Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[H-].[Na+].C(OC([C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:23][N:22]4[CH2:32][CH2:33][CH2:34][C:21]=34)[CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)=O)C>CN(C=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:31][C:27]1[N:26]=[C:25]([C:24]2[C:20]([C:17]3[CH:18]=[CH:19][C:14]4[N:15]([C:11]([C:1]([NH2:3])=[O:2])=[CH:12][N:13]=4)[CH:16]=3)=[C:21]3[CH2:34][CH2:33][CH2:32][N:22]3[N:23]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc2ccc(-c3c(-c4cccc(C)n4)nn4c3CCC4)cn12
Reactant: NC=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(C(N)=O)n4c2)CCC3)n1
Temperature: 155 °C
Yield: 99 %

Procedure:
Add formamide (36 mL) to a suspension of sodium hydride (2.04 g, 60% dispersion in mineral oil, 51.1 mmol) and 6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (3.6 g, 9.29 mmol) in DMF (15 mL) over 10 min. Heat at 155° C. for 40 min, cool, dilute with ethyl acetate, and carefully dilute with saturated aqueous sodium bicarbonate. Filter any un-dissolved solid and wash with ethyl acetate. Concentrate the remaining organic layer and adsorb onto a 1:1 mixture of SiO2 and Celite®. Flash chromatography using ethyl acetate methanol mixtures followed by trituration of the combined lots in diethyl ether gives the titled compound (3.32 g, 99%) as a white solid. TOF MS ES+ exact mass calculated for C10H9IN2O2 (p+1): m/z=359.1620 Found: 359.1617.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:30]=[CH:31][N:32]=3)[N:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:30]=[CH:31][N:32]=3)[N:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Temperature: 40 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a solution of methyl 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (220 mg, 0.51 mmol) in dioxane (10 mL) and water (9 mL) was added NaOH (200 mg, 5 mmol), then the mixture was heated to 40° C. with stirring for 4 h. The solution was concentrated to approximately 10 mL in vacuo and washed with dichloromethane (10 mL×3). Water (10 mL) was added and the solution was adjusted to pH=4 by the addition of concentrated HCl. The solid formed was filtered to give 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.185 g, 87%) as a light yellow solid. 1H NMR (300 MHz, DMSO): δ 9.72 (s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 8.09-8.02 (m, 3H), 7.69 (s, 1H), 7.44 (t, 1H, J=7.5 Hz), 6.73 (d, 1H, J=7.5 Hz), 6.08 (d, 1H, J=8.4 Hz), 4.23-4.20 (m, 1H), 3.58-3.56 (m, 2H), 2.08-1.97 (m, 3H), 1.68 (s, 1H), 1.12 (d, 1H, J=6.3 Hz). LC-MS: [M+H]+, 415, tR=1.652 min, HPLC: 98.19% at 214 nm, 97.87% at 254 nm, tR=5.967 min.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:12]3=[N:13][O:14][N:15]=[C:11]3[CH:10]=2)O1.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH:25]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:24][CH2:23]2.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:13]1[O:14][N:15]=[C:11]2[CH:10]=[C:9]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[CH:25]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:24][CH2:23]4)[CH:17]=[CH:16][C:12]=12
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCc2cc(Oc3ccc4nonc4c3)ccc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (0.313 mmol, 77 mg), N-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (0.157 mmol, 40 mg), copper (II)acetate (0.157 mmol, 28.5 mg), triethylamine (0.783 mmol, 0.110 mL, 79 mg) and 4A molecular sieves (100 mg) in DCM (1 mL) was stirred at room temperature for 60 h. The reaction mixture was filtered through dicalite and the pad washed with MeOH before the filtrate was concentrated to dryness. The residue was purified by prep HPLC to give a brown film (32. mg, 5.5%). MS (ESI): m/z [M+H]+ 374.0
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8]2[C:10]3[CH:11]4[CH2:21][CH2:20][CH:14]([C:15]=3[C:16]([O:18][CH3:19])=[CH:17][C:7]=2[CH2:6]1)[CH2:13][CH2:12]4)=[N+]=[N-]>[Pd]>[CH3:19][O:18][C:16]1[C:15]2[CH:14]3[CH2:20][CH2:21][CH:11]([CH2:12][CH2:13]3)[C:10]=2[C:8]2[O:9][CH:5]([CH2:4][NH2:1])[CH2:6][C:7]=2[CH:17]=1
Reactant: COc1cc2c(c3c1C1CCC3CC1)OC(CN=[N+]=[N-])C2
Agent: [Pd]
Product: COc1cc2c(c3c1C1CCC3CC1)OC(CN)C2
Yield: 74 %

Procedure:
Treatment of (±)-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methyl 4-methylbenzenesulfonate (5.45 g, 13.1 mmol) with sodium azide (3.419 g, 52.6 mmol) generally according to the procedure described for Intermediate 24 gave (±)-2-(azidomethyl)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.350 g) generally according to the procedure described for Example 2 gave 2.88 g (74%) of (±)-1-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>210° C.; Anal. calcd. for C16H21NO2HCl: C, 64.97; H, 7.5; N, 4.74. Found: C, 64.71; H, 7.69; N, 4.54.
Reaction SMILES: [C:1]1([C:7]2([OH:26])[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=4)[C:15]3=[O:25])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:33](Cl)(=[O:35])[CH3:34]>C1C=CC=CC=1>[C:1]1([C:7]2([OH:26])[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:33](=[O:35])[CH3:34])[CH:20]=4)[C:15]3=[O:25])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC(CN1CCC(O)(c3ccccc3)CC1)C2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc2c(c1)CCC(CN1CCC(O)(c3ccccc3)CC1)C2=O

Procedure:
3.5 g. of 2-(4-phenyl-4-hydroxypiperidinomethyl)-6-amino-1-tetralone are dissolved in 100 ml. of benzene. 5.3 g. of sodium carbonate are added and the mixture is cooled to 10° while a solution of 0.75 g. of acetyl chloride in 50 ml. of benzene is added dropwise at 10° with stirring. The mixture is stirred for 30 minutes. 5.3 g. more of sodium carbonate are added and the mixture is stirred for 3 hours more at 20°. It is then heated under reflux for 10 minutes, filtered and worked up in the customary manner. 2-(4-Phenyl-4-hydroxypiperidinomethyl)-6-acetamido-1-tetralone is obtained.
Reaction SMILES: [F:1][CH2:2][C:3]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])([CH2:8][C:9](Cl)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[N+:23](=[CH2:25])=[N-:24]>CCOCC>[F:1][CH2:2][C:3]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])([CH2:8][C:9](=[O:10])[CH:25]=[N+:23]=[N-:24])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)C(CF)(CC(=O)Cl)N1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Product: COC(=O)C(CF)(CC(=O)C=[N+]=[N-])N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-fluoromethyl-2-phthalimido-3-chlorocarbonyl-propionate (2.07 g, 6.33 mmol) in dry ether (24 ml) is slowly added with stirring to a cooled (ice) solution of diazomethane in ether (0.392 mol, 50 ml). After 30 minutes, the solvent is evaporated to give a yellow oil (2.1 g). This is purified by flash chromatography on silica gel (200 g, ethyl acetate/petroleum ether 4:6) to give the pure title compound as a yellow oil (1.7 g);
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([CH2:14][C:15]([NH2:17])=[O:16])[CH:13]=2)[CH2:4][CH2:3]1.C[O:22][C:23](=O)[C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([C:24]2[C:23](=[O:22])[NH:17][C:15](=[O:16])[C:14]=2[C:12]2[CH:13]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[N+:18]([O-:20])=[O:19])=[CH:27]1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(CC(N)=O)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[5-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]-acetamide (278 mg, 1.00 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (366 mg, 1.80 mmol) in dry THF (8.0 mL) is added a solution of 1.0 M t-BuOK in THF (4.0 mL, 4.0 mmol) at 0° C. under argon. After stirring for 30 min at 0° C. and 1 h at RT, TLC indicates the complete consumption of the acetamide. The purple reaction mixture is partitioned between EtOAc (50 mL) and brine (50 mL), the layers are separated, and the aqueous layer is extracted with EtOAc (50 mL). The combined organic layers are dried over Na2SO4 and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc/AcOH/H2O 7:1:1) to afford the title compound as its water soluble acetate salt. Orange solid. 1H NMR (DMSO-de, 400 MHz): δ 1.84 (s, 6H, CH3COO−), 1.97-2.15 (m, 4H), 2.03 (s, 3H), 2.95-3.21° (m, 4H), 6.51 (d, J=7.8 Hz, 1H), 6.54 (d, J=2.7 Hz, 1H), 6.73 (t, J=7.8 Hz, 1H), 7.01-7.07 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 8.00 (s, 1H), 8.13 (d, J=9.4 Hz, 1H), 10.8-11.4 (br, 1H), 11.95 (bs, 1H). ES+-MS: 431 [M+H]+.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([NH2:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1)#[N:2].[CH2:24]([SH:28])[CH2:25][CH2:26][CH3:27]>COCCOCCOC>[NH2:19][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=2)[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([C:1]([S:28][CH2:24][CH2:25][CH2:26][CH3:27])=[NH:2])[CH2:4][CH2:5]2)[N:18]=1
Reactant: CCCCS
Reactant: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC
Solvent: COCCOCCOC
Product: CCCCSC(=N)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 6.3 g. (0.02 mole) of 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline in 75 ml. of diethyleneglycol dimethyl ether is added dropwise over 15 minutes a solution of 1.8 g. (0.02 mole) n-butyl mercaptan in 25 ml. of the same solvent. The resulting mixture is stirred at 20°-25° C. for 2 hours, then the solvent is removed in vacuo. The residue is triturated with ethyl ether, filtered and dried to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.CCN(CC)CC>C(Cl)Cl>[CH:33]1([C:36]([N:1]2[CH2:2][CH:3]([CH2:5][C:6]3[N:7]([CH3:32])[C:8]4[C:13]([N:14]=3)=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=[C:10]([N:21]3[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]3[CH2:30][CH3:31])[N:9]=4)[CH2:4]2)=[O:37])[CH2:35][CH2:34]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C4CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (108 mg, 0.25 mmol), cyclopropane carbonyl chloride (27 mg, 0.25 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (1 mL) was allowed to stir at r.t. for 2 h then concentrated in vacuo. The resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) followed by triturating with Et2O affording 825 as a white solid (107 mg, 85%). LCMS (method I): RT 3.33 min, [M+H]+ 501.2. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.98 (1 H, m), 7.76-7.73 (1 H, m), 7.32-7.22 (2 H, m), 4.53 (1 H, t, J=8.31 Hz), 4.45-4.20 (4 H, brd s), 4.28 (1 H, t, J=9.30 Hz), 4.09 (1 H, dd, J=8.45, 5.41 Hz), 3.86 (5 H, t, J=4.77 Hz), 3.77 (3 H, s), 3.34-3.33 (3 H, m), 3.18-3.15 (2 H, m), 1.45-1.43 (4 H, m), 0.99-0.98 (2 H, m), 0.77-0.76 (2 H, m)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.[CH3:17][C:18]1[N:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>ClCCl>[CH:13]1([N:10]2[CH2:11][CH2:12][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:24]([C:21]4[CH:22]=[N:23][C:18]([CH3:17])=[CH:19][CH:20]=4)=[O:25])[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:14][CH2:15][CH2:16]1
Reactant: O=C(C1CNC1)N1CCN(C2CCC2)CC1
Reactant: Cc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCN(C4CCC4)CC3)C2)cn1
Yield: 19.3 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutylpiperazine (60 mg, 0.27 mmol) in dichloromethane (1 mL) at 0° C., was added 6-methylpyridine-3-carbonyl chloride (31 mg, 0.32 mmol) and DIPEA (142 μL, 0.81 mmol). After 4 hours the reaction was quenched by addition of saturated aq. NaHCO3 (1 mL) and the aqueous extracted with dichloromethane (2×5 mL), dried (MgSO4), filtered, and concentrated at reduced pressure. Purification by silica FCC (eluting with 90:9:1 Et2O/MeOH/NH3) followed by capture and release on an SCX-2 cartridge (washing with MeOH and releasing with 7M NH3 in MeOH) gave the title compound (17.8 mg, 19%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH3:24])[CH:10]=1.[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:33].[ClH:33].[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:10]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Temperature: 25 °C

Procedure:
To (5-{2-[(N-tert-butoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester (0.742 g, 1.6 mmol) in CH2Cl2 (3 mL) was added 4N HCl in 1,4-dioxane (4 mL), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was then concentrated to give [5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dihydrochloride.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[O:9].[CH2:18]([O:20][C:21](=[O:27])[C:22](OCC)=[O:23])[CH3:19].Cl>C1C=CC=CC=1>[Cl:17][C:12]1[CH:11]=[C:10]([C:8](=[O:9])[CH2:7][C:22](=[O:23])[C:21]([O:20][CH2:18][CH3:19])=[O:27])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of t-BuOK (0.05 mol, 5.6 g) in benzene (200 mL) was added dropwise a benzene (50 mL) solution of 3,4-dichloroacetophenone 5.1 (0.05 mol, 9.45 g) and diethyloxalate (0.055 mol, 8.1 g). The resultant mixture was stirred for 8 h at room temperature, then 10% aqueous HCl solution (100 mL) was added to the mixture. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography using dichloromethane as eluent to yield the title compound. Yield: 7.5 g (52%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O>O1CCCC1.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[NH2:17]
Reactant: Cc1cc(OCCc2ccccn2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(OCCc2ccccn2)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 2-methyl-4-[2-(2-pyridinyl)ethoxy]-1-nitrobenzene (2.0 g, 7.7 mmol) was dissolved in tetrahydrofuran (40 mL) and 10% palladium on carbon (0.20 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 2-methyl-4-[2-(2-pyridinyl)ethoxy]aniline as solid (1.4 g, y. 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C/C(=C\c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C(=C\c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
tert-Butyl (2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methylprop-2-enoate (59) (0.0702 g, 0.173 mmole) was dissolved in CH2Cl2 (1 mL) and TFA (1 mL). The solution was stirred at RT for 4 h, then was concentrated. The residue was triturated with CH2Cl2 to provide compound 60 (0.029 g, 47%) as a tan solid. 1H NMR (DMSO-d6): δ 12.49 (br s, 1H), 9.38 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 3.60 (m, 4H), 2.25 (m, 4H), 2.01 (s, 3H). LRMS (ESI): m/z 349 (M−H)−.
Reaction SMILES: [C:1](F)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[CH:12]([NH:19][CH3:20])[CH2:13][N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:18][CH:16]1[CH2:15][N:14]([CH2:13][CH:12]([NH:19][CH3:20])[C:11]([F:10])([F:21])[F:22])[CH2:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(CN1CC(O)C1)C(F)(F)F
Reactant: O=C(F)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(CN1CC(OC(=O)c2ccccc2)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 44.3 %

Procedure:
A solution of benzoyl fluoride (1.37 mL, 12.6 mmol) in DCM (5 mL) was added dropwise under argon to an ice cooled solution of 1-(3,3,3-trifluoro-2-(methylamino)propyl)azetidin-3-ol (Compound C3.1) (2.28 g, 11.5 mmol) and TEA (3.21 mL, 23 mmol) in DCM (45 mL). The stirring was continued at rt for 2.5 h. NaHCO3 (saturated, 20 mL) was added and the mixture was stirred vigorously for 40 min. The layers were separated, the aqueous layer was extracted with DCM, and the combined organic layers were washed with NaHCO3 (saturated), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC. After concentrating the fractions to approximately 30 mL the aqueous emulsion was extracted DCM (×2). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title product (1.54 g, 44%.) as a colourless oil. 1H NMR (500 MHz, DMSO-d6) δ 7.97 (2H), 7.67 (1H), 7.53 (2H), 5.16 (1H), 3.7-3.79 (2H), 3.25 (1H), 3.18 (1H), 2.92-3.02 (1H), 2.66 (1H), 2.59 (1H), 2.38 (3H), 1.99-2.06 (1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2].Br[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17])[CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2[nH]cnc2n(CC)c1=O
Reactant: C=CCCCBr
Product: C=CCCCn1cnc2c1c(=O)n(CC)c(=O)n2CC

Procedure:
is prepared analogously to Example 12 from 1,3-diethyl-xanthine and 5-bromopent-1-ene; the yield relative to the starting material used is 84%.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH:21]([OH:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a solution of 1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone (IV-1) (14.90 g, 0.043 mol) in THF (300 mL) at 0° C. were added portion wise LiAlH4 (2.05 g, 0.051 mol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (RS)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (V-B-1) 4.69 g (31%) as a white solid ES-MS m/e: 350.2 (M+H+) and (SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (V-A-1) 5.30 g (35%) as a white solid ES-MS m/e: 350.2 (M+H+).