Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(N(C(C)C)C(C)C)C>[C:16]([O:18][CH2:19][CH2:20][NH:11][C:10]1[CH:12]=[CH:13][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][CH:9]=1)(=[O:17])[CH3:15]
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCNc1ccc(-c2noc(C)n2)cc1

Procedure:
Prepared analogously to Example 1k from 4-(5-methyl-1,2,4-oxadiazol-3-yl)-aniline and ethyl bromoacetate in N-ethyl-diisopropylamine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([C:29]3[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][N:37]4[C:42]5[CH:43]=[CH:44][C:45]([CH2:47][O:48][Si](C(C)(C)C)(C)C)=[CH:46][C:41]=5[CH2:40][N:39]([CH:56]([CH3:58])[CH3:57])[S:38]4(=[O:60])=[O:59])[CH2:33][CH:34]=3)=[CH:25][NH:26]2)=[CH:22][CH:21]=1>C1COCC1>[F:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([C:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]4[C:42]5[CH:43]=[CH:44][C:45]([CH2:47][OH:48])=[CH:46][C:41]=5[CH2:40][N:39]([CH:56]([CH3:57])[CH3:58])[S:38]4(=[O:59])=[O:60])[CH2:31][CH:30]=3)=[CH:25][NH:26]2)=[CH:22][CH:21]=1
Reactant: CC(C)N1Cc2cc(CO[Si](C)(C)C(C)(C)C)ccc2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)N1Cc2cc(CO)ccc2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (2 ml, 0.002 mol, 1M in THF) was added to a suspension of 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-6-t-butyldimethylsiloxymethyl-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (1.1 g, 0.0018 mol) in THF (18 ml) under argon then stirred at room temperature for 2 h, evaporated to dryness and purified by flash chromatography using dichlormethane/methanol (97:3) as eluent, to give 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3,4-dihydro-6-hydroxymethyl-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as a pale yellow solid. Mp: 113-115° C. 1H-NMR (CDCl3, 300 Mz), δ: 8.09 (NH, s), 7.76 (1H, dd), 7.22 (1H, d), 7.11 (1H, d), 7.08 (1H, s), 7.01 (1H, dd), 6.98 (1H, d), 6.88 (1H, dt), 6.13 (1H, t), 3.29 (2H, s), 2.85-2.81 (4H, m), 2.58 (2H, s), 1.11 (6H, d).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:16][CH:17]2[C:42](=[O:43])[N:19]3[C:20]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=4)=[O:30])=[C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:22][S:23][C@H:18]23)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl.[NH2:54][C:55]1[S:59][N:58]=[C:57]([C:60](=[N:64][O:65][CH2:66][CH3:67])[C:61](Cl)=[O:62])[N:56]=1>C(Cl)Cl.O.N1C=CC=CC=1.CO>[NH2:54][C:55]1[S:59][N:58]=[C:57]([C:60](=[N:64][O:65][CH2:66][CH3:67])[C:61]([NH:16][CH:17]2[C:42](=[O:43])[N:19]3[C:20]([C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=4)=[O:30])=[C:21]([O:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:22][S:23][C@H:18]23)=[O:62])[N:56]=1
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Reactant: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OS(C)(=O)=O)CS[C@H]12)c1nsc(N)n1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of phosphorus pentachloride (57 g) in methylene chloride (1 () was added pyridine (22 ml) at -20° C. and the mixture was stirred for 30 minutes at -20° C. p-Nitrobenzyl 7-(2-phenylacetamido)-3-mesyloxy-3-cephem-4-carboxylate (50 g) was added to the solution at 5° C. and stirred at the same temperature for 1 hour. Methanol (56 ml) was added to the solution at -30° C. and stirred at -15° C. for 30 minutes. To the solution were added pyridine (80 ml) and diisopropylethylamine (31.4 ml) at -30° C. 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride hydrochloride (syn isomer) (26.7 g) was added to the solution at -30° C. by portions and stirred at -15° C. for 1 hour Water (1 l) was added to the solution and stirred for 30 minutes. A resultant precipitate was collected by filtration and washed with diisopropyl ether and air-dried to give p-nitrobenzyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-mesyloxy-3-cephem-4-carboxylate (syn isomer) (40 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][NH:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][N:48]1[C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:10]([N:7]1[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]1)=[O:11])=[CH:20][CH:19]=2)=[O:23]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCc5ccccc5C4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3,4-Dihydro-1H-isoquinoline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:14][C:15]1[CH:32]=[C:31]([C:33]2[C:42]3[C:43]4[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=4[S:45][C:41]=3[C:40]([Br:50])=[C:39]3[C:34]=2[CH:35]=[CH:36][CH:37]=[CH:38]3)[CH:30]=[C:29]([Br:51])[C:16]=1[O:17][C@H:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([NH2:21])=O.N1C=CC=CC=1.O1CCOCC1>CCOCC>[Br:14][C:15]1[CH:32]=[C:31]([C:33]2[C:42]3[C:43]4[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=4[S:45][C:41]=3[C:40]([Br:50])=[C:39]3[C:34]=2[CH:35]=[CH:36][CH:37]=[CH:38]3)[CH:30]=[C:29]([Br:51])[C:16]=1[O:17][C@H:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:19]#[N:21]
Reactant: NC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#C[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 105 °C
Yield: 84.1 %

Procedure:
Trifluoroacetic anhydride (0.375, 2.65 mmol) was added to a stirred, room temperature suspension of (R)-2- [2,6-dibromo-4-(6-bromo-benzo[b]naphtho [2,3-d ]thiophen-11-yl)-phenoxy]-3-phenyl-propionamide (1.68 g, 2.37 mmol), pyridine (0.393 mL, 4.74 mmol) and dioxane (5.4 mL). Dissolution occurred and the solution was heated in a 105° C. oil bath for 2 h. The reaction mixture was cooled to room temperature, diluted with ether, washed with 5% HCl and brine. Silica gel was added to the ether phase and the solvent was removed. The adsorbate was flash chromatographed (ether as eluent) to provide the title compound as a white solid (1.38 g, 84%): mp 160-165° C.: NMR (DMSO-d6): δ8.29 (d, J=8 Hz, 1 H), 8.07 (d, J=8 Hz, 1 H), 7.93 (d, J=2 Hz, 1 H), 7.91 (d, J=2 Hz, 1 H), 7.80 (ddd, 8, 7, 1 Hz, 1 H), 7.65-7.33 (m, 8 H), 7.23 (ddd, 8, 7, 1 Hz, 1 H), 6.65 (d, J=8 Hz, 1 H), 5.87 (t, J=7 Hz, 1 H), 3.58 (m, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 689 (30%), 691 (95%) 693 (100%) 695 (40%); Anal. Calc. for C31H18Br3NOS: C, 53.74, H, 2.62, N, 2.02. Found: C, 53.60, H, 2.60, N, 1.83.
Reaction SMILES: [F:1][C:2]([F:22])([C:18]([F:21])([F:20])[F:19])[C:3]([F:17])([F:16])[C:4]([F:15])([F:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O.[BrH:23].S(=O)(=O)(O)O>O>[Br:23][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:15])([F:14])[C:3]([F:17])([F:16])[C:2]([F:22])([F:1])[C:18]([F:21])([F:20])[F:19]
Reactant: OCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 15.22 g of 8-(nonafluorobutyl)-1-octanol and 200 mL of 48 weight percent hydrobromic acid was slowly added 20 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 18 hr and poured into 800 mL of water. The mixture was extracted with 2×200 mL portions of hexanes, and the combined organic phases were washed with 2×200 mL portions of saturated aqueous sodium bicarbonate, 2 ×200 mL portions of 3 formal aqueous sodium thiosulfate, and one 100 mL portion of brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated to a dark liquid, which was eluted through 2 inches (5 cm) of silica with 500 mL of hexanes. Concentration of the eluent yielded a clear, light yellow liquid, and bulb-to-bulb distillation gave 9.14 g of 1-bromo-8-(nonafluorobutyl)octane as a clear, light yellow liquid, b.p. 105-110° C. at 0.05 torr (7 Pa).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:19][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ti]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([O:5][CH:1]([CH3:3])[CH3:2])[CH:10]1[OH:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12
Agent: [Ti]
Solvent: CO
Product: CC(C)OC1c2ccccc2CC(NC(=O)OC(C)(C)C)C1O
Temperature: 96 °C
Yield: 94.9 %

Procedure:
Under argon to a solution of (±)-(1S,2R,3R)-3-tertbutoxycarbonylamino -1,2-epoxy-1,2,3,4-tetrahydro- naphthalene (96 mg) in methanol (4 ml) was added titanium isopropoxyde (0.19 ml). The mixture was warmed for 14 hours in an oil bath maintained at 96° C. Evaporation of the warm mixture under an argon flow gave a residue which was purified on a silica gel column (22 g, elution with ethyl acetate:cyclohexane, 1:4). After evaporation of solvents was recovered an oil which was crystallized from a pentane/diethyl ether mixture to afford the title compound as a white solid (56 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:40][N:41]1[CH:45]=[CH:44][C:43]([C:46]([OH:54])([C:48]#[C:49][Si](C)(C)C)[CH3:47])=[N:42]1>C1COCC1.C(=O)(O)[O-].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:49]#[C:48][C:46]([C:43]4[CH:44]=[CH:45][N:41]([CH3:40])[N:42]=4)([OH:54])[CH3:47])[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Reactant: Cn1ccc(C(C)(O)C#C[Si](C)(C)C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cn1ccc(C(C)(O)C#Cc2ccc3c(C(C)(C)O)nn(-c4ccnc(N)n4)c3c2)n1
Temperature: 50 °C

Procedure:
To a solution of 2-[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol (135 mg, 0.31 mmol) in dry THF (4 mL) under an atmosphere of nitrogen was introduced bis(triphenylphosphine)palladium(II) chloride (21.6 mg, 0.03 mmol), TBAF (0.37 mL of a 1M solution in THF, 0.37 mmol) and 2-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylsilyl)but-3-yn-2-ol (137 mg, 0.62 mmol). The reaction mixture was warmed to 50° C. for 1.5 hr. After cooling to RT, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (4 ml) and extracted with EtOAc (2×10 mL extractions). The combined extracts were washed with water (5×5 mL), brine (5 mL), dried (Na2SO4) and filtered. After concentration of the filtrate in vacuo, the residue was purified by silica gel flash column chromatography (DCM containing a 1-10% methanol gradient) to furnish the title compound as an off-white solid: 1H NMR (DMSO, 500 MHz) delta 1.63 (6H, s), 1.83 (3H, s), 3.82 (3H, s), 5.57 (1H, s), 6.02 (1H, s), 6.36 (1H, d, J=2.1 Hz), 6.99 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.31 (1H, d, J=8.4 Hz), 7.61 (1H, d, J=2.0 Hz), 8.11 (1H, d, J=8.3 Hz), 8.27 (1H, d, J=5.5 Hz), 8.84 (1H, s); LC-MS: m/z=+418.10 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.[C:24]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)(=[O:26])[CH3:25].[OH-].[Na+]>ClC(Cl)C.C(OCC)(=O)C.C(O)(=O)C>[C:24]([N:27]1[CH2:32][CH2:31][CH:30]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: COc1cccc(N)c1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc(NC2CCN(C(C)=O)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Under ice cooling, sodium triacetoxyborohydride (12.0 g) was added to a liquid mixture of m-anisidine (4.40 g), 1-acetylpiperidin-4-one (5.0 g) and acetic acid (8 ml) in dichloroethane (80 ml). Then the reaction mixtures were stirred at room temperature overnight. The reaction mixtures were diluted with ethyl acetate (200 ml) and a 5 N aqueous solution (35 ml) of sodium hydroxide was added thereto. The organic layer was separated, washed successively with water and brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound (7.80 g) as a brown oil (yield: 87.9%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH2:13](I)[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([N:6]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:14]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ncc([N+](=O)[O-])c1C(=O)OC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate (5.0 g), EtI (2.8 mL) and K2CO3 (8.1 g) in acetone (50 mL) was stirred at 50° C. for 4 h. After stirring at room temperature overnight, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (2.2 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@:6]([O:18][CH3:19])([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([C:20]2([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=3)[S:24][CH2:23][N:22]=[N:21]2)[CH2:3]1.[CH3:32]N1[C@H]2[C@@](OC)(C3C=CC=C4C=3C(C2)=CN4)C[C@@](C2N=C(C3C=NC=C(Br)C=3)ON=2)(C)C1>>[CH3:32][N:12]1[C:11]2[C:17]3[C:14]([CH2:15][C@@H:16]4[C@@:6]([O:18][CH3:19])([C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:20]2([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=3)[S:24][CH2:23][N:22]=[N:21]2)[CH2:3][N:2]4[CH3:1])=[CH:13]1
Reactant: CO[C@]12C[C@@H](C3(c4cncc(Br)c4)N=NCS3)CN(C)[C@@H]1Cc1c[nH]c3cccc2c13
Reactant: CO[C@]12C[C@](C)(c3noc(-c4cncc(Br)c4)n3)CN(C)[C@@H]1Cc1c[nH]c3cccc2c13
Product: CO[C@]12C[C@@H](C3(c4cncc(Br)c4)N=NCS3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Yield: 35 %

Procedure:
Operating as in Example 2, but employing 6-methyl-8β-[5-(5-bromo-pyridin-3-yl)-1,3,4-thiadiazol-5-yl]-10α-methoxy-ergoline instead 6-methyl-8β-methy-[5-(5-bromo-pyridin-3-yl)-1,2,4-oxadiazol-3-yl]-10α-methoxy-ergoline, the title compound was obtained in 35% yield, m.p.131-137° C.
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCC2CCCCC2)CC1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(Cc2ccccc2)CC2CCCCC2)CC1
Yield: 52.2 %

Procedure:
4-Amino-5-chloro-N-((1-(5-(cyclohexylmethylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide (0.79 g) as starting compound, benzaldehyde (0.19 g) and sodium cyanoborohydride (0.23 g) were reacted and treated in the same manner as in Example 136 to give 0.49 g of 4-amino-N-((1-(5-(N-benzyl-N-(cyclohexylmethyl)amino)pentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CCN1CCNCC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CCN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 45 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-ethylpiperazine to give the title compound in 45% yield; NMR Spectrum: 0.95 (t, 3H), 2.25 (q, 2H), 2.32 (br s, 4H), 2.50 (hidden under DMSO, 4H), 2.78 (t, 2H), 4.41 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.48 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)O)C=CC=CC=1.C(O)(=O)CC(O)=O.[C:28]1([C:34]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:35][C:36]([Cl:38])=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:51]1([C:57]2([C:63]([O:65]CC)=O)[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(O)C.C1C=CC=CC=1.CCOCC.Cl.CC(C)=O.C(N(CC)CC)C>[ClH:38].[C:28]1([C:34]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:35][CH2:36][N:60]2[CH2:59][CH2:58][C:57]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([CH2:63][OH:65])[CH2:62][CH2:61]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(O)CC(=O)O
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCOCC
Solvent: c1ccccc1
Product: OCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 2 parts of triphenylcarbinol and 8 parts of malonic acid are heated at 170° for 31 hours. This mixture is cooled and then dissolved in hot ethanol. 3,3,3-Triphenylpropionic acid, melting at 182°, crystallizes from the ethanol upon cooling. 1 Part of 3,3,3-triphenylpropionic acid is then refluxed with 5 parts of thionyl chloride for 4 hours and the excess thionyl chloride is removed in vacuum to provide the crude 3,3,3-triphenylpropionyl chloride. 9 Parts of this 3,3,3-triphenylpropionyl chloride are then reacted with 27.0 parts of ethyl 4-phenyl-4-piperidinecarboxylate in the presence of 4 parts of triethylamine in benzene. The resulting amide is reduced with 5 parts of lithium aluminum hydride in ether at reflux for 2.5 hours. The reaction mixture is cooled and treated with 15% aqueous sodium hydroxide solution to decompose any unreacted lithium aluminum hydride. The reaction mixture is then filtered and washed with ether. The ether solution is evaporated to give an oil. This oil is then slurried in 10% HCl and extracted with ether. The aqueous phase which contains an insoluble oil is extracted with methylene chloride, and the methylene chloride extract dried over anhydrous sodium sulfate. Evaporation of this methylene chloride solution gives a solid which is taken up in acetone and precipitated with ether to give 1-(3,3,3-triphenylpropyl)-4-(phenyl)-4-piperidinemethanol hydrochloride, melting at about 256°-259° C.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.[OH-].[Na+].[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].O.O.C(O)(=O)C(O)=O>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[ClH:1].[CH3:21][O:20][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][C:15]=1[O:18][CH3:19])[CH:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[CH:33]=3)=[CH:4][CH:5]=1)[NH:9][CH2:10][CH2:11]2
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Br)cc1)NCC2
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1cccc(-c2ccc(CC3NCCc4cc(OC)c(OC)cc43)cc2)c1
Temperature: 25 °C

Procedure:
6,7-dimethoxy-1-(3′-methoxy-biphenyl-4-ylmethyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride (35) was prepared as follows: 1-(4-bromo-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride (0.403 g, 1.01 mmol) was added to a mixture of 20 mL CH2Cl2 and 20 ml of 1N NaOH. The reaction mixture was stirred at room temperature. After dissolving of precipitate, the organic phase was separated, dried over Na2SO4, filtered, and evaporated. A residue was dissolved in 5 mL i-PrOH and 3-methoxy-phenyl-boronic acid (0.170 g, 1.12 mmol) was added. The resulting solution was stirred for 30 min at room temperature. Pd(OAc)2 (3 mg, 0.0134 mmol), PPh3 (8 mg, 0.0305 mmol) and 2N Na2CO3 (0.7 mL, 1.4 mmol) were added, the reaction mixture was refluxed for 6 h under Ar and evaporated. A residue was dissolved in chloroform and washed with 1N NaOH. The organic phase was dried under Na2SO4, filtered, and evaporated. A residue was dissolved in MeOH, and a solution of oxalic acid dihydrate (0.264 g, 2.08 mmol) was added under reflux. Oxalic acid salt was crystallized from McOH-Et2O mixture. Oxalic acid salt was added to a mixture of 20 mL CH2Cl2 and 20 ml of 1N NaOH. The reaction mixture was stirred at room temperature. After dissolving of precipitate, the organic phase was separated, dried over Na2SO4, filtered, and evaporated. A residue was dissolved in MeOH and 5 mL of 1M solution of IICl in Et2O was added. Hydrochloride was crystallized from the MeOH-Et2O mixture. Yield is 0.245 g (56.9%).
Reaction SMILES: [CH:1]([C:12]([O:14]CC)=O)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:12]([CH:1]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: NCc1ccc(Cl)cc1
Product: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Yield: 30.5 %

Procedure:
Triethyl methanetricarboxylate (2.32 g) and 4-chlorobenzylamine (1.42 g) are stirred at room temperature for 16 h. Insoluble material is filtered off and the filtrate is purified by column chromatography (hexanes/acetone, 5/1) to give 1 g (12%) of the title compound as an oil which slowly solidifies. Physical characteristics: MS (ESI+) m/z 330 (M+H)+. 1H NMR (CDCl3) δ 7.70, 7.31, 7.26, 4.48,4.38, 4.28, 1.30.