Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[CH:4][CH:3]=1.IC1C=CC(O)=CC=1.[H][H]>O1CCCC1.[Ni].O>[I:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(I)cc2)nc1
Agent: [Ni]
Agent: Oc1ccc(I)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Oc2ccc(I)cc2)nc1
Yield: 92.1 %

Procedure:
2-(4-Iodo-phenoxy)-5-nitro-pyridine (50 grams, 146.1 mmol) and 4-iodo-phenol (96.5 grams, 438.6 mmol) were dissolved in tetrahydrofuran (500 mL) and added to a Parr shaker flask which contained Raney nickel (30 grams of a 50% slurry in water). The above mixture was shaken under hydrogen gas (50 psi) for 2 hours, at which time uptake of hydrogen gas had ceased and thin liquid chromatography indicated complete consumption of starting material. The Raney nickel was then removed by filtration through a pad of celite under nitrogen. The pad was rinsed several times with methylene chloride. The filtrate was diluted with methylene chloride and the organic layer was washed with 1M sodium hydroxide (4×200 mL) and brine (1×200 mL). The organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum to give 42 grams (92%) of the title compound which was used without further purification. MS m/z: ESI+ 313.0 (M+H)+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:19]([F:20])=[C:18]([C:21]2[N:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][N:22]=2)[CH:17]=[CH:16][C:15]=1[OH:36].[CH3:37][Si:38]([CH3:51])([CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:51][Si:38]([CH3:37])([CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:36][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][N:26]=2)=[C:19]([F:20])[C:14]=1[F:13]
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)c(F)c2F)nc1
Reactant: C[Si](C)(C)C[Si](C)(C)CCCCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCc1cnc(-c2ccc(OCCCCCC[Si](C)(C)C[Si](C)(C)C)c(F)c2F)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.087 g, 0.500 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 2,3-difluoro-4-(5-nonylpyrimidin-2-yl)-phenol (0.134 g, 0.400 mmol), compound 14 (0.108 g, 0.440 mmol) and triphenylphosphine (0.130 g, 0.500 mmol) in THF (20 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH:18]2[CH2:20][CH2:19]2)=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([Br:17])[CH:10]=2)=[O:5])C.C[Al](C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.CCOC(C)=O.C1CCCCC1>C1(C)C=CC=CC=1>[Br:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([CH3:16])=[C:6]([C:4]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)=[O:5])[C:7]([CH:18]3[CH2:19][CH2:20]3)=[N:8]2)=[CH:13][CH:12]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1c(C2CC2)nc2cc(Br)ccc2c1C
Agent: C[Al](C)C
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2ccc(F)cc2)c(C2CC2)nc2cc(Br)ccc12
Temperature: 120 °C
Yield: 73.6 %

Procedure:
To a stirred solution of 1.0 g (2.99 mmol) 7-bromo-2-cyclopropyl-4-methylquinoline-3-carboxylic acid ethyl ester in toluene (10 ml) were added 10.5 ml (2M solution in toluene, 20.9 mmol) Me3Al at RT followed by the addition of 3.74 g (29.9 mmol) 4-fluorobenzylamine. The reaction mixture was heated at 120° C. for 16 h. Then the reaction was quenched with water (15 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with 2N aq. HCl and brine, dried over MgSO4 and concentrated in vacuum. After CC (EtOAc/cyclohexane 1:2) of the residue, 900 mg (2.2 mmol, 73%) 7-Bromo-2-cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-quinoline-3-carboxylic acid amide (example 28) were obtained. MS: m/z 413.1 [M+H]+.
Reaction SMILES: [H][H].[C:3]([OH:24])(=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C@@H:10]1[C@@H:14]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][CH2:11]1>[Pd].C(OCC)(=O)C>[C:3]([OH:24])(=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CCCCCCC#C[C@H]1CCC[C@@H]1SCCCCCC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCC[C@H]1CCC[C@@H]1SCCCCCC(=O)O
Yield: 85.6 %

Procedure:
To a suspension of 50 mg of 10% palladium on charcoal in 1 ml of ethyl acetate, which had been pre-reduced with hydrogen gas was added 7-thia-13-prostynoic acid (15 mg) in 1.5 ml of ethyl acetate. After 5 hrs the catalyst was removed by filtration washed with ethyl acetate and the combined filtrates evaporated to yield 13 mg of a semisolid. Analysis by nmr indicated that there still remained starting material plus some 7-thia-13-cis-prostenoic acid. The material was therefore reduced again with 50 mg of fresh palladium catalyst for 1/2 hour and the reduced material isolated by filtration and removal of the solvent. 8 Milligrams of the saturated acid was obtained, which after recrystallization from hexane melted at 40°-41°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH-:9])(=[O:8])=[O:7].C(Cl)(=O)[C:11](Cl)=[O:12]>ClCCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]=[C:11]=[O:12])(=[O:8])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [NH-]S(=O)(=O)c1cccs1
Solvent: ClCCCl
Product: O=C=NS(=O)(=O)c1cccs1

Procedure:
A mixture of 2-thiophenesulfonylamide (1.5 g) and oxalyl chloride (6 mL) in 10 mL of 1,2-dichloroethane was refluxed for 14 h. The solvent was removed under vacuum and the crude used as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[C:5]2([CH3:16])[CH3:15].[OH:17][CH:18]([CH3:22])[C:19](O)=O.N>Cl>[CH2:12]([N:7]1[C:8]2[CH:9]=[C:10]3[N:11]=[C:19]([CH:18]([OH:17])[CH3:22])[NH:1][C:2]3=[CH:3][C:4]=2[C:5]([CH3:15])([CH3:16])[C:6]1=[O:14])[CH3:13]
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: CC(O)C(=O)O
Agent: Cl
Agent: N
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(C(C)O)nc3cc21
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
A mixture of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (10 g, 46 mmol), 2-hydroxy-propionic acid (9.13 g, 91.2 mmol) in HCl (100 mL, 4N) was refluxed for 16 h. After cooling, neutralization with aqueous ammonia (25%) and stirring for 1.5 h the precipitate was filtered and dried in vacuo at 50° C. yielding 12.29 g (95%) of a grey solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1([C:18]2[N:19]=[CH:20][NH:21][CH:22]=2)[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[O:8][C:7](=[O:17])[CH2:6]1.C(N(C(C)C)C(C)C)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C>ClCCl.O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[O:8][C:7](=[O:17])[CH2:6][C:5]3([CH2:4][CH2:3][CH2:2][N:19]4[CH:20]=[N:21][CH:22]=[C:18]34)[C:14]2=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)OC(=O)CC2(CCCO)c1c[nH]cn1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(=O)CC21CCCn2cncc21
Reaction time: 3 h

Procedure:
A solution of 1.20 mmol of 4-(3-hydroxypropyl)-4-(1H-imidazol-4-yl)-7-methoxychroman-2-one and 1.44 mmol of N-ethyldiisopropylamine in 10 ml of dichloromethane is admixed dropwise at room temperature with 1.20 mmol of methanesulphonyl chloride and the reaction mixture is subsequently stirred for 3 hours. The conversion to the mesylate intermediate is observed by means of HPLC. The reaction mixture is poured into 10 ml of water and subjected to extraction and the aqueous phase is re-extracted with dichloromethane (2×). The combined organic phases are washed with brine, dried over sodium sulphate and evaporated (bath temperature: 30° C.). The residue is taken up in 10 ml of acetonitrile and heated at boiling on an oil bath for about 20 hours. The reaction mixture is left to cool and then evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(Oc2ccc(F)cc2F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Oc2cc([N+](=O)[O-])c(F)cc2F)cc1
Temperature: 0 °C
Yield: 63 %

Procedure:
In 16.ml of concentrated sulfuric acid, 3.29 g (11.8 mmol) of ethyl 4-(2,4-difluorophenoxy)benzoate was dissolved at the temperature not higher than 5° C. To the resulting mixture, 520 pl of fuming nitric acid was added at -5° C. or lower under stirring, followed by stirring for 30 minutes at the same temperature. The reaction mixture was poured into ice water and the insoluble matter so precipitated was collected by filtration. The resulting compound was dissolved in chloroform. The resulting solution was washed successively with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (developing solvent: hexane:ethyl acetate=8:1) to give 2.42 g (63%) of ethyl 4-(2,4-difluoro-5-nitrophenoxy)benzoate.
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[OH:19]S(O)(=O)=O.N([O-])=O.[Na+]>O>[F:13][C:12]([F:15])([F:14])[C:11]([N:8]1[CH2:9][CH2:10][C:4]2[CH:3]=[C:2]([OH:19])[CH:18]=[CH:17][C:5]=2[CH2:6][CH2:7]1)=[O:16]
Reactant: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Into a 250 ml flask, the product of step (c) (2 g, 7.75 mmol) dissolved in water (8.5 ml) and concentrated H2SO4 (1.5 ml) was added. The stirred mixture was heated to 70° C., followed by the addition of a solution NaNO2 (615 mg, 8.91 mmol) in water (20 ml). The reaction mixture was stirred at 70° C. for 1 hour. The mixture was then allowed to cool to room temperature and diluted with water (50 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as a brown solid (1.8 g) that was used without further purification. MS: ESI (positive): 260 (M+H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([Br:10])[C:4]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br-].[Na+]>C(O)C>[CH2:12]([O:11][C:4]1[C:3]([Br:2])=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[Br:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1c(Br)cc(F)cc1Br
Reactant: BrCc1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Fc1cc(Br)c(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.21 g (96 mmol) of sodium is dissolved in 66 ml of ethanol with exclusion of moisture. 21.6 g (80 mmol) of 2,6-dibromo-4-fluorophenol is added to this solution. A suspension results. 20.5 g (120 mmol) of benzyl bromide is added to the suspension. It is stirred for 30 minutes at room temperature and then is refluxed for 1 hour. A sample of the suspension then reacts neutrally to moist reaction paper. The precipitate of the sodium bromide is suctioned off, the filtrate is evaporated to dryness and the residue is crystallized from ethanol. 23.7 g (66 mmol)=82.5% of the theoretical yield is obtained as a crystallizate. Melting point 83° C.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17].C(N(CC)CC)C>C(OCC)C>[OH:17][C:11]1[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=1[NH:9][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A solution of tert-butylacetyl chloride (2.7 g, 0.020 mol) in diethyl ether (20 ml) was added dropwise to a solution of 2-amino-4bromophenol (3.8 g, 0.020 mol) and triethylamine (2.1 g, 0.020 mol) in diethyl ether (160 ml) and the mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was evaporated in vacuo. Purification by flash column chromatography on silica gel, eluting initially with ethyl acetate:dichloromethane 1.5:98.5 and then with ethyl acetate:dichloromethane 2.5:97.5, gave N-(2-hydroxy-5-bromophenyl)-3,3-dimethylbutyramide (1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[H-].[Na+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:19](=[S:20])[N:18]([CH3:22])[CH3:17])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC(=S)N(C)C)ccc2o1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (2 g, 10 mmol) in 50 mL dry DMF was treated portionwise with NaH (252 mg of a 95% dispersion in mineral oil, 10 mmol). After 30 min, dimethylthiocarbamoyl chloride (1.9 g, 15 mmol) was added and the reaction stirred at 40° C. for 1.5 hours. The reaction mixture was then concentrated in vacuo, and the residue taken up in EtOAc. The organic layer was then washed 1×water, 1×brine, dried (Na2SO4) and the solvent removed in vacuo to give 3.5 g of the crude title compound. Recrystallization from CHCl3/hexanes, gave 1.3 g (45%) of the title compound. 400 MHz 1H NMR (DMSO-d6) δ 7.72 (s, 1H), 7.68 (d, 1H, J=9.8 Hz), 7.43 (s, 1H), 7.17 (d, 1H,J=9.8 Hz), 3.85 (s, 3H), 3.32 (s, 3H), 3.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)=[O:12].C(O)(=O)C>CCO.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[O:12])[CH:4]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(N)ccc2Cl)cc1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
A solution of ethyl (4-{[(2-chloro-5-nitrophenyl)carbonyl]amino}phenyl)acetate (2.27 g, 6.3 mmol) in EtOH (20 ml) was heated at 50° C. A 20% aqueous solution of acetic acid (10 ml) was added followed by iron (6 eq, 37.6 mmol, 2.1 g). The mixture was heated at 80° C. for 30 minutes. On cooling the mixture was filtered through celite washing with EtOH. Solvent evaporated in vacuo. Residue taken up in EtOAc and aqueous sodium bicarbonate. Layers separated, aqueous layer extracted with EtOAc (×2). Organic layers combined and washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography (Biotage SP4, 100 g silica column) eluting with 25-75% ethyl acetate in hexanes to afford the title compound as a light yellow oil (1.8 g). MS (ES+) m/z 333 [M+H]+ (C17H1735ClN2O3). 1H-NMR (400 MHz, d6-DMSO) δ 1.18 (3H, m), 3.61 (2H, s), 4.05 (2H, m), 5.47 (2H, s), 6.65 (2H, m), 7.12 (1H, d, J 8.4), 7.22 (2H, d, J 8.4), 7.64 (2H, m).
Reaction SMILES: C(N(CC(O)=O)CC(O)=O)[CH2:2][N:3](CC(O)=O)CC(O)=O.C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:33](O)[C@H:34]1O[C@H:38]([O:40][C@:41]2(CO)[O:45][C@H:44](CO)[C@@H:43](O)[C@@H:42]2O)[C@H:37](O)[C@@H:36](O)[C@@H:35]1O.CC[Hg]SC1C(C([O-])=O)=CC=CC=1.[Na+]>C(O)C(N)(CO)CO>[CH3:33][CH:34]([NH:3][CH3:2])[CH2:35][C:36]1[CH:42]=[CH:43][C:44]2[O:45][CH2:41][O:40][C:38]=2[CH:37]=1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: CC[Hg]Sc1ccccc1C(=O)[O-]
Agent: NC(CO)(CO)CO
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CNC(C)Cc1ccc2c(c1)OCO2
Reaction time: 2 h

Procedure:
The wells of an enhanced binding 96 well polystyrene microtiter plate were coated with the IgG fraction of the antiserum raised to Immunogen 7 (Example 8), diluted in 10 mM Tris, pH8.5 (125 μl/well). The appropriate antibody coating dilution was determined using standard ELISA chequerboard techniques. The plate was incubated for 2 hours at 37° C., washed 4 times with Tris buffered saline containing Tween 20 (TBST) and tapped dry. Standard solutions of MDMA were prepared in TBST at 0, 1, 10, 50, 100, 250, 500 and 1000 ng/ml and 25 μl of each was added to the appropriate wells (FIG. 2). Conjugates (detection reagents)-hapten 7-HRP (Example 9) and hapten 10-HRP (Example 12)—were diluted in Tris buffer, pH7.2, containing EDTA, D-mannitol, sucrose, thimerosal and BSA, appropriate dilutions being determined by standard ELISA chequerboard techniques, and 100 μl of each was added to the appropriate wells (FIG. 2). The plate was incubated at 37° C. for 2 hours. Excess unbound conjugate was removed by washing 6 times over a 10 minute period with TBST.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[CH2:15][CH2:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[CH2:15][CH2:14][N:13]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2=NCCc3ccc(Cl)cc32)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(C2=NCCc3ccc(Cl)cc32)ccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.4 %

Procedure:
3 g of 1-(3-methoxy4-nitrophenyl)-7chloro-3,4-dihydroisoquinoline (starting compound B1) are suspended in methanol, and 2.4 g of ammonium formate and 60 mg of palladium on charcoal (10%) are added to this suspension. The reaction mixture is stirred at RT for 5 h, filtered through Celite and concentrated. The residue is purified by flash chromatography on silica gel. It is stirred out of diethyl ether/n-hexane, filtered with suction and dried. 2.4 g of the title compound are obtained.
Reaction SMILES: NC1C=CC(B(O)O)=CC=1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O>C(N(CC)CC)C>[CH3:26][Si:25]([CH3:28])([CH3:27])[N:16]([Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[CH:13][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Nc1ccc(B(O)O)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Yield: 65 %

Procedure:
4-Aminophenylboronic acid by Grignard reaction on N,N-bis(trimethylsilyl)-4-bromoaniline 10.0 g (58.1 mmol) of 4-bromoaniline were dissolved in 200 ml of triethylamine and admixed with 25 ml (130 mmol) of trimethylsilyl trifluoromethanesulfonate. The mixture was heated to reflux for 8 h. The reaction mixture was concentrated and the crude product distilled under high vacuum. 11.9 g (37.8 mmol, 65%) of N,N-bis(trimethylsilyl)-4-bromoaniline were obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[OH-].[K+].[CH2:37]([OH:39])[CH3:38]>>[CH2:37]([O:39][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:18][CH2:19][CH2:20]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1)[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 0 °C
Yield: 42 %

Procedure:
A mixture of tert-butyl {1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.2 (0.050 g, 0.11 mmol) and potassium hydroxide (powder, 0.050 g, 0.89 mmol, 8.5 equiv) in ethanol (0.8 mL) was irradiated in a microwave apparatus at 120° C. for 120 min. The resulting mixture was added to ice water (10 mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (4×10 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; SNAP 10 g cartridge: 100% DCM 4.0 min., gradient to 95% DCM/5% MeOH 1 min., 95% DCM/5% MeOH 3.5 min., gradient to 90% DCM/10% MeOH 1 min., 90% DCM/10% MeOH 3.5 min., gradient to 80% DCM/20% MeOH 6 min., 80% DCM/20% MeOH 4.7 min.) to give 1-[4-(6-ethoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.017 g, 42%):
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[N:6]1([C:13]([C@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]2[C:21](=[O:23])[CH3:22])=[O:14])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>ClC(Cl)C>[CH:1]1([N:9]2[CH2:10][CH2:11][CH2:12][N:6]([C:13]([C@H:15]3[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]3[C:21](=[O:23])[CH3:22])=[O:14])[CH2:7][CH2:8]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1C[C@H](O)C[C@@H]1C(=O)N1CCCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(Cl)Cl
Product: CC(=O)N1C[C@H](O)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1
Reaction time: 14 h
Yield: 63.9 %

Procedure:
A solution of cyclobutanone (137 mL, 1.83 mol) and (2R,4R)1-[2-([1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidin-1-yl]-ethanone (358 g, 1.4 mol) in dichloroethane (3.7 L) was stirred for 1 h at rt. Sodium triacetoxyborohydride (422.4 g, 1.99 mol) was then added in 4 portions over 2 h. The mixture was stirred for 14 h and then NaOH(aq) (50 wt %, 210 mL) was added. The mixture was stirred for 2 h and then MgSO4 (264 g) was added. After an additional 1.5 h of stirring, the mixture was filtered and then concentrated. Purification by FCC (5% 2 M NH3 in MeOH/95% CH2Cl2) provided the title compound as an oil (277 g, 64%). MS (ESI): mass calcd. for C16H27N3O3, 309.2; m/z found, 310.2 [M+H]+. 1H NMR (CDCl3): 6.11-6.04 (m, 1H), 4.93-4.70 (m, 1H), 4.46-4.34 (m, 1H), 3.96-3.44 (m, 6H), 2.96-2.83 (m, 1H), 2.76-2.37 (m, 4H), 2.30-2.20 (m 1H), 2.10-1.55 (m, 12H).