Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:52]=[CH:51][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:22]=[CH:21][C:20]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=3)[CH2:37][S:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[O:33])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:22]=[CH:21][C:20]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=3)[CH2:37][S:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:33])[CH:14]=2)=[O:12])=[CH:51][CH:52]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(C(C)(C)C)cc3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=O)c2ccnc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((4-tert-butylbenzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate (100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (2 mL), and trifluoroacetic acid (160 mg, 1.40 mmol, 10.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (95 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 50 mg (46%) of a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 9.03-9.05 (d, J=5.4 Hz, 1H), 8.80-8.83 (d, J=9.3 Hz, 1H), 8.42 (s, 1H), 8.16-8.17 (d, J=2.7 Hz, 1H), 8.00 (s, 1H), 7.90-7.90 (d, J=1.5 Hz, 1H), 7.87-7.89 (m, 2H), 7.71-7.75 (dd, J=9.02 Hz, J′=2.7 Hz, 1H), 7.60-7.62 (m, 1H), 7.50-7.55 (m, 1H), 7.40-7.42 (m, 2H), 7.31-7.39 (m, 2H), 4.61 (s, 2H), 3.91 (s, 2H), 3.70-3.73 (m, 4H), 2.70 (m, 2H), 2.56-2.51 (m, 2H), 2.06-2.09 (m, 4H), 1.84-1.86 (m, 1H), 1.32-1.33 (m, 9H). MS (ES, m/z): 665 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.O.[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]#[N:17])=[CH:3][C:4]=1[O:10][C:11]([F:14])([F:13])[F:12])=[O:7]
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(C=O)c(OC(F)(F)F)c1

Procedure:
10.63 g (39.51 mmol) of 4-bromo-2-(trifluoromethoxy)benzaldehyde, 3.43 g (29.24 mmol) of zinc cyanide and 1.37 g (1.19 mmol) of tetrakis(triphenylphosphine)palladium(0) are dissolved in 80 ml of DMF. The reaction mixture is then reacted in several portions in a single mode microwave (Emrys Optimizer, 5 min at 220° C.). The combined mixtures are mixed with water and extracted twice with toluene. The combined organic phases are washed with saturated sodium chloride solution and dried with sodium sulfate, and then the solvent is removed in a rotary evaporator. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 10:1). 3.32 g (78% of theory) of the title compound are obtained with a purity of 80% (according to LC-MS).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[I:13][C:14]1[CH:15]=[C:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:13][C:14]1[CH:15]=[C:16]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[N:17]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH:18]=1
Reactant: O=C(c1cc(I)c[nH]1)C(F)(F)F
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(I)cc2C(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 33.4 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.63 g), 4-iodo-2-(trifluoroacetyl)pyrrole (0.89 g) and potassium carbonate (0.57 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4-iodo-1-(3-methyl-4-nitrobenzyl)-2-trifluoroacetyl-1H-pyrrole (0.45 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)C(C(NCCNC(=O)OC(C)(C)C)=O)=[N:3]1.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27].CCCCCC>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:27]([C:26]([O:29][CH2:30][CH3:31])=[O:28])=[N:3]1
Reactant: Cn1cc(-c2ccccc2)c(C(=O)NCCNC(=O)OC(C)(C)C)n1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1nn(C)cc1-c1ccccc1

Procedure:
In an analogous manner to that described in Examples I6 and 17. from 6.6 g (28.7 mmol) of ethyl 1-methyl-4-phenyl-3-pyrazolecarboxylate there were obtained 4.6 g 71.5%) of t-butyl [2-(1-methyl-4-phenyl-3-pyrazolecarboxamido)ethyl]carbamate as white crystals, melting point 145° (from ethyl acetate/hexane).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[CH2:15][NH:16][C:17](=[O:31])[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:32]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][NH:16][C:17](=[O:31])[C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: O=C(NCC(=O)N1CCN(Cc2ccccc2)CC1)c1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
Under an inert atmosphere, 10% Pd/C (111 mg) was added to a stirred solution of N-[2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-4-phenoxy-benzamide (490 mg, 1.14 mmol) in MeOH (90 mL). Hydrogen gas was then passed into the reaction mixture by means of a hydrogen filled bladder and the mixture was stirred at room temperature overnight. The mixture was filtered over celite and the celite was washed with MeOH. The filtrate was collected and concentrated under reduced pressure to afford 390 mg (quantitative yield) of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide as a solid. LC-MS purity: 88.65, 1H NMR (CDCl3): δ 7.8 (d, 2H), 7.38 (m, 2H), 7.26 (bs, 1H), 7.18 (tt, 1H), 7.08-7.0 (m, 4H), 4.24 (d, 2H), 3.66 (t, 2H), 3.5 (s, 1H), 3.44 (t, 2H), 2.9 (q, 4H), 2.5-2.6 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]#[CH:20])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>COCCOC>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[S:17][CH:18]=[C:19]([CH2:20][OH:30])[C:15]=3[CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C#CCSc1ccc(OS(=O)(=O)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(Oc1ccc2scc(CO)c2c1)c1ccccc1
Reaction time: 2 h
Yield: 187.8 %

Procedure:
The compound (3) (65.47 g, 183 mmol) obtained in above (2) was dissolved in 1,2-dimethoxyethane (1.6L) and the solution was refluxed for 4 hours. To the solution were added water (64 ml) and p-toluenesulfonic acid monohydrate (19.2 g, 100 mmol) and refluxing was continued for 2 hours. The reaction mixture was concentrated under reduced pressure. After water (200 ml) was added to the resulting oil, the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 60.18 g of the title compound (4) as oil. Crude yield: 103%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)[N:10]3[CH:32]=[CH:33][N:34]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[B-](F)(F)(F)[F:36].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(=O)C>CC#N>[F:36][C:32]1[N:10]2[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)=[N:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][C:9]2=[N:34][CH:33]=1
Reactant: F[B-](F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: Cn1cc(-c2cc3ncc(F)n3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Temperature: 80 °C
Yield: 20.6 %

Procedure:
2-(3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (Example 96; 0.200 g, 0.407 mmol), Selectfluor (0.288 g, 0.814 mmol) and acetic acid (0.233 mL, 4.07 mmol) were suspended in MeCN (20 mL) and heated to 80° C. overnight. The reaction mixture was cooled to ambient temperature and the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The combined organic extracts were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 1-2% (9:1 MeOH:NH4OH)/dichloromethane to provide 2-(3-(4-(3-fluoro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (0.043 g, 0.084 mmol, 21% yield). MS (apci) m/z=510.1 (M+H).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20](O)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2>>[C:11]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][C:20]3[C:21]4[C:26]([CH:27]=[C:18]([CH3:17])[C:19]=3[CH:9]=[CH:8]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(O)c2ccccc2c1
Product: Cc1cc2ccccc2c2c1C=CC(c1ccccc1)(c1ccccc1)O2

Procedure:
The procedure of Step 2 of Example 1 was followed except that 1,1-diphenyl-2-propyn-1-ol was used in place of 1,1-bis(4-methoxyphenyl)-2-propyn-1-ol and 3-methyl-1-hydroxynaphthalene was used in place of methyl,1,4-dihydroxy-2-naphthoate to produce 2,2-diphenyl-5-methyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][S:12][CH3:13])=[CH:7][CH:6]=1)[OH:4].[S:16](Cl)([C:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:24]([N:25]([CH3:27])[CH3:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].C1N2CCN(CC2)C1.O>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[CH:3]([O:4][S:16]([C:19]1[C:31]2[C:23](=[C:24]([N:25]([CH3:27])[CH3:26])[CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:6]=[CH:7][C:8]([S:11][S:12][CH3:13])=[CH:9][CH:10]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CSSc1ccc(C(O)C(F)(F)F)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: CSSc1ccc(C(OS(=O)(=O)c2cccc3c(N(C)C)cccc23)C(F)(F)F)cc1
Reaction time: 4 h
Yield: 28.4 %

Procedure:
2,2,2-Trifluoro-1-(4-methyldisulfanyl-phenyl)-ethanol (6) (12 mg, 0.047 mmol) and dansyl chloride (15 mg, 0.057 mmol) were dissolved in dry CH2Cl2 (0.2 mL). A solution of DABCO (63 mg, 0.56 mmol) dissolved in dry CH2Cl2 (0.1 mL) was added dropwise to the above solution. After 4 hours at room temperature, the reaction was poured into H2O (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with H2O (3×30 mL), followed by brine (1×30 mL) and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation. Flash chromatography on silica gel using 0-15% acetone/hexanes to yield Compound 1 as a yellow solid (6.5 mg, 28%). 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J=8.5 Hz, 1H), 8.2 (d, J=8.7 Hz, 1H), 8.07 (d, J=7.3 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 5.59 (q, J=6.3 Hz, 1H), 2.84 (s, 6H), 2.37 (s, 3H); 19F NMR (376 MHz, CDCl3): δ −76.3 (d, J=6.3 Hz). HRMS calc'd for C21H21F3NO3S3: 488.0636. found: 488.0647.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.[BH4-].[Na+].O>CO>[CH3:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: CC1CCC(N)CC1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCC(NCc2ccc(-c3cccc(C(N)=O)c3)cc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 4′-formylbiphenyl-3-carboxylic acid amide (700 mg, 3.1 mmol) in methanol (15 mL) was added 4 Å molecular sieves (700 mg) and 4-methylcyclohexylamine (421 mg, 3.7 mmol). The mixture was stirred for 16 h before adding sodium borohydride (588 mg, 15.5 mmol). After 1 h water (10 mL) was added, the mixture was filtered through celite and the solvent removed in vacuo. Purification of the residue by column chromatography (0.5% NH3: 6% MeOH: DCM) gave the title compound: RT=2.53 min; m/z (ES+)=323.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)(=[O:11])=[O:10].[CH3:23][O:24][C:25](=[O:38])[C@@H:26]([NH2:37])[C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[CH3:28]>>[CH3:23][O:24][C:25](=[O:38])[C@@H:26]([NH:37][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:13]=1[NH:12][S:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])(=[O:11])=[O:10])[C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1)[CH3:28]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)[C@H](C)c1ccc(Cl)c(Cl)c1
Product: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F)[C@H](C)c1ccc(Cl)c(Cl)c1

Procedure:
2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to (2S,3R)-2-amino-3-(3,4-dichloro-phenyl)-butyric acid methyl ester as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=12.39 min. MS (ESI+): mass calcd. for C24H19Cl2F2IN2O5S, 683.29; m/z found, 683/685 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.29 (s, 1H), 8.11 (d, J=1.6, 1H), 7.52-7.47 (m, 1H), 7.42 (dd, J=8.3, 1.6, 1H), 7.37 (d, J=13.9, 1H), 7.24 (d, J=2.1, 2H), 7.11 (d, J=8.3, 1H), 7.02-6.98 (m, 3H), 6.65 (d, J=8.3, 1H), 4.95-4.91 (m, 1H), 3.26 (s, 3H), 3.31 (quin, J=7.2, 1H), 1.43 (d, J=7.2, 3H).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(OCC)(=O)C.N1C=CC=CC=1>[C:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)(=[O:16])[CH3:15]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCc2c([nH]c3ccccc23)C1
Reaction time: 0.5 h

Procedure:
2-acetyl-1,2,3,4-tetrahydro-β-carboline was prepared as follows: 1 g of 1,2,3,4-tetrahydro-β-carboline (Sigma) was dissolved in a minimum of ethyl acetate, and pyridine 3 mL) was added along with acetic anhydride (1.5 mL). After 30 minutes, the mixture was dried and the resulting 2-acetyl-1,2,3,4-tetrahydro-β-carboline was recrystallized from acetone.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39]N)=[CH:35][CH:34]=1>>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:37]4[C:36](=[CH:35][CH:34]=[C:33]([CH3:32])[CH:38]=4)[NH:39][C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 494.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[O:20][C:21]([CH3:24])=[N:22][N:23]=2)[CH:14]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>>[CH3:24][C:21]1[O:20][C:19]([C:15]2[CH:14]=[C:13]([N:12]3[C:3]4[CH:4]=[CH:5][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:2]=4[NH:1][C:26](=[O:27])[C:25]3=[O:29])[CH:18]=[CH:17][CH:16]=2)=[N:23][N:22]=1
Reactant: Cc1nnc(-c2cccc(Nc3ccc4ccccc4c3N)c2)o1
Reactant: O=C(Cl)C(=O)Cl
Product: Cc1nnc(-c2cccc(-n3c(=O)c(=O)[nH]c4c5ccccc5ccc43)c2)o1
Yield: 40 %

Procedure:
1-Amino-2-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]aminonaphthalene (95 mg, 0.3 mmol) and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound as white crystal (43 mg, yield 40%).
Reaction SMILES: [F:1][C:2]([F:23])([Cu])[C:3]([F:21])([F:20])[C:4]([F:19])([F:18])[C:5]([F:17])([F:16])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[CH2:24](Br)[C:25]#[CH:26]>>[F:1][C:2]([F:23])([CH:24]=[C:25]=[CH2:26])[C:3]([F:21])([F:20])[C:4]([F:19])([F:18])[C:5]([F:17])([F:16])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9]
Reactant: C#CCBr
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[Cu]
Product: C=C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 10 %

Procedure:
L. Coe and N. E. Milner, Journal of Organometallic Chemistry, 70, 147(1974) disclosed the reaction of perfluoro-n-heptyl copper with propargyl bromide at 110° C. to be an extremely violent exothermic reaction that afforded, after a difficult workup that included a minor explosion, a 10% yield of 1-(perfluoro-n-heptyl)-1,2-propadiene. There is no disclosure nor suggestion relating to a means of performing said conversion in a safe, controllable, reproducible, high-yield manner.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C@@H:4]([CH2:6][CH:7]2[O:11][CH2:10]O[O:8]2)[N:3]1C(=O)C(OC)=O.[N+](=C)=[N-]>CO.C(OCC)C>[O:1]=[C:2]1[NH:3][C@@H:4]([CH2:6][C:7]([O:11][CH3:10])=[O:8])[CH2:5]1
Reactant: COC(=O)C(=O)N1C(=O)C[C@H]1CC1OCOO1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C[C@H]1CC(=O)N1
Temperature: 0 °C
Yield: 17.1 %

Procedure:
A solution of methyl [(4R)-2-oxo-4-(1,2,4-trioxolan-3-ylmethyl)azetidin-1-yl]glyoxylate (60 mg) in methanol (5 ml) was heated at 65°-70° for two hours. The yellowish solution was cooled to 0° C. and treated with a solution of diazomethane (excess) in diethyl ether. After removal of the solvent, the residue was chromatographed on silica gel (1.5 g) eluting with 20% acetone in dicloromethane to give methyl 2-[(2R)-4-oxoazetidin-2-yl]acetate (6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20](O)[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:20][CH3:21])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A suspension of 55.4 g. of 5-(p-chlorobenzoyl)-1-methyl-pyrrole-2-acetic acid, 44 ml. of absolute ethanol, 1g. of p-toluenesulfonic acid and 650 ml. of benzene is heated under reflux with azeotropic removal of water for 7 hours. The reaction mixture is filtered, washed with sodium bicarbonate solution, dried over anhyrous magnesium sulfate and the solvent evaporated in vacuo. The crystalline residue is recrystallized twice from cyclohexane to give ethyl 5-(p-chlorobenzoyl)-1-methyl-pyrrole-2-acetate as a yellow solid, m.p. 74°-76°C.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[C:31]([Cl:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[ClH:39].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[C:21]([NH:23][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:20]=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
40 mg (0.11 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzothiophene-2-carboxamide dihydrochloride are dissolved in 2 ml of DMF, and 59.6 μl (0.43 mmol) of triethylamine are added. 30 mg (0.21 mmol) of benzoyl chloride are added. The reaction mixture is stirred at RT for 18 h and then separated by preparative HPLC. The product fraction is concentrated under reduced pressure, a mixture of acetonitrile and 1N hydrochloric acid is added, and the mixture is then again concentrated and dried under high vacuum. 32 mg (67.8% of theory) of the title compound are obtained.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[NH:35]N>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([S:20]([N:23]([CH3:24])[CH3:25])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Product: CN(C)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cc(F)ccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=458.2 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>O>[N:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: Brc1ccncc1
Reactant: C1CNCCN1
Solvent: O
Product: c1cc(N2CCNCC2)ccn1
Temperature: 145 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To piperazine (3.6 g) dissolved at 110° C. was added 4-bromopyridine (1.0 g) and the mixture was stirred at 140-150° C. for 1 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (0.64 g) as a pale-yellow solid.