Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:19]=1)([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][C:8]=3[N:9]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3cc(N)ccc3o2)cc1
Reaction time: 16 h
Yield: 59 %

Procedure:
To 5-nitro-2-p-tolylbenzo[d]oxazole (4.8 g, 18.90 mmol) in ethyl acetate/acetic acid (250 ml/1 mL) was added palladium on carbon (480 mg). The reaction vessel was purged three times with nitrogen, followed by hydrogen three times, and then left stirring under hydrogen for 16 h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite®, which was washed with ethyl acetate. The organic solution was washed with saturated aqueous Na2CO3, followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 2.5 g (60%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:30](=[O:31])[N:7]2[CH:8]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:32])[C:5]1=[O:33])=[CH:15][C:14]([O:19][CH:20]([F:22])[F:21])=[CH:13][CH:12]=4.[CH3:34][NH2:35]>O1CCCC1>[F:21][CH:20]([F:22])[O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH:8]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[N:7]3[C:30](=[O:31])[N:4]([CH2:3][CH2:2][NH:35][CH3:34])[C:5](=[O:33])[C:6]3([CH3:32])[CH2:18][C:17]2=1
Reactant: CC12Cc3c([nH]c4ccc(OC(F)F)cc34)C(c3cccc(O)c3)N1C(=O)N(CCBr)C2=O
Reactant: CN
Solvent: C1CCOC1
Product: CNCCN1C(=O)N2C(c3cccc(O)c3)c3[nH]c4ccc(OC(F)F)cc4c3CC2(C)C1=O

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-6-(1,1-difluoro-methoxy)-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 36) and a 2 M solution of methyl amine in tetrahydrofurane as starting materials. MS: m/z (MH+)=471.2
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]3[C:16]([CH3:17])=[C:15]([CH3:18])[NH:14][C:13]=23)=[CH:4][CH:3]=1.[Cl:21][CH:22]=[CH:23][CH2:24]Cl>>[Cl:21][CH:22]=[CH:23][CH2:24][N:14]1[C:13]2=[C:8]([O:7][CH2:6][C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[N:10][CH:11]=[C:12]2[C:16]([CH3:17])=[C:15]1[CH3:18]
Reactant: Cc1[nH]c2c(OCc3ccc(F)cc3)nncc2c1C
Reactant: ClC=CCCl
Product: Cc1c(C)n(CC=CCl)c2c(OCc3ccc(F)cc3)nncc12
Yield: 31.4 %

Procedure:
The title compound (cis/trans=1/1) was prepared as a pale yellow powder in 31.4% yield in a similar procedure to that described in Example 41 by using 7-(4-fluorobenzyloxy)-2,3-dimethylpyrrolo[2,3-d]pyridazine and 1,3-dichloropropene (a mixture of cis and trans isomers).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]>FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>[CH3:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:2](=[O:4])[C:1](=[O:8])[NH:18]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc(N)c1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Product: Cc1cccc2[nH]c(=O)c(=O)[nH]c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
According to Step 1 of Reference Example 10-3, diethyl oxalate (4.5 mL, 33 mmol) and ytterbium trifluoromethanesulfonate (254 mg, 0.41 mmol) were added to 2,3-diaminotoluene (1.0 g, 8.2 mmol) and the mixture was stirred at 80° C. for 2 hours. After water was added to the reaction mixture, the precipitate was washed with ethanol. Thus, 5-methylquinoxaline-2,3(1H,4H)-dione (1.1 g, yield: 78%) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2)(=[O:23])=[O:22]
Reactant: OCCc1ccc2nonc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2nonc2c1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
5-(2-Hydroxyethyl)benzofurazan (1.48 g, 9 mmol) was dissolved in dichloromethane (45 ml) and triethylamine (1.88 ml, 1.37 g, 13.5 mmol) was added. The mixture was cooled to -30° C. and methanesulfonyl chloride (0.84 ml, 1.24 g, 10.8 mmol) was added dropwise over 5 min. The mixture was stirred at -30° C. for 15 min. and dichloromethane (100 ml) was added. The mixture was washed with water (100 ml), dried (Na2SO4) and evaporated under reduced pressure to give the benzofurazan as a yellow solid (2.10 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([O:21]C)=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([NH2:29])=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: NC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (137c, 75 mg, 200 μmol) in methanolic NH3 (7 M, 1 ml) was stirred at r.t. overnight to give a clear solution. Then the solvent was removed in vacuo, and the crude product was freeze-dried go give white solid material, 60 mg (83%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[Br:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:15][CH2:16][C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Br:1])=[O:18]
Reactant: Nc1ccccc1Br
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CBr)Nc1ccccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of 2-bromoaniline (2.0 g, 11.63 mmol) in 25 mL of dichloromethane was added pyridine (1.13 mL, 13.95 mmol). The solution was cooled to 0° C. and bromoacetyl chloride (1.01 mL, 12.79 mmol) was added over a 5 min. period. The cooling bath was removed and the reaction mixture was stirred at RT for 90 min and partitioned between 1N HCl and dichloromethane. The dichloromethane layer was successively washed with saturated aqueous sodium carbonate, brine, dried over sodium sulfate and concentrated to yield 2.9 g of the title compound, which was used as such for the subsequent step without further purification.
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[O:14][N:13]=[C:12]([C:15](=[O:17])[CH3:16])[CH:11]=1)(C)(C)C.COC(OC)OC.C([O-])(O)=O.[Na+]>C(O)CO>[OH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15](=[O:17])[CH3:16])[CH:11]=1
Reactant: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)on1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: COC(OC)OC
Product: CC(=O)c1cc(CO)on1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(tert-butyl-dimethyl-silanyloxymethyl)-isoxazol-3-yl]-ethanone (1.99 g, 7.79 mmol) in ethylene glycol (8.69 mL) was treated with trimethylorthoformate (1.71 mL, 15.58 mmol) followed by LiBF4 (146 mg, 1.56 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (2×50 mL). The combined org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (40:60 EA-Hept) gave the title compound as a yellow oil. TLC:rf (40:60 EA-Hept)=0.25. LC-MS-conditions 02: tR=0.54 min.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:20]([C:23]1[S:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21].OS(O)(=O)=O>CC(O)=O.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:28][C:26]2[S:27][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1C(=Cc2ccc([N+](=O)[O-])s2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 96 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with 5-nitrothiophene-2-carboxaldehyde (0.123 g, 0.78 mmol) in a mixture of HOAc (1 mL) and concentrated H2SO4 (0.100 mL) at room temperature overnight. The reaction was diluted with water, and the resulting precipitate was collected, washed well with water, and dried in vacuo at 60° C. to afford 0.296 g (80%) of the title compound as a brown powder, mp >240° C.: APCI-MS m/e 396.1 M++1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([NH2:11])[CH3:10]>C(Cl)Cl.O>[CH2:9]([NH:11][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])[CH3:10]
Reactant: CCN
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
A solution of 2-thiophenecarboxylic acid chloride (7.3 g, 50 mmol) in 30 mL CH2Cl2 was added to 70% ethylamine in water (11 g) at -5° C. and the resulting solution was stirred at RT for 18 h. After that, water was added. The organic layer was separated, washed with water, brine, dried and concentrated. Purification of the residue by flash chromatography with 25% ethyl acetate-hexane gave 6.4 g (83.1% yield) of N-ethyl-2-thiophenecarboxamide as a white solid, m.p. 75°-78° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:58][CH3:59])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:52][Si](C)(C)C)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:60])=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:52])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:58][CH3:59])=[CH:31][C:30]=2[CH3:60])=[CH:27][CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.8 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.364 mL, 0.364 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxytetrahydro-pyran-4-ylethynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 130-(5); 43.5 mg, 0.073 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 15 minutes. Then, the reaction mixture was diluted with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (34.4 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:24]1[C:25]([C:31]([OH:33])=[O:32])=[N:26][CH:27]=[C:28]([Cl:30])[N:29]=1>C1COCC1>[Cl:30][C:28]1[N:29]=[C:24]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=2[F:1])[C:25]([C:31]([OH:33])=[O:32])=[N:26][CH:27]=1
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Reactant: O=C(O)c1ncc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Nc2nc(Cl)cnc2C(=O)O)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of 2-fluoro-4-trimethylsilanyl-phenylamine (3.8 g, 20.7 mmol, 2.0 eq) in anhydrous THF (150 mL) at −78° C. under N2 was added dropwise a solution of 1.0 M LHMDS in THF (33.2 mL, 30 mmol, 3.2 eq) over 20 minutes. After 1 hour at −78° C., a solution of 3,5-dichloro-pyrazine-2-carboxylic acid (2.0 g, 10.3 mmol) in anhydrous THF (30 mL) was added. The mixture was stirred at −78° C. for 30 minutes, and then stirred at ambient temperature for 18 hours. The mixture was quenched with water and the pH adjusted to pH 2 by the addition of 2 N HCl. The reaction mixture was extracted with ethyl acetate, and the organic layer washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 20 to 50% ethyl acetate in hexane, followed by 0% to 30%, methanol in dichloromethane) to give the desired compound as a yellow solid (2.95 g, 83.8%). 1H NMR (CDCl3, 400 MHz) δ ppm 10.41 (s, 1H), 8.28 (t, J=7.79 Hz, 1H), 7.93 (s, 1H), 7.40-7.23 (m, 2H), 0.27 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=O)[CH2:4][CH2:5][C:6](O)=[O:7].[NH2:11][NH2:12]>C(O)C>[CH:2]([C:3]1[CH2:4][CH2:5][C:6](=[O:7])[NH:11][N:12]=1)([CH3:10])[CH3:1]
Reactant: NN
Reactant: CC(C)C(=O)CCC(=O)O
Solvent: CCO
Product: CC(C)C1=NNC(=O)CC1

Procedure:
5-Methyl-4-oxohexanoic acid (3.60 g, 25.0 mmol) and anhydrous hydrazine (0.80 g, 26.0 mmol) were heated for 3 hours in ethanol (36.0 ml) under stirring. After the reaction solution was concentrated under reduced pressure, hexane was added to the residues to precipitate crystals, and the crystals were collected by filtration to give 4,5-dihydro-6-isopropyl-3(2H)-pyridazinone as crystals. The yield was 3.10 g.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>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.[Cu]I>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:41]#[C:40][C:39]([OH:38])([CH3:43])[CH3:42])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 3-hydroxy-3-methylbutyne (168 mg, 2.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (40 mg), and copper(I) iodide (20 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, elution with 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-but-1-ynyl)-pyrazin-2-yl]-propionamide (412 mg, 84%) as a fluffy solid: (ES)+-HRMS m/e calcd for C24H28ClN3O4S (M+H)+ 490.1562, found 490.1553.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[N:10][C:9]([S:17][CH3:18])=[CH:8][C:7]2=1)([O-])=O.C(O)C>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[N:10][C:9]([S:17][CH3:18])=[CH:8][C:7]2=1
Reactant: CSc1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1cc2c(cn1)[nH]c1ccc(N)cc12

Procedure:
950 mg of 6-nitro-3-methylthio-β-carboline are hydrogenated in 80 ml of tetrahydrofuran and 80ml of ethanol with 200 mg of palladium/carbon (10%) for 7.5 hours at room temperature under normal hydrogen pressure. After filtration and concentration, the residue is chromatographed on silica gel with methylene chloride/acetone=1:1 as eluant. 600 mg of 6-amino-3-methylthio-β-carboline with a 202° C. melting point are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:45]=[CH:46][CH:47]=1)[CH2:38][NH:39][C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:46]2[CH:47]=[CH:35][CH:36]=[C:37]([CH2:38][NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[CH:45]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(NCc1cccc(Br)c1)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NCc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1)C1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), cyclopropanecarboxylic acid 3-bromo-benzylamide (41.7 mg, 0.16 mmol), and Pd[P(Ph)3]4 (15.1 mg, 8.0 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.0 mg. MS: 498.3 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.55-0.70 (m, 4H), 1.50-1.60 (m, 1H), 1.73-1.98 (m, 3H), 2.07-2.29 (m, 1H), 3.35-3.56 (m, 2H), 4.24-4.37 (m, 3H), 4.85-5.08 (m, 2H), 6.97-7.54 (m, 12H), 7.63-780 (m, 1H), 8.50-8.59 (m, 1H), 10.06-10.13 (s, 1H).
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)#[N:9].BrN1C(=[O:31])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O>[C:8]([N:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]([OH:31])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)#[N:9]
Reactant: N#CN1c2ccccc2CCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 87.5 °C
Yield: 52.2 %

Procedure:
190 ml of chlorobenzene and 25 g of (I) are loaded into a 500 ml pyrex round-bottom flask, under nitrogen. Afterwards, 21.2 g of N-bromosuccinimide and 2.2 g of dibenzoylperoxide are added and the mixture is heated to 85-90° C., keeping this temperature for 1.5 hours. 150 ml of water and 5 g of PEG 6000 are added, heating to 85°-90° C. for 2 hours. After decanting at 60° C., water is removed and the organic phase is washed with further water (2×100 ml). Chlorobenzene is evaporated off under vacuum at 5 mm/Hg and the residue is taken up with 50 ml of ethyl acetate. The mixture is cooled to 0° C. for 2 hours, filtered and dried at 60° C. for 4 hours, to obtain 14 g of (VI), m.p. 111-112° C., with good purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.CN.[C:13]([BH3-])#[N:14].[Na+].Cl>CO>[CH3:13][NH:14][CH:5]1[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4]1
Reactant: [BH3-]C#N
Reactant: CC1(C)CCC(=O)CC1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC1CCC(C)(C)CC1
Reaction time: 1 h

Procedure:
To a solution of 4,4-dimethylcyclohexanone (25.2 g) in dry methanol under an atmosphere of nitrogen was added methylamine hydrochloride (13.2 g) and 3 Åmol sieves (1 g). The reaction mixture was stirred for 1 hr then sodium cyanoborohydride (12.7 g) added portionwise. The mixture was stirred for 17 hrs. A saturated solution of hydrogen chloride in methanol (200 ml) was added and the reaction mixture stirred for 1 hr the filtered through hyflo and concentrated in vacuo. The residue was partitioned between 1N sodium hydroxide (300 ml) and dichloromethane (200 ml). The layers were separated and the aqueous re-extracted with dichloromethane (2×200 ml). The combined organics were washed with saturated sodium hydrogen concentrated in vacuo. The residue was distilled under reduced pressure. Bpt 40°-45° C. at 0.1 mmHg. 1H NMR (CDCl s) δ0.92 (6H, s), 1.10-1.30 (5H, m), 1.30-1.50 (2H, m), 1.66-1.72 (2H, m), 2.26 (1H, m), 2.42 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O=S(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:26]2[CH2:27][CH2:28][CH:23]([N:20]3[CH2:21][CH2:22][CH:17]([CH2:16][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:18][CH2:19]3)[CH2:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCC(N2CCC(Cc3ccccc3)CC2)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(C2=CCC(N3CCC(Cc4ccccc4)CC3)CC2)cc1

Procedure:
4-Fluorophenyl magnesium bromide (10 mmole) and 4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanone (7.38 mmole) were reacted by the method described in Example 13 to give the intermediate mixture of cis and trans alcohols. This crude mixture was then dehydrated using SOCl2 in CH2Cl2 by the method described in Example 35 to give the crude product which was purified by chromatography on silica gel using ethyl acetate as the eluent. The pure product was converted the HCl salt in acetone using 12N HCl (23.3% overall, mp: 214-217° C.). Calc'd for C24H28NF.HCl.0.25H2O: C, 73.83%; H, 7.62%; N, 3.59%. Found: C, 73.85%; H, 7.61%; N, 3.56%.
Reaction SMILES: C([NH:9][C:10]([CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)([CH:14]=[C:15]=[CH2:16])[C:11]([OH:13])=[O:12])(=O)C1C=CC=CC=1>Cl.O>[NH2:9][C:10]([CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)([CH:14]=[C:15]=[CH2:16])[C:11]([OH:13])=[O:12]
Reactant: C=C=CC(Cc1c[nH]cn1)(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Product: C=C=CC(N)(Cc1c[nH]cn1)C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.0 g of 2-(benzoylamino)-2-(imidazol-4-ylmethyl)-penta-3,4-dienoic acid was taken in 20 ml of 20% HCl and heated at 80° C. for 48 hours. The solution was cooled, diluted with 20 ml of water and washed with methylene chloride 3×40 ml. The aqueous phase was adjusted to pH 7.0, cooled to 0° C. and an excess of sodium borohydride added. After two hours at 0° C., the pH was adjusted to 2.0 and the solution introduced onto an ion-exchange chromotography (BioRad Ag 50×8 column), and eluted with 0.3M ammonium acetate buffer pH 4.5-8.0. Fractions between pH 6.5-8.0 were pooled and desalted with 20% pyridine-water. Concentration of the pyridine-water fractions gave an oil which upon fractional crystallization gave the title compound.