Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([OH:23])[C:4]=1[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27].[H-].[Na+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([O:23][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:4]=1[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CCC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(CC=C(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Then, 30 ml of dimethylformamide was added to 5.2 g of 1-[4,6-dimethoxy-2-hydroxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxyphenyl)-1-propanone and 335 mg of sodium hydride, and the mixture was stirred at 0° C. for 1 hour. Then, 2.2 g of methyl α-bromoacetate was added to the mixture, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours to effect reaction. After the reaction, the reaction mixture was extracted with ethyl acetate and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chrometography [230-400 mesh silica gel; eluting solvent=n-hexane/ethyl acetate (4/1)]. to obtain 5.6 g (yield=91.0%) of 1-[4,6-dimethoxy-2-methoxycarbonylmethoxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([O:24][N:25]=[C:26]1[C:30]2([CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]2)[CH2:29][NH:28][CH2:27]1)[CH3:23].C(#N)C>C(N(CC)CC)C>[C:37]([O:36][C:34]([N:32]1[CH2:33][C:30]2([C:26](=[N:25][O:24][CH2:22][CH3:23])[CH2:27][N:28]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[C:9]([NH2:17])[C:10]=3[F:16])[CH2:29]2)[CH2:31]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
400 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, 690 mg of t-butyl 8-(ethoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 2 g of Amberlite® IRA-420 were added to 15 ml of acetonitrile and thereto 1.5 ml of triethylamine was dropped and the resulting mixture was refluxed for 5 days and filtered. The filtrate was concentrated under the reduced pressure and to the resulting residue 10 ml of isopropanol was added and the resulting solution was stirred for 1 hour at room temperature. The precipitated solid was filtered and dried to give 380 mg of the titled compound(yield: 51.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](=S)=[S:13].[OH-].[K+]>O.C(O)C>[SH:13][C:12]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(S)nc2c1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A mixture of 3,4-diaminobenzoic acid (1.52 g, 10 mmol), carbon disulfide (0.837 g, 11 mmol), and potassium hydroxide (0.617 g, 11 mmol) in water (30 mL) and ethanol (8 mL) was heated under reflux for 16 h and then cooled to rt. The reaction mixture was evaporated in vacuo and then taken up in water (25 mL). The resulting mixture was neutralized by the addition of 1 N HCl and the resulting brown solid isolated by vacuum filtration, washed with water and air dried to provide the title compound (1.15 g, 59% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.20 (d, J=8.09 Hz, 1H) 7.66 (s, 1H) 7.76 (dd, J=8.46, 1.47 Hz, 1H) 12.76 (s, 1H) 12.82 (s, 1H). MS (ESI−) m/z 193.0 (M−H)−.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl.[CH2:30]([C:34]1[C:35]([CH2:47]Cl)=[C:36]([Cl:46])[N:37]=[N:38][C:39]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:31][CH2:32][CH3:33].CCCCCC>CC#N.CCOC(C)=O>[CH2:30]([C:34]1[C:35]([CH2:47][N:12]([CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)=[C:36]([Cl:46])[N:37]=[N:38][C:39]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCOc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Reactant: CCCCc1c(-c2ccccc2)nnc(Cl)c1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCc1c(-c2ccccc2)nnc(Cl)c1CN(Cc1cccc(OCC)c1)Cc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (0.211 g, 0.7 mmol) and K2CO3 (0.69 g, 3 mmol) is added to a solution of 5-butyl-3-chloro-4-chloromethyl-6-phenyl-pyridazine hydrochloride (0.175 g, 0.6 mmol) in CH3CN (15 mL). The mixture is stirred at 80° C. overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The organic layer is washed with water (15 mL), brine (15 mL), then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residue provides a light yellow oil. LC-MS (M+1) 558 1H NMR (δ, CDCl3) 7.36-7.48 (m, 5H), 7.18 (t, J=7.2 Hz, 1H), 6.72-6.89 (m, 6H), 4.21 (s, 4H), 4.01 (q, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.56 (s, 2H), 3.50 (s, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.41 (t, J=6.9 Hz, 3H), 0.84-1.02 (m, 4H), 0.58 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>CN(C=O)C.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>[O:22]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[O:10][CH2:9][C:8]4[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=4[C:6]=3[CH:5]=[C:4]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=23)=[CH:23]1
Reactant: OB(O)c1ccoc1
Reactant: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1-c1ccoc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
A mixture of 7-bromo-5H-dibenzo[c,g]chromene-3,9-diol (342 mg, 1.0 mmol), furan-3-boronic acid (224 mg, 2 mmols) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmoles) in DMF (20 ml) is heated at 120° C. with stirring for 4 h. The mixture was filtered through celite, extracted with ethyl acetate (×3), washed with brine, dried over sodium sulfate, filtered, stripped of solvent and purified by silica column chromatography (18%–25% ethyl acetate-hexane) to yield 200 mg (61%) of the title compound as a yellowish solid: mp 216–218° C.; 1H NMR (DMSO-d6): δ 5.00 (2H, s), 6.66 (2H, m), 6.84 (1H, dd, J=8.45 Hz, J=2.35 Hz), 6.93 (1H, dd, J=8.77 Hz, J=2.35 Hz), 7.04 (1H, d, J=2.17 Hz), 7.76 (1H, d, J=8.83 Hz), 7.80–7.85 (3H, m), 8.16 (1H, s), 9.61 (1H, s), 9.71 (1H, s); MS (ESI) m/z 329 (M−H)−, 331(M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[C:19]([NH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:27]3[CH:28]=[C:23]([NH:22][C:19](=[O:21])[CH3:20])[CH:24]=[CH:25][CH:26]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a 100 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.5 g, 0.0045 mol—Preparation 3), 3-acetamidophenylboronic acid (0.769 g, 0.0043 mol), sodium carbonate (1.2 g, 0.0113 mol), toluene (30 mL), ethanol (30 mL) and water (10 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.159 g, 0.00022 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to provide the title compound (1.3 g, 76%). 1H NMR (300 MHz, DMSO-d6): δ 10.15 (s, 1H), 9.05 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 8.11 (s, 1H), 7.46-7.66 (m, 3H), 4.52 (br s, 4H), 3.81 (t, J=5.1 Hz, 4H), 2.09 (s, 3H): LC-MS (ESI): Calculated mass: 383.1; Observed mass [M+H]+: 383.8. (RT=1.31 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:11])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[NH:12]1[C:20]2[C:15](=[CH:16][C:17](B(O)O)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C([O-])(=O)C.N1C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:11])=[N:8][N:9]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][CH:13]=[CH:14]3)[CH:10]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1c[nH]nc1C
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc3[nH]ccc3c2)nc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
3-Methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.43 g, 9.27 mmol) and 1H-indol-5-ylboronic acid (1.50 g, 9.29 mmol) were dissolved in N,N-dimethylformamide (93 mL). Cupper (II) acetate (1.27 g, 6.98 mmol) and pyridine (1.50 mL, 18.5 mmol) were added, and the mixture was stirred for 3 days at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give the title compound (1.2433 g, 4.62 mmol, 50% Yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[CH:15]=1)=[O:4].[I:18]N1C(=O)CCC1=O.O>C(#N)C>[F:17][C:2]([F:16])([F:1])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[I:18])=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(Nc1cn2cc(F)ccc2n1)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(Nc1nc2ccc(F)cn2c1I)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide (0.89 g, 0.0036 mol) was dissolved in acetonitrile (20 mL) and was cooled at 0° C. N-Iodosuccinimide (0.89 g, 0.0040 mol) was added and the reaction was stirred for 30 minutes. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were dried with magnesium sulfate and the solvent removed. The residue was chromatographed on silica (60% ethyl acetate/hexanes) to give 2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide 4 Rf 0.40, 60% ethyl acetate/hexanes; MS m/z 374 (M+H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].O>C(#N)C>[C:15]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: O=C1NC2C=CC1C2
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)N1C(=O)C2C=CC1C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
45.1 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (310 ml) and pyridine (39 ml) under nitrogen. At 10° C., 54.1 g of isobutyryl chloride were added dropwise over the course of 1 h. The reaction was then stirred at room temperature for 5 h. 140 ml of water were added to the mixture, and the acetonitrile was evaporated off in vacuo. The aqueous phase was extracted with 4×120 ml of ethyl acetate. The combined organic phases were washed with 1N HCl (50 ml), saturated NaHCO3 (50 ml) and NaCl (50 ml) solutions, dried with sodium sulphate and completely evaporated. The residue was boiled under reflux in n-hexane (240 ml) with active charcoal. After filtration of the active charcoal, the filtrate was cooled to 0° C. and the title compound was filtered. 54.5 g of product were obtained. The yield was 76%.
Reaction SMILES: [O:1]([CH3:11])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4].C(N(CC)CC)C.[C:19]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([CH:9]([OH:10])[C@H:7]1[O:8][C@@H:2]([O:1][CH3:11])[C@H:3]([OH:4])[C@@H:5]1[OH:6])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a mixture of methyl β-D-ribofuranoside (Sigma Chemical Co., 460 mg, 2.8 mmol) and anhydrous methylene chloride (20 ml) were added triethylamine (0.468 ml, 3.36 mmol), t-butyldiphenylchlorosilane (0.9 ml, 3.46 mmol), and DMAP (13.7 mg, 0.112 mmol) successively at room temperature. The reaction mixture was stirred for 18 h at room temperature under nitrogen. The reaction mixture was washed with water (20 ml), saturated ammonium chloride (20 ml), and brine (20 ml), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was separated by silica gel column chromatography (CHCl3 --MeOH, 50:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside [Rf =0.48 (CHCl3 --MeOH, 10:1), 618 mg, 54.8%] as a thick syrup. 1H NMR (DMSO-d6) d 0.96 (s, 9H, t-Bu), 3.22 (s, 3H, --OCH3), 3.61 (dd, J=11.0 and 5.3 Hz, 1H), 3.74 (d, J=4.4 Hz, 1H), 3.81 (dd, J=11.0 and 2.7 Hz, 1H), 3.90 (m, 1H), 4.00 (m, 1H), 4.68 (s, 1H, H-1'), 4.84 (br s, 1H, exchangeable with D2O, OH), 5.05 (br s, 1H, exchangeable with D2O, OH), 7.45 and 7.67 (m, 10H, Ph2). Anal. Calcd for C22H30O5Si: C, 65.64; H, 7.51; Found: C, 65.73; H, 7.55.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][CH:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]2SCCS2)[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2].O.S(Cl)(Cl)(=O)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]=[O:33])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)NC1C[C@@H]2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Reaction time: 3 h
Yield: 61 %

Procedure:
Under argon, 2.12 g (5 mmol) of 1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8ergolinyl]urea is dissolved in 40 ml of chloroform. Then 3.5 g of silica gel is added and, under vigorous agitation, 3.5 ml of water is introduced dropwise. During a time period of 30 minutes, a solution of 1.18 ml of sulfuryl chloride in 30 ml of chloroform is added dropwise. After 3 hours of agitation at room temperature, 7.5 g of potassium carbonate is added and the mixture vigorously stirred for 20 minutes. The precipitate is filtered off and rinsed with chloroform. The precipitate is moistened with ethanol and introduced into 300 ml of saturated sodium chloride solution which is then repeatedly extracted with chloroform. The chloroform extracts and the chloroform filtrate are dried together over magnesium sulfate and evaporated. Subsequent crystallization takes place from ethyl acetate, thus isolating 1.16 g of 1,1-diethyl-3-(6-methyl-2-formyl-8α-ergolinyl)urea (61% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:39]1([CH3:48])[CH:44]=[CH:43][C:42]([C@@H:45]([NH2:47])[CH3:46])=[CH:41][CH:40]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:47][C@H:45]([C:42]2[CH:43]=[CH:44][C:39]([CH3:48])=[CH:40][CH:41]=2)[CH3:46])=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc([C@H](C)NC(=O)C2COCCN2c2nc(Cl)ncc2Br)cc1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x31 using 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 1 g, 3.10 mmol), EDC (0.892 g, 4.65 mmol), HOBt (0.712 g, 4.65 mmol), triethylamine (1.296 mL, 9.30 mmol) and (S)-1-p-tolylethanamine (0.629 g, 4.65 mmol) in DMF (15 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.37 (dd, J=6.95, 3.66 Hz, 3H), 2.27 (s, 3H), 3.55 (d, J=9.35 Hz, 2H), 3.66-3.77 (m, 1H), 3.82-3.92 (m, 1H), 4.21-4.39 (m, 2H), 4.83-5.01 (m, 2H), 7.12 (d, J=7.83 Hz, 2H), 7.16-7.28 (m, 2H), 8.45 (d, J=10.86 Hz, 2H). ESI-MS m/z [M+H]+ calc'd for C18H20BrClN4O2, 439.05. found 439.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:14]([C@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][NH:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(C[C@H]2CN(Cc3ccccc3)CCN2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C[C@H]2CNCCN2)cc1
Yield: 47.3 %

Procedure:
A mixture of 0.32 gm (1.2 mMol) 1-benzyl-3(S)-benzylpiperazine and 0.06 gm 20% palladium(II) hydroxide on carbon in 50 mL methanol was hydrogenated at room temperature over night at an initial hydrogen pressure of 50 p.s.i. The reaction mixture was filtered, the solid washed with methanol, and the filtrate concentrated under reduced pressure to provide 0.10 gm (50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH2:15]Cl)[C:8](=[O:17])[CH2:7]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:15][CH2:14][CH2:13][N:9]2[C:10](=[O:12])[CH2:11][N:6]([CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[O:2][CH3:1])[CH2:7][C:8]2=[O:17])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccccc1CN1CC(=O)N(CCCCl)C(=O)C1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: COc1ccccc1CN1CC(=O)N(CCCN2CCN(C(=O)OCc3ccccc3)CC2)C(=O)C1

Procedure:
This compound was prepared according to the process described in Example 5 by condensing 4-(2-methoxybenzyl)-1-(3-chloropropyl)piperazine-2,6-dione with 4-benzyloxycarbonylpiperazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])/[C:5](/[O:18][CH:19]([CH3:21])[CH3:20])=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)[CH3:2].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH:19]([O:18]/[C:5](=[CH:6]\[C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([C:12]([NH:30][CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)=[O:14])[CH:15]=1)/[C:4]([O:3][CH2:1][CH3:2])=[O:22])([CH3:21])[CH3:20]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)/C(=C/c1ccc(OC)c(C(=O)O)c1)OC(C)C
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
65 mg of 5-[(Z)-3-ethoxy-2-isopropoxy-3-oxo-1-propenyl]-2-methoxybenzoic acid and 37 mg of 4-(trifluoromethyl)benzylamine were dissolved in 1 ml N,N-dimethylformamide, and 33 μl diethyl cyanophosphonate and 30 μl triethylamine were added under ice-cooling. After stirring the reaction mixture at room temperature for 16 hours, it was poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), 77 mg of ethyl (Z)-2-isopropoxy-3-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)phenyl]-2-propenoate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([F:16])=[C:9]([F:17])[C:8]=1[F:18])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:11]1[C:10]([F:16])=[C:9]([F:17])[C:8]([F:18])=[C:7]([O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:12]=1
Reactant: CCOC(=O)Oc1cc([N+](=O)[O-])c(F)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1cc(N)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
1.43 g (5.40 mmol) of the above O-ethoxycarbonyl-2,3,4-trifluoro-5-nitrophenol was dissolved in 20 mL of ethyl acetate under argon atmosphere, 200 mg of 10% palladium/carbon was added thereto, the gaseous phase in the reaction vessel was substituted with hydrogen and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered and the solvent was distilled off under reduced pressure to give 1.27 g of 5-amino-O-ethoxycarbonyl-2,3,4-trifluorophenol (yield: 100%).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][NH:4]1)[CH3:2].[CH2:12]([NH:14][C:15](=[NH:18])SC)[CH3:13].Br>C(#N)C>[CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:15](=[NH:18])[NH:14][CH2:12][CH3:13])[CH3:2]
Reactant: CCC1NCCc2[nH]cnc21
Reactant: CCNC(=N)SC
Agent: Br
Solvent: CC#N
Product: CCNC(=N)N1CCc2[nH]cnc2C1CC

Procedure:
A solution of 1.5 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.18 g of N-ethyl-S-methyl-isothiourea in 15 ml of acetonitrile is refluxed for 8 h. After evaporation to dryness the residue is treated with one equivalent of ethanolic hydrogen bromide. After cooling, 1.5 g of 4-ethyl-5-(N-ethyl-guanyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine monohydrobromide, m.p. 275°, are collected.