Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][OH:2].[CH3:3][C:4]1[CH2:9][CH2:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1>CO>[CH3:11][CH:10]([C:7]12[O:2][O:1][C:4]([CH3:3])([CH:9]=[CH:8]1)[CH2:5][CH2:6]2)[CH3:12]
Reactant: CC1=CC=C(C(C)C)CC1
Reactant: OO
Solvent: CO
Product: CC(C)C12C=CC(C)(CC1)OO2
Reaction time: 1.5 h

Procedure:
At 35° C., 45 μl of H2O2 (50%) were added to a solution of 325 μl of α-terpinene and 48.5 mg of Na2MoO4.2H2O in 4 ml of methanol. Five further 45 μl portions of H2O2 (50%) were added to this mixture as soon as the red-colored reaction mixture turned yellow again. After 1.5 hours, the reaction mixture was analyzed by means of HPLC. Analysis gave a quantitative formation of ascaridol.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:16]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].O>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH2:27][CH2:28][N:29]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[N:16]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)cc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 1-(2-chloro-phenyl)-5-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate (80.0 mg, 0.14 mmol) prepared in Example 10 in dichloromethane (1.0 mL), was added triethylamine (59.0 uL, 0.43 mmol). Methanesulfonyl chloride (16.5 uL, 0.22 mmol) was dropwisely added at 0° C. to the reaction mixture, which was then stirred at room temperature for 2 hours. Distilled water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 50.8 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)[CH3:9].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:8]([O:10][C:11](=[O:14])[CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CNc1ccccc1
Yield: 78.6 %

Procedure:
A mechanically stirred mixture of aniline (71 g; 0.76 mol), ethylbromoacetate (127.5 g; 0.76 mol), and anhydrous sodium acetate (62.6 g; 0.76 mol) in absolute ethanol (10 mL) was heated at reflux for 6 hours. The mixture was cooled, water was added to precipitate the product, and the solid was filtered and dried. The crude product was crystallized from ethanol-water to give N-phenylglycine ethyl ester (107 g; 79%) having amp 48°-49° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](I)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]([O:38]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:37].Cl.[OH-].[Na+].[F-].[K+]>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>[C:36]([C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:33])[CH3:32])=[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:22]=1)(=[O:38])[CH3:37]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccccc1-c1cc(I)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of 300 mg (0.495 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 27) and 0.20 ml (0.59 mmol) 1-ethoxyvinyltri-n-butyltin in 1 ml toluene was deoxygenated by three freeze-thaw cycles. After addition of 17 mg (0.025 mmol) bis(triphenylphosphine)palladium(II) chloride the reaction mixture was heated at reflux for 16 h. Cooling to room temperature was followed by addition of 1 ml 2 M aqueous hydrochloric acid solution. After 15 min 2 ml 1N aqueous sodium hydroxide solution and 35 mg (0.59 mmol) potassium fluoride were added, followed by extraction with four portions of ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated. Column chromatography afforded 147 mg (57%) of the title compound as a colorless gum.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=O)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].Cl.[NH2:30][OH:31].O>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:30][OH:31])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NO)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
7-Oxo-5-androstene-3β,17β-diol diacetate (1 g, 2.57 mmol) and hydroxylamine hydrochloride (0.5 g) were taken in dry pyridine (8 Ml) and heated in a steam bath for 2 h. The reaction mixture was poured into water and precipitate obtained was filtered, washed with water and dried. The crude product on crystallization from methanol afforded pure oxime 7-oximino-5-androstene-3β,17β-diol diacetate (0.85 g, 86.54%), mp 236-238° C. (lit 226° C.) [Singh H., et al Indian J. Chem. 1969, 7, 1084-1087].
Reaction SMILES: [CH2:1]([C:3]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([CH2:18][CH3:19])[C:4]#[C:5][CH2:6]OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[Br-:27].[Na+].CCOCC>CN(C=O)C.CCOCC.CCCCC>[Br:27][CH2:6][C:5]#[C:4][C:3]([CH2:18][CH3:19])([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:1][CH3:2]
Reactant: [Br-]
Reactant: CCC(C#CCOS(=O)(=O)c1ccc(C)cc1)(CC)OC1CCCCO1
Agent: [Na+]
Solvent: CCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C#CCBr)(CC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of Compound 402 (7.0 g) and sodium bromide (7.0 g) in DMF (50 ml) was stirred at r.t. for 4 h. Ether (300 ml) was added and the mixture was worked up with chromatography with ether/pentane 1:1 (v/v) as eluent to give the title compound (3.9 g). 1H NMR: 0.96 (t, 3H), 0.96 (t, 3H) 1.45-1.90 (m, 10E), 3.51 (m, 1H), 3.95 (m, 1H), 3.98 (s, 2H), 5.00 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH3:16])[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.[Ni]>[F:1][C:2]1[C:3]([C:17]([F:20])([F:18])[F:19])=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH3:16])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCN1CC=C(c2cccc(F)c2C(F)(F)F)CC1
Agent: [Ni]
Solvent: CCO
Product: CCCN1CCC(c2cccc(F)c2C(F)(F)F)CC1
Reaction time: 48 h
Yield: 77.8 %

Procedure:
To a solution of 4-[3-fluoro-2-(trifluoromethyl)phenyl]-1-propyl-1,2,3,6-tetrahydro pyridine (1.73 g, 6.0 mmol) in ethanol (30 ml) was added Raney nickel (slurry in water, 10 ml) and the reaction mixture was hydrogenated under hydrogen (50 psi) for 2 days. Filtration through a pad of celite and evaporation of the filtrate gave 1.35 g of crude product. MS m/z (relative intensity, 70 eV) 289 (M+, 4), 261 (16), 260 (bp), 176 (6) 70 (20).
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[C:8]([F:29])[C:9]([F:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:15](=[O:16])[C:14]2[CH:13]=[C:12]3[CH:11]=[C:10]([F:27])[C:9]([F:28])=[C:8]([F:29])[C:7]3=[N:6][C:5]=2[N:24]([CH2:25][CH3:1])[CH:23]=1)=[O:19])[CH3:22]
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reaction time: 1 h
Yield: 62.2 %

Procedure:
4.5 g of ethylamine are added in the course of 10 minutes, at between 5° and 10° C., to a stirred suspension of 7.1 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 100 cm3 of ethanol kept at a temperature close to 5° C., the mixture is stirred for 1 hour at between 5° and 10° C. and the temperature is allowed to rise to about 20° C. 4 g of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) are added to the solution obtained and the mixture is heated at a temperature close to 75° C. for 1 hour and a half. After cooling to a temperature close to 20° C., the product is drained and washed with twice 30 cm3 of ethanol and twice 50 cm3 of diisopropyl ether. 4 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a cream solid melting at 284° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:31])[CH:2]=[CH2:3].Br[C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[O:18][C:19]=3[CH:20]([CH3:22])[CH3:21])[C:8]=2[CH:7]=[CH:6][C:5]=1[O:31][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: C=CCc1c(O)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCc1c(OC(C)(C)C(=O)OCC)ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc12
Yield: 87.5 %

Procedure:
7-Allyl-6-hydroxy-3-[2-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]ethyl]-1,2-benzisoxazole (92 mg, 0.20 mmol), ethyl 2-bromo-2-methylpropionate (196 mg, 1.00 mmol) and potassium carbonate (138 mg, 1.00 mmol) were suspended in methyl ethyl ketone (5.0 mL). The suspension was refluxed for 20 hours, and allowed to room temperature. After insoluble was filtered off, the filter cake was washed with methyl ethyl ketone. The filtrate and washings were combined, and concentrated. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (5/1) to give the desired compound (100 mg) as colorless oil (quantitative yield).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cccnc1

Procedure:
A mixture of 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1, 60 mg), pyridin-3-ylboronic acid (25 mg), 2 M Na2CO3 (0.2 mL, 0.4 mmol) and DME (4 mL) was flushed with argon, PdCl2(dppf)(CH2Cl2) (10 mg, 0.012 mmol) was added and the mixture was subjected to MW irradiation at 140° C. for 30 min. The RM was filtered through aa PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 6) tR=0.91 min, m/z=432.9 [M+H]+.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=O.[C:13]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:32])[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][CH3:31])[CH2:24][CH2:23]1>>[C:13]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]([O:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][N:30]([CH3:31])[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:11][CH3:12])=[O:10])[CH2:26][CH2:27]1)=[O:32]
Reactant: COC(=O)CCCCCC(=O)[O-]
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Product: COC(=O)CCCCCC(=O)N(C)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 102.5 %

Procedure:
Monomethyl pimelate (79 mg, 0.450 mmol) and 1-[2-(methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (159 mg, 0.450 mmol) were used to give the title compound (235 mg; yield, 100%) as a colorless oily substance according to the method described in Example 12a.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10](I)[C:3]=12.[CH3:32][C@@H:33]([OH:36])[C:34]#[CH:35].N(C(C)C)C(C)C>C1COCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10]([C:35]#[C:34][C@H:33]([OH:36])[CH3:32])[C:3]=12
Reactant: C#C[C@@H](C)O
Reactant: Cc1ccccc1-n1c(Cn2nc(I)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-n1c(Cn2nc(C#C[C@@H](C)O)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Yield: 69.7 %

Procedure:
3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1611) (522 mg, 1 mmol) and (R)-but-3-yn-2-ol (84 mg, 1.2 mmol) were dissolved in anhydrous THF (40 mL). The mixture was degassed and back-filled with nitrogen three times. Pd(PPh3)2Cl2 (12 mg, 0.1 mmol), CuI (47 mg 0.25 mmol) and (i-Pr)2NH (505 mg, 5 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon three times and then stirred at reflux for 4 h. The mixture was allowed to cool to RT, filtered through silica gel (10 g) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the product, 3 (R)-3-((4-amino-3-(3-hydroxybut-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1802) (324 mg, 70% yield) as a slightly yellow solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH:20]1([CH2:25][C:26](O)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:26](=[O:27])[CH2:25][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)CC1CCCC1
Product: O=C(CC1CCCC1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-cyclopentylacetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.88-8.04 (m, 2H), 7.73-7.75 (m, 1H), 7.59-7.69 (m, 4H), 2.33 (d, J=7.4 Hz, 2H), 2.16-2.28 (m, 1H), 1.75-1.87 (m, 2H), 1.59-1.69 (m, 2H), 1.49-1.58 (m, 2H), 1.19-1.31 (m, 2H); MS (ESI−) M/Z 380 (M−H)−.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1
Reactant: O=C(O)c1ccncc1F
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(-c2ccncc2F)nc2cc(C(F)(F)F)cnc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of 5.51 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 6.10 g of 3-fluoroisonicotinic acid, 8.28 g of WSC and 58 ml of pyridine was stirred for 3 hours while heating at 120° C. After cooling down to room temperature, water was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 6.77 g of 2-(3-fluoropyridin-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 36).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:18]=[CH:17][C:10]2[O:11][CH:12]([CH3:16])[C:13](=[O:15])[NH:14][C:9]=2[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:18]=[CH:17][C:10]2[O:11][CH:12]([CH3:16])[C:13](=[O:15])[NH:14][C:9]=2[CH:8]=1
Reactant: COc1ccc2c(c1)NC(=O)C(C)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1Oc2ccc(O)cc2NC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
Under N2, a 50 mL round-bottomed flask was charged with a 1M solution of BBr3 (3.11 mL, 3.11 mmol), then cooled in an ice/brine bath. To the cooled solution, was added drop-wise, 6-methoxy-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 394B (0.2 g, 1.035 mmol) in anhydrous DCM (4 mL). The reaction was stirred under N2 and then allowed to slowly warm to 23° C. After 2 hr, ice cold water (25 mL) was slowly added to the reaction mixture. The product was collected by vacuum filtration, washed with water, and dried in vacuo to give a light tan solid (0.116 g, 62.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.57 Hz, 3H) 4.44-4.57 (m, 1H) 6.24-6.32 (m, 1H) 6.36 (d, J=2.78 Hz, 1H) 6.74 (d, J=8.59 Hz, 1H) 9.15 (s, 1H) 10.50 (s, 1 H). ESI-MS: m/z 180.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccncn2)cc1
Product: O=C/C=C/c1ccc(-c2ccncn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 18) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [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)[N:14]([CH2:23][CH2:24][CH3:25])[C:13]=3[CH:26]=[CH2:27])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:29]([N:3]([CH2:1][CH3:2])[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)[N:14]([CH2:23][CH2:24][CH3:25])[C:13]=3[CH2:26][CH3:27])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:30]
Reactant: C=Cc1c2c3c(cccc3n1CCC)[C@H]1C[C@H](NC(=O)N(CC)CC)CN(C)[C@@H]1C2
Agent: [Ni]
Solvent: CCO
Product: CCCn1c(CC)c2c3c(cccc31)[C@H]1C[C@H](NC(=O)N(CC)CC)CN(C)[C@@H]1C2
Yield: 43.1 %

Procedure:
At room temperature and under hydrogen normal pressure, 150 mg of 1,1-diethyl-3-(2-vinyl-1-propyl-6-methyl-8α-ergolinyl)urea is hydrogenated in 20 ml of ethanol with 0.1 g of Raney nickel (B 115 Z). After the catalyst has been filtered off over kieselguhr, evaporation of the filtrate, and chromatography over silica gel with toluene:ethanol:water=80:20:1 as the eluent, 65 mg of 1,1-diethyl-3-(2-ethyl-1-propyl-6-methyl-8α-ergolinyl)urea is obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: NCCO
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NCCO)nc1
Yield: 96 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (110 mg, 96%), which was obtained as a white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH3:25].[OH-].[Na+]>COCCOC.C(OCC)(=O)C.C(Cl)Cl>[I:1][C:2]1[C:10]2[N:9]([CH3:25])[C:8]3[CH2:11][CH2:12][NH:13][CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(I)cccc3c2C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Cn1c2c(c3cccc(I)c31)CNCC2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
Tert-butyl 6-iodo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (6.8 g, 17 mmol) was dissolved in DME (50 mL), and potassium hydroxide (4.8 g, 85.4 mmol) and iodomethane (15.7 g, 110.5 mmol) were added and heated at 80° C. in a pressure vessel for 3 h. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). The solids were removed by vacuum filtration. The filtrate was concentrated under reduced pressure to give a brown oil (5.5 g, 79% crude yield). The oil was dissolved in CH2Cl2 (30 mL). Trifluorocacetic acid (30 mL) was added in ten portions over 5 minutes and stirred for 30 minutes. The reaction was basified with 50% sodium hydroxide to pH 10. This mixture was extracted with CH2Cl2 (3×150 mL). The organics were collected, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give 6-iodo-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.85 g, 73%). 1H NMR (CDCl3 300 MHz) δ 7.62 (d, 1H, J=7.6 Hz), 7.33 (d, 1H, J=7.7 Hz), 6.74 (t, 1H, J=7.5 Hz), 4.03 (s, 2H), 3.95 (s, 3H), 3.26 (t, 2H, J=5.6 Hz), 2.71 (t, 2H, J=5.6 Hz) ppm.