Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH:26](Cl)([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH:26]([CH3:28])[CH3:27])[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: CC(C)Cl
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nn(C(C)C)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 72.6 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and isopropyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 72.6%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[Cl:1][C:2]1[N+:3]([O-:19])=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1nccc2ccsc12
Solvent: ClCCl
Product: [O-][n+]1ccc2ccsc2c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
To a solution of 7-chlorothieno[2,3-c]pyridine (5.00 g, 29.5 mmol) in DCM (200 mL) was added m-chloroperbenzoic acid (13.2 g, 59.0 mmol). The combined mixture was stirred at RT for 24 h. After that time, it was purified by ISCO chromatography (0 to 6% MeOH:DCM) to afford 3.18 g (58%) of the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J=7.2 Hz, 1 H), 7.69 (d, J=5.2 Hz, 1 H), 7.57 (d, J=6.8 Hz, 1 H), 7.35 (d, J=5.2 Hz, 1 H); MS (ESI): 185.95, 187.96 [M+H]+; HPLC tR=0.88 min (TOF: polar—3 min).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH2:32]([CH:34]([CH2:38][CH3:39])[C:35](Cl)=[O:36])[CH3:33].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:35](=[O:36])[CH:34]([CH2:38][CH3:39])[CH2:32][CH3:33])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Reactant: CCC(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)C(CC)CC)cc1OC

Procedure:
0.5 g of the compound obtained in Example 5 step B) in 20 ml of DCM was mixed with 0.5 g of 2-ethylbutyroyl chloride and 0.5 g of pyridine. The mixture was concentrated under vacuum, extracted with ethyl ether and then washed with water, with 1N hydrochloric acid and then with water. The residue was chromatographed on silica using DCM as the eluent to give the expected product, which crystallized from isopropyl ether. m=0.17 g. M.p.=168° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[CH:10]([Si:12]([Cl:15])(Cl)[Cl:13])=[CH2:11]>>[Cl:13][Si:12]([Cl:15])([CH:10]=[CH2:11])[NH:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: C=C[Si](Cl)(Cl)Cl
Product: C=C[Si](Cl)(Cl)N[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
In a 250 ml three-neck flask, 50 ml of hexamethyldisilazane (38.7 g, 0.24 mol) are admixed with 70 ml of vinyltrichlorosilane (88.9 g, 0.55 mol) and stirred overnight at room temperature. The mixture is fractionated under reduced pressure. After trimethylchlorosilane and excess vinyltrichlorosilane have been distilled off, (1,1-dichloro-1-vinyl)trimethyldisilazane goes over as a clear, colorless liquid. The boiling point is 40° C. at 11 mbar, and the yield is 80%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1.CO.ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1)=[O:37]
Reactant: Cn1c(-c2ccccc2Sc2nc3ccccc3[nH]2)nc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Cn1c(-c2ccccc2S(=O)c2nc3ccccc3[nH]2)nc2ccccc21
Temperature: 25 °C

Procedure:
The product of step (d) above (0.99 g) was dissolved in dichloromethane (60 ml) and methanol (5 ml) and cooled to -10°. 85% m-Chloroperbenzoic acid (0.56 g) was added and the whole was slowly warmed to room temperature with stirring. After 2 hours the reaction mixture was washed with metabisulphate solution, then bicarbonate solution and finally with brine, dried over magnesium sulphate and evaporated to dryness in vacuo and the residue was purified by flash chromatography (SiO2 /CH2Cl2 2:3 ethyl acetate) to afford the title compound as a white solid, mp 164°.
Reaction SMILES: [ClH:1].C(O[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1)=[NH:6])C.[CH2:34]([NH2:36])[CH3:35]>C(O)C>[ClH:1].[CH2:34]([NH:36][C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:11][CH:12]=1)=[NH:6])[CH3:35]
Reactant: CCOC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Reactant: CCN
Agent: Cl
Solvent: CCO
Product: CCNC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Into a suspension (4 ml) of N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (169 mg) in ethanol was added ethylamine (1 ml). The resulting mixture was stirred at room temperature for 4 days and was then concentrated. The residue was suspended in ethyl acetate, 4 N hydrochloric acid/ethyl acetate was added and the precipitate was collected by filtration. The precipitate was recrystallized from ethyl acetate/methanol to obtain N-(4-ethylamidinophenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (compound 43) (25 mg) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([CH3:32])[CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][C:25]=2[CH3:32])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: COc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)c(C)c1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-methoxy-2-methylbenzoic acid. MS (m/e): 421.0 (MH−, 100%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH:19]([OH:22])[CH2:20]O)=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:22][CH:19]([CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:24][CH:23]=2)[CH2:20][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: OCC(O)COc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Clc1ccc(OCC2COC(CBr)(c3ccc(Cl)cc3)O2)cc1

Procedure:
A mixture of 11.7 parts of 2-bromo-4'-chloroacetophenone, 12.2 parts of 1-(p-chlorophenoxy)-2,3-propanediol, 3 parts of p-toluenesulfonic acid and 240 parts of benzene is stirred and refluxed for 20 hours in a four-necked round-bottom flask equipped with a watertrap. The benzene solution is washed successively with a diluted sodium hydroxide solution and with water. The solvent is removed in vacuo. The residue is triturated in methanol. The precipitated product is filtered off (methanol filtrate is set aside) and crystallized from toluene, yielding A-2-(bromomethyl-4-(p-chlorophenoxymethyl)-2-(p-chlorophenyl)-1,3-dioxolane; m.p. 165°C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of methyl 5-chloro-2-pyrazinecarboxylate (Bio-Farma; 1.50 g, 8.69 mmol) in a mixture of methanol (16 ml) and water (8 ml) was stirred at room temperature and treated with potassium carbonate (1.201 g, 8.69 mmol). The resulting solution was stirred for 2 hrs and the methanol removed under reduced pressure. The residue was partitioned between ethyl acetate and water (20 ml) and the aqueous layer acidified by addition of 5M hydrochloric acid. Extraction (×2) with ethyl acetate and drying over MgSO4 followed by removal of the solvent under reduced pressure, gave the title compound (1.00 g) as a white solid;
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]CC)=O.S(O)(O)(=O)=O.[CH2:17]([NH:19][C:20]([NH2:22])=[NH:21])[CH3:18].[Na].C(O)(=O)C>C(O)C>[CH2:17]([NH:19][C:20]1[N:22]=[C:4]([OH:6])[CH:3]=[C:2]([CH2:9][CH2:10][CH3:11])[N:21]=1)[CH3:18]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCNC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1cc(O)nc(NCC)n1
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Ethyl 3-oxo-hexanoate (4.74 g; 30 mM) and N-ethylguanidine sulphate (4.08 g; 30 mM) were dissolved in a solution prepared by dissolving sodium (1.4 g; 0.65 g atom) in ethanol (100 ml) and the mixture was heated under reflux on the steam bath for 18 hours. Acetic acid (5 ml) was added to the cooled mixture which was stirred for 10 minutes. Insoluble material was removed by filtration and the filtrate was evaporated. The residue was partitioned between water (50 ml) and methylene chloride (50 ml). The aqueous layer was extracted twice with methylene chloride (50 ml). The combined extracts were dried and the solvent evaporated. The residue was crystallised from cyclohexane to give 2-ethylamino-4-hydroxy-6-propylpyrimidine as a solid (4.6 g; 85% yield), m.p. 108°-110° C.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][S:14][N:13]=2)=[CH:8][CH:7]=1.[CH2:20](O)[CH3:21]>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][S:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CCO
Reactant: O=C(O)c1csnc1-c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1csnc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethanol (10 mL), thionyl chloride (440 mg, 3.70 mmol, 1.00 equiv), 3-(4-chlorophenyl)-1,2-thiazole-4-carboxylic acid (860 mg, 3.69 mmol, 1.00 equiv). The resulting solution was stirred for 6 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum and taken up in 150 mL of dichloromethane, washed with 1×30 mL of brine. The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.72 g (75%) of ethyl 3-(4-chlorophenyl)-1,2-thiazole-4-carboxylate as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:43][NH:44][C@@H:45]([CH2:52][CH2:53][CH3:54])[CH2:46][N:47]1[CH2:50][CH:49]([OH:51])[CH2:48]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:44]([C@@H:45]([CH2:52][CH2:53][CH3:54])[CH2:46][N:47]1[CH2:48][CH:49]([OH:51])[CH2:50]1)[CH3:43])=[O:7]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CCC[C@@H](CN1CC(O)C1)NC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.3 %

Procedure:
3,4-Difluorobenzoic acid (0.184 g, 1.16 mmol), TBTU (0.373 g, 1.16 mmol) and DIPEA (0.303 mL, 1.74 mmol) was stirred in DCM (2 mL) for 40 min before (S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4) (0.1 g, 0.58 mmol) was added. The resultant mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue dissolved in a mixture of MeOH (3 mL) and NaOH (aq. 1 mL, 1M). The resultant mixture was stirred at rt for 90 min before the MeOH was removed on a vacuum centrifuge. The crude product was extracted with DCM and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (102 mg, 56%). Mixture of rotamers: (600 MHz, DMSO-d6) δ 0.67-0.76, 0.79-0.91, 0.92-1.04, 1.06-1.48, 2.30-2.76, 3.23-3.42, 3.43-3.53, 4.05-4.17, 4.37-4.47, 5.17-5.26, 7.14-7.27, 7.36-7.56. Total no of protons: 22. HRMS (M+H)+: calculated 313.1728. found 313.1714.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: NCC(=O)[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])CNc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a stirred solution of 1-bromo-2,5-difluoro-4-nitrobenzene (1.100 g, 4.622 mmol, as prepared above) in DMF (11.0 mL) at 70° C., was added, dropwise, a solution of sodium glycinate (0.451 g, 4.65 mmol, Aldrich, used as received) in water (5.0 mL). The resulting solution was stirred overnight at 70° C. The solution was cooled to room temperature and the bright orange solid was filtered, washed with cold acetone (10 mL) and dried under vacuum to give 0.469 g (35%) of the title compound as a bright orange powder; 1H NMR (DMSO-d6): δ 3.458 (d, 2H, J=3.9 Hz), 7.148 (d, 1H, J=6.0 Hz), 7.944 (d, 1H, J =9.3 Hz), 8.740 (s, 1H).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]([NH2:13])=[CH:8][CH:9]=[C:10]([F:12])[CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH3:26])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([C:23](=[O:24])[NH:13][C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[NH:5][CH:1]1[CH2:2][CH2:3][CH2:4]1)[CH3:26])([CH3:15])([CH3:16])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1NC1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1NC1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
A mixture of N2-cyclobutyl-4-fluorobenzene-1,2-diamine (0.63 g, 3.5 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.73 g, 3.9 mmol), HOAt (0.53 g, 3.9 mmol), 4-methylmorpholine (0.85 mL, 7.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.75 g, 3.9 mmol) in DCM (12 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(2-cyclobutylamino-4-fluorophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester (853 mg, 69%). LCMS (Method J): RT 3.54 min [M+H]+ 352.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25](Br)[N:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2>CN1CCCC1=O.O>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)[N:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Brc1cc2cccnc2c(Br)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Br)cc3cccnc23)C1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
To (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.776 g, 4.17 mmol) in N-methyl-2-pyrrolidinone (12 mL) at 0° C. was added NaH (0.139 g, 3.47 mmol). The mixture was stirred for 5 minutes. Next, 6,8-dibromo-1,7-naphthyridine (1 g, 3.47 mmol) was added and the reaction mixture was stirred at RT for 5 minutes and then heated at 135° C. for 30 minutes in a microwave reactor. The reaction mixture was diluted with water and extracted with EtOAc (2×). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified using silica column chromatography eluting with a gradient of 0-75% EtOAc in hexane over a 45 minute period to give the title compound as a yellow solid (1.3 g, 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with p-anisidine to yield 2-[(4-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH2:7][N:6]1[CH2:26][CH2:27][CH3:28].[OH-].[K+].ClCCl>CO>[CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[CH2:20][OH:21])[CH2:7][N:6]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCN1C[C@@H](NC(=O)COC(C)=O)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCN1C[C@@H](NC(=O)CO)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21

Procedure:
530 mg of N-(2-methyl6n-propyl-8alpha-ergolinyl)-acetoxyacetamide (1.38 mmol) is dissolved in 20 ml of methanol and 0.5 ml of KOH and stirred for 15 minutes at room temperature. Then it is mixed with ice and shaken out with dichloromethane. The organic phases are dried, concentrated by evaporation and crystallized from diisopropyl ether/hexane, yield 321 mg (63% of theory). [α]D +20° (0.5% in chloroform).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[C:21](=[O:22])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].Cl.[F:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([CH:31]2[CH2:36]CNC[CH2:32]2)=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([CH:31]2[CH2:32][CH2:2][N:3]([CH2:5][CH:6]3[C:21](=[O:22])[C:10]4[C:11]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[F:20])=[N:12][O:13][C:9]=4[CH2:8][CH2:7]3)[CH2:4][CH2:36]2)=[O:30])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CN(C)CC1CCc2onc(-c3ccccc3F)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)C1CCN(CC2CCc3onc(-c4ccccc4F)c3C2=O)CC1
Temperature: 25 °C
Yield: 8.1 %

Procedure:
To a solution consisting of 6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride (1. 86 g) in distilled water (18.5 ml) was added 4-(4-fluorobenzoyl)piperidine hydrochloride (2.7 8 g) and potassium carbonate (0.80 g). The reaction mixture was heated at reflux for 3 hours. Upon cooling to room temperature, ethyl acetate was added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 40% ethyl acetate/hexane) afforded 1.20 g of 6,7-dihydro-5-(4-(4-fluorobenzoyl) -1-piperidinyl)methyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one. The compound was flushed through alumina with dichloromethane to give an oil which solidified on standing. The product was then recrystallized from ether/hexane, m.p. 99°-102° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:23]1[C:24]([CH3:46])=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:29]>COCCOC.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>[CH3:46][C:24]1[C:23]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:37][C:27]([C:28]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:29])=[C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]=1
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)Nc2cccnc2)cc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2cccnc2)cc1-c1cnn(C)c1
Temperature: 120 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (86 mg, 0.42 mmol), palladium tetrakis (26.2 mg, 0.02 mmol) and Na2CO3 (0.76 ml, 0.76 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 6; 150 mg, 0.38 mmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated at 120° C. in a microwave for 1 hour. The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 73 mg.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][C@@H:13]([CH2:17][C@H:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[O:19][CH3:20])[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:33]O>>[CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][C@@H:13]([CH2:17][C@H:18]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[O:19][CH3:20])[C:14]([O:16][CH3:33])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CO[C@H](C[C@H](CC=CCOCc1ccccc1)C(=O)O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](CC=CCOCc1ccccc1)C[C@@H](OC)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of ((S)-6-(benzyloxy)-2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)hex-4-enoic acid in 10 mL methanol was added concentrated H2SO4 (150 μL) at room temperature and the resulting solution stirred for 8 h. The reaction mixture was concentrated under reduced pressure, the residue treated with water, and the mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The product was isolated by flash column chromatography eluting with 0% to 20% ethyl acetate/hexane gradient solvent to give 494 mg of the title compound as a colorless oil.