Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[S:20][C:19]([NH:21]C(=O)OC(C)(C)C)=[N:18][CH:17]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.ClCCl>[N:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[S:20][C:19]([NH2:21])=[N:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccccc2COc2ccncc2)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ncc(-c2ccccc2COc2ccncc2)s1
Reaction time: 4 h
Yield: 78.5 %

Procedure:
20 ml of a 4M gaseous hydrochloric acid solution in ethyl acetate are added to 1 g of tert-butyl 5-{2-[(4-pyridinyloxy)methyl]phenyl}-1,3-thiazol-2-ylcarbamate, obtained in step 7.3, in 20 ml of dichloromethane. The mixture is left for 4 hours at room temperature. The reaction medium is concentrated and it is brought to a basic pH with a 5% sodium hydrogen sulphate solution. The precipitate formed is filtered and chromatographed on a silica gel column, eluting with a dichloromethane/methanol 95/5 (V/V) mixture to give 0.58 g of a beige foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(O)c1ccc(Br)cc1
Product: CC(O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 4-bromo-methylbenzylalcohol (181 mg, 1.0 mmol, [CAS 5391-88-8]) according to general procedure II. Obtained as an orange solid (115 mg, 24%). MS (ISP) 476.2[(M+H)+]; mp 175-178° C.
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CC=CC=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)(=[O:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1C=CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)C1C=CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.6 %

Procedure:
To a solution of 0.320 g (3.26 mmol) of 2-cyclohexen-1-ol and 0.76 mL (9.40 mmol) of pyridine in 20 mL of CH2Cl2 was added 1.04 mnL (8.96 mmol) of benzoyl chloride via syringe. The reaction mixture was yellow with a white precipitate. The reaction was stirred at room temperature for 17 h. The reaction was quenched by the addition of 50 mL of H2O; the aqueous layer was washed with 4×50 mL of Et2O, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (35 mm, 20 cm, 10% CH2Cl2/hexane) gave 0.635 g (99%) of 3-benzoylcyclohexene as a pale yellow oil: TLC Rf=0.35 (10% CH2Cl2/hexane); IR (CCl4) 3100 (w), 3081 (w), 3038 (w), 2931 (s), 1725 (s), 1550 (s); 1H NMR (CDCl3) δ1.66-2.12 (m, 6H), 5.49 (bs, 1H), 5.79-5.83 (m, 1H), 5.97-6.01 (m, 1H), 7.41 (t, J=7.7, 2H), 7.52 (t, J=7.4, 1H); 8.02-8.04 (m, 2H); 13C NMR (CDCl3) δ19.0, 25.0, 28.4, 68.6, 125.8, 128.3, 129.6, 130.9, 132.7, 132.8, 166.2; LRMS (EI) 203 ((M+1), 3), 202 ((M+), 20), 105 (100); HRMS (EI) calculated for C13H14O2 202.0994 (M+), found 202.1003. The IR, 1H NMR, and 13C NMR matched spectral data reported by Akemark, B. et al., J. Org. Chem. 59:5729-5799 (1994).
Reaction SMILES: SC1C=CC(S[C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:25])[C:16]([CH3:24])([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH3:17])=[CH:11][CH:10]=2)=CC=1.[SH:26][CH2:27][CH:28]([OH:33])[CH:29]([OH:32])[CH2:30][SH:31].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:33][CH:28]([CH:29]([OH:32])[CH2:30][SH:31])[CH2:27][S:26][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:25])[C:16]([CH3:17])([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH3:24])=[CH:13][CH:14]=1
Reactant: CC(C)(C(=O)c1ccc(Sc2ccc(S)cc2)cc1)N1CCOCC1
Reactant: OC(CS)C(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCC(O)C(O)CS)cc1)N1CCOCC1
Reaction time: 17 h

Procedure:
1.0 g (4.0 mmol) of 1-[4-(4-mercaptophenylthio)phenyl]-2-methyl-2-morpholine-4-yl-propane-1-one and 1.37 g (8.9 mmol) of 1,4-dimercapto-2,3-butanediol are dissolved in 50 ml of dry dimethylacetamide, 1.10 g (8.0 mmol) of potassium carbonate are added and the mixture is stirred for 17 h. The resulting suspension is poured into water and extracted with ethyl acetate, the combined organic phases are washed with water. The solvent is distilled off and the residual oil is purified by column chromatography on silica gel with ethanol-methylene chloride (5:95) as eluent. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.31 (s,6H), 1.55 (t,1 H), 2.57 (m,4H), 2.75 (m, 1H), 3.24 (m,5H), 3.70 (m,5H), 4.18 (s,1H), 7.53 (d,2H), 8.49 (d,2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]1[CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][N:6]1[CH2:15][CH3:16])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+].CN(C=O)C>O>[CH2:1]([O:3][C:4](=[O:17])[C@@H:5]1[CH2:9][CH:8]([N:18]=[N+:19]=[N-:20])[CH2:7][N:6]1[CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1CC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1CC(N=[N+]=[N-])CN1CC
Yield: 73.2 %

Procedure:
A mixture of 3.50 g of N-ethyl-4-mesyloxy-L-proline ethylester, 1.54 g of sodium azide and 10 ml of DMF was reacted at an inner temperature of 90° C. for 4 hours and after cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to obtain an oily product. This was purified by means of silica column chromatography to obtain 2.05 g of 4-azido-N-ethyl-L-proline ethylester.
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.[CH3:47][O:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][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]([N:52]2[CH2:53][CH2:54][CH:49]([O:48][CH3:47])[CH2:50][CH2:51]2)=[O:23])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: COC1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
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: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)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), 4-methoxy piperidine (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: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].O.[CH3:19][NH:20][C:21](=[O:24])[CH2:22]Cl>CC(C)=O>[CH3:19][NH:20][C:21](=[O:24])[CH2:22][O:11][C:4]1[CH:3]=[C:2]([C:12]([F:13])([F:14])[F:15])[CH:1]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:5]=1
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNC(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a stirred solution containing 5 g (0.022 mole) of 3,5-ditrifluoromethylphenol, 1.6 g (0.024 mole) of 85% potassium hydroxide, 10 ml of water and 200 ml of acetone, 0.024 mole of N-methyl chloroacetamide was added in one portion. The stirred reaction mixture was heated at 56°-60° C. for 22 hours. After cooling to 0° C., 600 g of ice water was added and stirring continued at 0°-10° C. for 30 minutes. The resulting solid was collected by filtration, washed with water until neutral to litmus and air-dried at 25°-30° C. A product with a melting point of 98°-99° C. (determined after recrystallization from heptane) was obtained with a 24% yield.
Reaction SMILES: [C:1]1([O:11][C:12](=[O:61])[C@H:13]([CH2:34][CH2:35][CH2:36][N:37](C(OCC2C=CC=CC=2)=O)[C:38](=[NH:50])[NH:39]C(OCC2C=CC=CC=2)=O)[NH:14][C:15](=[O:33])[C@H:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:62].O1CCOCC1.[H][H]>CN(C=O)C.[Pd]>[ClH:62].[C:1]1([O:11][C:12](=[O:61])[C@H:13]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:50])[NH:14][C:15](=[O:33])[C@H:16]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12
Yield: 92 %

Procedure:
In 10 ml of DMF was dissolved 1.07 g of the above ester, after which 0.5 g of 10% Pd-C and 1.65 ml of 2 N hydrochloric acid-dioxane solution were added thereto. The mixture was stirred with ice-cooling for 3 hrs while passing hydrogen gas therethrough. After the reaction, the reaction mixture was filtered to remove the Pd-C, and 500 ml of anhydrous diethyl ether was added to the filtrate. The white powder thus precipitated was collected and vacuum-dried over P2O5 at 110° C. for 3 hrs to obtain 700 mg (yield 92%) of benzoyl-L-phenylalanyl-L-arginine 1-naphthyl ester hydrochloride, m.p. 112° C.-(decomp.).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3,4-dichlorobenzoic acid: MS (ESI): m/z 437 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][CH3:24])[N:15]=[C:14]([NH:25][CH3:26])[N:13]=2)[CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7])[CH3:2].CCN(C(C)C)C(C)C.[NH2:37][NH2:38]>CCO>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][CH3:24])[N:15]=[C:14]([NH:25][CH3:26])[N:13]=2)[CH:9]=[C:8]2[C:5]=1[C:6]([NH2:7])=[N:37][NH:38]2)[CH3:2]
Reactant: NN
Reactant: CCOc1cc(-c2cc(N3CCC[C@H]3CC)nc(NC)n2)cc(F)c1C#N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(-c2cc(N3CCC[C@H]3CC)nc(NC)n2)cc2[nH]nc(N)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
In a microwave tube, 2-(ethyloxy)-4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-6-fluorobenzonitrile (137 mg, 0.371 mmol), 5 mL of EtOH, Hunig's base (0.065 mL, 0.371 mmol), and hydrazine anhydrous (0.070 mL, 2.225 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), and dried under reduced pressure to afford the title compound (120 mg) as a white solid. LC-MS (ES) m/z=382 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, J=7.3 Hz, 3H), 1.35 (m, 1H), 1.44 (t, J=7.0 Hz, 3H), 1.80 (m, 2H), 1.93 (m, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.39 (m, 1H), 3.40-3.45 (m, 1H), 3.48-3.62 (m, 1H), 4.05 (m, 1H), 4.13-4.25 (q, J=7.0 Hz, 2H), 4.99 (s, 2H), 6.17 (s, 1H), 6.40 (s, 1H), 6.92 (s, 1H), 7.44 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.[C:15](O)(=O)[CH3:16]>>[CH:3]([C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[OH:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:2][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:15][CH3:16]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(=O)O
Agent: Cl
Product: CCCCCCCCCCC=CC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
2.5 g (14.4 mmol) of 2-hydroxy-1,4-naphthoquinone was added to 50 ml of acetic acid, and 5.4 g (2.03 mol times relative to 2-hydroxy-1,4-naphthoquinone) of n-dodecylaldehyde and 7.5 g (1.4 mol times relative to 2-hydroxy-1,4-naphthoquinone) of concentrated hydrochloric acid were added as catalyst, and the reaction was conducted at 85° C. for two hours. The reaction solution thus obtained was cooled to about 5° C., whereby no crystal precipitated. Therefore, the reaction solution was poured into 300 ml of water and extracted with 200 ml of benzene. This organic layer was washed twice with 150 ml of a 1% sodium carbonate aqueous solution and once with 150 ml of water and dried over anhydrous sodium sulfate. Benzene was distilled off, and the obtained oil layer was purified by silica gel column chromatography to obtain 1.97 g of 2-(1-dodecenyl)-3-hydroxy-1,4-naphthoquinone. The yield was 40.2 mol %.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[C:11](Cl)[N:10]=1>O1CCCC1.[C].[Pd]>[N:10]1[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:14][CH:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc(Cl)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccncn1
Reaction time: 6 h
Yield: 86605.9 %

Procedure:
Triethylamine (48.03 g, 0.475 mmol) was added to a solution of ethyl 2,6-dichloropyrimidine-4-carboxylate (38.60 g, 0.175 mmol) in tetrahydrofuran (700 ml). 5% Palladium-carbon was added and the mixture was stirred under a hydrogen atmosphere for 6 hrs. The solid in the reaction system was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give ethyl pyrimidine-4-carboxylate (23.06 g, 87%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1.CCCCCC>[CH3:8][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([CH3:11])=[CH:3][C:2]=1[B:17]([OH:22])[OH:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(C)c(Br)cc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(B(O)O)cc1C
Temperature: -62.5 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of 4-bromo-2,5-dimethylanisole (5, 172 g, 0.8 mol) in anhydrous THF (800 ml) was treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexane, 352 mL, 0.88 mol, 1.1 equiv) in hexane at −60-−65° C. under N2. The resulting reaction mixture was stired at −60-−65° C. for an additional 30 min before being treated dropwise with B(OiPr)3 (165.44 g, 203.2 mL, 0.88 mol, 1.1 equiv) at −60 to −65° C. The reaction mixture was stirred at −60 to −65° C. for an additional 1 h. The reaction was then quenched with saturated NH4Cl aqueous solution (750 mL) at −60 to −65° C., and the resulting mixture was gradually warmed to 0° C. for 1 h and subsequently to room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc/THF (1:1, 400 mL). The combined organic extracts were then washed with H2O (400 mL), and saturated NaCl solution (400 mL), dried over MgSO4, and concentrated in vacuo. The residual white solids were then suspended in heptane (500 mL), and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with heptane (2×200 mL), dried in vacuo at 40-45° C. for overnight. The crude product (6, 116.7 g, 144.0 g theoretical, 81%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:18][CH2:19][CH3:20])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:21][N:22](C)[CH:23]=O>>[CH3:21][N:22]([CH3:23])[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([O:18][CH2:19][CH3:20])[C:3]=1[C:1]#[N:2])=[O:17]
Reactant: CN(C)C=O
Reactant: CCOc1nsc(NC(=O)Oc2ccccc2)c1C#N
Product: CCOc1nsc(NC(=O)N(C)C)c1C#N
Temperature: 25 °C

Procedure:
A solution of 9.5 g of phenyl (4-cyano-3-ethoxy-5-isothiazolyl)carbamate in 45 ml of dimethylformamide was placed in a pressure bottle; and while being stirred, was cooled below 0°. A total of 3.7 g of dimethylamine was collected in a dropping funnel by condensing the gas in a dry-ice trap. The liquified amine was added to the pressure bottle, and the bottle sealed. The contents of the bottle were allowed to warm to ambient temperature, then heated at 80° while being stirred overnight. The bottle was cooled to 5° and opened. The reaction mixture was evaporated to dryness under reduced pressure to give a brown solid. This solid was recrystallized from ethanol to give 5.9 g of 1,1-dimethyl-3-(4-cyano-3-ethoxy-5-isothiazolyl)urea, m.p. 204°-205°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][Cl:11])[CH2:4][CH2:3]1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[C:18]1([CH3:27])[C:19](C(Cl)=O)=[CH:20][CH:21]=[CH:22][CH:23]=1.O>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:27][C:18]1[CH:19]=[CH:20][C:21]([C:12]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][Cl:11])[CH2:4][CH2:3]2)=[O:15])=[CH:22][CH:23]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: NC1CCN(CCCCl)CC1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CCN(CCCCl)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(4-aminopiperidin-1-yl)-1-chloropropane (1g; preparation 9), sodium carbonate (0.42 g) and toluoyl chloride (0.58 ml) in 20 ml of ethyl acetate and 20 ml of saturated aqueous sodium bicarbonate solution was stirred at room temperature for 3 hour, then poured into 100 ml of water. The organic phase was separated, dried over sodium sulfate and concentrated to dryness. The residue (1.4 g) was crystallized from 20 ml of hexane and the collected solid dried under vacuum at 50° C. to give 1.05 g of the product, m.p. 150-152° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:32][C:33](=[NH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH3:16])[C@@H:10]([C:11]1[O:13][N:40]=[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=1)[OH:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: N=C(NO)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)[C@H](O)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 16 h. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 h. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate) to yield (290 mg, 0.83 mmol) of (S)-2-tert-butoxycarbonylamino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol. (S)-2-tert-Butoxycarbonylamino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield (S)-2-amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [CH2:1]([N:4]1[CH:13]2[CH:8]([C:9]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:10]=3[C:11](=[CH:14][NH:15]4)[CH2:12]2)[CH2:7][C@@H:6]([C:20](O)=[O:21])[CH2:5]1)[CH:2]=[CH2:3].Cl.[CH3:24][N:25]([CH3:34])[CH2:26][CH2:27][CH2:28][N:29]=[C:30]=[N:31][CH2:32][CH3:33].C(N(C(C)C)C(C)C)C.CN(C)C=[O:47]>>[CH3:33][CH2:32][NH:31][C:30]([N:29]([C:20]([C@H:6]1[CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[C@H:13]2[C@@H:8]([C:9]3[C:10]4[C:11]([CH2:12]2)=[CH:14][NH:15][C:16]=4[CH:17]=[CH:18][CH:19]=3)[CH2:7]1)=[O:21])[CH2:28][CH2:27][CH2:26][N:25]([CH3:24])[CH3:34])=[O:47]
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C=O
Reactant: C=CCN1C[C@H](C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN1C[C@H](C(=O)N(CCCN(C)C)C(=O)NCC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 30 h

Procedure:
17 g of (9R)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylic acid were suspended in 300 ml of dimethylformamide. 20.6 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added and 18.2 ml of ethyldiisopropylamine were slowly added drop wise in the reactor vessel. The mixture was stirred for 30 hours at room temperature. The solvent was evaporated when the reaction was finished. Further 60 ml of dichloromethane was added and the obtained solution was washed with 2 portions of 40 ml of 2% water solution of ammonia, 2 portions of 40 ml of water and 40 ml of 10% water solution of NaCl. First two alkaline solutions are extracted again with another 30 ml of dichloromethane and evaporated. The obtained crude cabergoline was purified on the RP-18 column with mobile phase of acetonitrile/water. The obtained solution was extracted with dichloromethane at pH=7. Organic phase was evaporated to the oily, foamy or semi-solid material of amorphous cabergoline with 0.2% (w|w) of total impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].Cl.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([CH:12]=[CH:13][C:14]([CH3:15])=[N:5]2)=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C/C=C/C=O
Reactant: COc1ccc(N)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc2ccc(C)nc2cc1Cl
Temperature: 100 °C
Yield: 50.1 %

Procedure:
To 3-chloro-4-methoxyaniline (1A) (5.0 g, 31.7 mmol) was added 6 M HCl (100 mL) and the reaction was heated to 100° C. with stirring. Toluene (30 mL) was added followed by the slow addition of crotonaldehyde (5.3 mL, 63.5 mmol) at 100° C. The mixture was stirred at 100° C. for 2 hours and cooled to room temperature. The water layer was separated and neutralized with 2 M NaOH solution to pH ˜8. The solid that formed was filtered and collected. The crude product was purified by flash column chromatography to give 1B as white solid (3.3 g, 50%). LCMS-ESI+ (m/z): 208.2, 210.2 (M+H)+.