:16][C:17]2[O:18][CH2:3][O:4][C:5]=2[CH:6]=1)=[O:45]
Reactant: CC1(C)COCCN1CC#CCCl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1cc2c(cc1CC1CNCCN1)OCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)COCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 2-(3,4-methylenedioxybenzyl)piperazine dihydrochloride (104 mg) and potassium carbonate (196 mg) in N,N-dimethylformamide (4 ml) was added 4-(4-chloro-2-butynyl)-3,3-dimethylmorpholine hydrochloride (84.5 mg) at 5° C. under nitrogen atmosphere and the mixture was gradually warmed to room temperature over night. To the above stirred suspension was added 3,5-bis(trifluoromethyl)benzoyl chloride (98.2 mg) at 5° C. and the mixture was stirred for 1 hour at this temperature. The mixture was extracted with ethyl acetate and the extract was washed with water, and dried over magnesium sulfate. The usual work up followed by flash chromatography on silica gel with a mixture of dichloromethane and methanol (50:1) gave 1-[3,5-bis-(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(3,4-methylenedioxybenzyl)piperazine, which was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give 1-[3,5-bis-(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(3,4-methylenedioxybenzyl)piperazine dihydrochloride (107 mg) as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Si:17]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Temperature: 23 °C
Reaction time: 48 h
Yield: 97.6 %

Procedure:
To a solution of 2-amino-5-nitrophenol (1 g, 6.49 mmol) and imidazole (0.88 g, 12.3 mmol) in DMF (15 mL), tert-butyldimethylsilyl chloride (11.2 mL, 64.9 mmol) was added. The resulting mixture was allowed to stir at 23° C. for 48 hours. The reaction mixture was partitioned between 0.1% HCl and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane:ethyl acetate; 5:1) gave the titled compound (1.7 g, 98%). 1H NMR (CDCl3): δ 7.78 (dd, 1H, J=6.7 Hz and J=2.7 Hz), 7.61 (d, 1H, J=2.7 Hz), 6.7 (d, 1H, J=8.8 Hz), 1.0 (s, 9H), 0.28 (s, 6H).
Reaction SMILES: [OH:1][C:2]1([CH3:11])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][C:9]#[CH:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1([CH3:11])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][C:9]#[CH:10])(=[O:14])[CH3:13]
Reactant: C#CCC1C(=O)C=CC1(C)O
Reactant: CC(=O)OC(C)=O
Product: C#CCC1C(=O)C=CC1(C)OC(C)=O

Procedure:
Into the same flask as used in Example 1, dl-3-hydroxy-2-propargyl-3-methyl-4-cyclopentenone (30 g) and acetic anhydride (70 g) were charged, and the resultant mixture was stirred at 100°-120° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 1 to give 36.4 g of dl-3-acetoxy-2-propargyl-3-methyl-4-cyclopentenone. Yield, 95%. B.P., 82°-86° C./0.2-0.3 mmHg).
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][N:14]=[CH:15]OCC)[N:9]=1.[C:19]1(C)[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:30]O>>[C:21]1([CH3:30])[C:22]([S:25]([NH:28][CH:15]=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][CH:3]=[N:2][NH2:1])[S:6][CH:7]=2)(=[O:26])=[O:27])=[CH:23][CH:24]=[CH:19][CH:20]=1
Reactant: CO
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC=NCCSCc1csc(NC=NN)n1
Product: Cc1ccccc1S(=O)(=O)NC=NCCSCc1csc(NC=NN)n1
Temperature: 25 °C

Procedure:
To the crude product composed by ethyl N-[2-[[[2-[(aminoimino-methyl)amino]-4-thiazolyl]methyl]thio]ethyl]formimidate, 5.6 g of p-toluensulfonamide in 50 ml of methanol are dropwise added under stirring and at room temperature. The mixture is kept under stirring for 1 hour at room temperature, the solvent is removed by distillation under reduced pressure, and the obtained residue is purified by 60-silicagel column chromatography. 9.8 g of N-toluen-sulphonyl-N'-[2-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]ethyl]formamidine are obtained, having the same physico-chemical properties as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30]([N:35]=[C:36]=[O:37])=[CH:29][C:28]=2[O:27]1.C(Cl)Cl.CO>C(#N)C>[O:34]1[C:33]2[CH:32]=[CH:31][C:30]([NH:35][C:36]([NH:1][C:2]3[C:15]4[C:6](=[CH:7][C:8]5[C:9]6[C:14]=4[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:11](=[O:22])[C:10]=6[CH:23]=[CH:24][CH:25]=5)[CH:5]=[CH:4][CH:3]=3)=[O:37])=[CH:29][C:28]=2[O:27][CH2:26]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)Nc5ccc6c(c5)OCO6)c4c(c23)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 4 mL of acetonitrile was stirred at 20° C. 3,4-(methylenedioxy)phenyl isocyanate (2 molar equivalents) in 3 mL acetonitrile were added. The mixture was magnetically stirred at 20° C. during 18 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95:5 volume ratio) to provide 125 mg (yield: 84%) of the desired product (formula below) as an orange powder.
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([OH:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH-].[CH2:19]([N+:25]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:38]([N+:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: [OH-]
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Perfluorobutanesulfonic acid tetrahexylammonium salt is prepared by neutralising perfluorobutanesulfonic acid and tetrahexylammonium hydroxide in aqueous solution. Tetrahexylammonium hydroxide is obtainable from Fluka.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=O.[CH3:14][NH:15][CH3:16].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:15]([CH3:16])[CH3:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: CNC
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (2.0 g, 7.9 mmol, Combi-blocks) in methylene chloride (10 mL) was added a solution of 2.0M dimethylamine in tetrahydrofuran (7.9 mL, 16 mmol) and the reaction was stirred for 15 minutes at room temperature. The reaction was then cooled to 0° C. and sodium triacetoxyborohydride (2.5 g, 12 mmol) was added. The resulting mixture was warmed to room temperature and was stirred for 24 hours. The solvents were removed in vacuo. Saturated sodium bicarbonate solution was added and the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography, eluting with a gradient from 10-40% ethyl acetate in hexanes afforded product as a colorless oil (1.58 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.65 (s, 1H), 7.57-7.46 (m, 1H), 3.45 (s, 2H), 2.25 (s, 6H); 19F NMR (282 MHz, CDCl3) δ−63.10 (s); LCMS (M+H)+: 282.0, 284.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CN1C(=O)CCC1.C(N(CC)CC)C.F[C:23]1[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([NH2:29])[CH:28]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:23]2[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([NH2:29])[CH:28]=2)[CH2:4][CH2:3]1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq) and 5-fluoro-2-nitrophenylamine (1.0 eq) were heated at 90° C. for 1 hours. The reaction was allowed to cool to room temperature and then poured into water and let stand for 12 hours. The resulting solid was collected and dried and utilized without further purification. MH+=237.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C@@H:7]([CH3:15])[CH2:6]1)=[O:4].C(N(CC)C(C)C)(C)C.[C:25](Cl)(=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C>[CH3:1][O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:7]([CH3:15])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](C)Nc2ccccc21
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OC)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.6 %

Procedure:
A round bottom flask with magnetic stirrer was charged with cis-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (5.42 g, 26 mmol) in dichloromethane (100 mL) under an argon atmosphere at room temperature. To the reaction was added N,N-diisopropylethylamine (11.8 mL, 68 mmol), followed by p-anisoyl chloride (6.31 g, 37 mmol). The reaction was stirred at room temperature for 18-20 hours and poured into saturated sodium bicarbonate (1000 mL), diluted with dichloromethane (50 mL), and shaken vigorously. The resulting organic layer was separated, washed with brine (1×100 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford an oily residue. Diethyl ether (50 mL) was added to the residue and the resulting white solid was collected via suction filtration to afford cis-1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (6.94 g, 78%).
Reaction SMILES: Br.Br.[CH:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]3[C:20]4[CH:28]=[C:27]([OH:29])[C:26]([OH:30])=[CH:25][C:21]=4[O:22][C:23](=[O:24])[C:16]=3[CH2:15]1)[CH2:4]2.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:41][CH3:42])(=O)=O.[CH3:46][C:47](C)=O>>[CH:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]3[C:20]4[CH:28]=[C:27]([O:29][CH2:41][CH3:42])[C:26]([O:30][CH2:46][CH3:47])=[CH:25][C:21]=4[O:22][C:23](=[O:24])[C:16]=3[CH2:15]1)[CH2:4]2
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)=O
Reactant: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CC3CCC(CC3)C1)CC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc2oc(=O)c3c(c2cc1OCC)CCN(CCN1CC2CCC(CC2)C1)C3

Procedure:
A mixture 3-[2-(3-azabicyclo-[3.2.2]non-3-yl)ethyl]-1,2,3,4-tetrahydro-8,9-dihydroxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one dihydrobromide (11.5 g, 0.020 moles), potassium carbonate (15.0 g, 0.11 moles), and diethyl sulfate (10.4 g, 0.067 moles) in 2.5 l of acetone is stirred at reflux for 21 hours. Additional diethyl sulfate (59 g, 0.38 moles) is added, and the mixture is heated for an additional 30 hours. The cooled mixture is filtered, and the filter cake is digested twice in hot acetone (500 ml) and refiltered. The combined filtrates are evaporated, and the residue is distributed between dichloromethane (1500 ml) and water (750 ml). The organic layer is separated, washed four times with 2.5% aqueous sodium hydroxide (750 ml), dried over sodium sulfate, and evaporated. The crude product was recrystallized twice as the free base from acetonitrile to yield the final product (5.4 g), mp 132°-134° C.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C@H:14]([N:18]1[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:19]1)[CH2:13][CH2:12]2.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:24]2[CH2:23][CH2:22][C:20]3([CH2:19][N:18]([C@H:14]4[C:15]5[C:11](=[CH:10][C:9]([C:4]6[N:5]=[CH:6][CH:7]=[CH:8][N:3]=6)=[CH:17][CH:16]=5)[CH2:12][CH2:13]4)[CH2:21]3)[CH2:26][CH2:25]2)=[O:37])=[CH:31][CH:30]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: c1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ncccn5)ccc42)C3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.3 %

Procedure:
A mixture of 2-[(1R)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1e, 600 mg, 1.40 mmol), p-methoxyphenylacetic acid (232 mg, 1.40 mmol), HBTU (529 mg, 1.40 mmol) and triethylamine (1.2 mL, 8.6 mmol) in 5 mL of DMF was stirred at room temperature for 20 hours. The solvent was removed in vacuo, the residue was azeotroped with toluene and partitioned between 1N NaOH (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 24 g silica column (1-15% MeOH in DCM in 30 minutes) to give the product as a light foam. This solid was stirred with diethyl ether (80 mL) for 18 h and filtered to give the title compound as a light grey solid (540 mg, 82%). MS (ES+) 469.5 (M+H)+ 1H NMR (CDCl3) δ 1.52-1.58 (m, 2H), 1.65-1.72 (m, 2H), 1.87-1.95 (m, 1H), 2.12-2.21 (m, 1H), 2.82-2.90 (m, 1H), 3.02-3.15 (m, 5H), 3.33 (t, 2H), 3.52 (t, 2H), 3.65 (s, 2H), 3.78 (s, 3H), 3.94-3.97 (m, 1H), 6.82-6.87 (m, 2H), 7.12-7.17 (m, 3H), 7.35 (d, 1H), 8.24 (d, 1H), 8.28 (s, 1H), 8.78 (d, 2H). [α]D20=+43.2 deg (c=8 mg/mL, MeOH).
Reaction SMILES: [OH-:1].[Na+].Br[C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6](Br)([CH2:7]3)[CH2:5]1)[CH2:11]2.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br-].[Br-].[Br-].[Al+3]>O>[OH:21][C:15]1[CH:20]=[CH:19][C:18]([C:4]23[CH2:13][CH:8]4[CH2:9][CH:10]([CH2:12][C:6]([C:4]5[CH:13]=[CH:8][C:7]([OH:1])=[CH:6][CH:5]=5)([CH2:7]4)[CH2:5]2)[CH2:11]3)=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: [OH-]
Reactant: BrC12CC3CC(C1)CC(Br)(C3)C2
Agent: [Al+3]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C23CC4CC(C2)CC(c2ccc(O)cc2)(C4)C3)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A 500 mL five-neck flask equipped with a thermometer, an agitator, a reflux tube, a nitrogen introduction tube and an exhaust tube to a trap containing 30% aqueous sodium hydroxide was cooled in an ice bath. 6.47 g (0.022 mol) of 1,3-dibromo-adamantane, 200 ml of phenol and 2.6 g (0.01 mol) of aluminum tribromide were added to the flask and agitated at 0° C. for 6 hours. The mixture was heated to react at 60° C. for 4 hours. A reactant was poured into a 2,000 L of acid iced water. After the ice was melted, an organic layer was filtered, washed by pure water and saturated sodium chloride aqueous solution, and added into methanol so as to separate a product. The obtained product was dried under reduced pressure, thus obtaining 3.5 g of the product.