Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[C:10]3[CH:11]=[CH:12][C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:21]N>[Pd].C(O)C>[NH2:21][C:19]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=12
Reactant: c1ccc(-c2cc3ccc4ccccc4n3n2)cc1
Reactant: NN
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccccc2)nn2c1ccc1ccccc12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
1.0 g. 2-Phenylpyrazolo[1,5-a]quinoline (see J. Het. Chem., 12, 481/1975) are nitrosated analogously to Example 3. There is obtained 1 g. (89% of theory) of the corresponding 3-nitroso compound which is suspended in 90 ml. ethanol and mixed with 200 mg. palladium on carbon. The mixture is heated to 80° C. and 0.25 ml. hydrazine hydrate added portionwise thereto. After 10 minutes, the palladium-carbon is filtered off and the filtrate is evaporated. The residue is dissolved in ethanol and mixed with ethanolic hydrogen chloride. The precipitated hydrochloride is filtered off with suction to give 0.7 g. (72% of theory) of the title compound; m.p. 255°-258° C. TLC (Silica gel/methylene chloride): Rf =0.2
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][C:3]1([CH3:31])[CH3:30].[H-].[Na+].Br[CH2:35][CH2:36][CH2:37][CH2:38]Br>O1CCCC1>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([O:1][CH2:35][CH2:36][CH2:37][CH2:38][O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][C:3]2([CH3:30])[CH3:31])[C:3]([CH3:30])([CH3:31])[CH2:4]1)(=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: BrCCCCBr
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCCCCON2C(C)(C)CC(OC(=O)CCCCCCCCCCCCCCCCC)CC2(C)C)C(C)(C)C1

Procedure:
The title compound is prepared by reaction of a tetrahydrofuran solution of 1-hydroxy-4-octadecanoyloxy-2,2,6,6-tetramethylpiperidine with sodium hydride followed by reaction with 0.5 molar equivalent of 1,4-dibromobutane.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]([OH:27])[CH3:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.O=[Mn]=O>[C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 100.4 %

Procedure:
To a solution of 1-(1-trityl-1H-imidazol-4-yl)ethanol (4.0 g, 11.3 mmol) in anhydrous 1,4-dioxane (150 mL) was added activated MnO2 (2.5 g, 28.2 mmol) at 0° C. The mixture was refluxed for 2 hours. TLC (EtOAc/Petroleum ether 1:2) showed the starting material was consumed completely, and the mixture was filtered. The filter cake was washed with dry CH2Cl2 (5×50 mL) and the filtrate was evaporated to afford the title compound (4.0 g, 100%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH3:38])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[C:34]([F:36])[C:31]([C:32]#[N:33])=[C:30]([Cl:37])[CH:29]=2)=[N:24]1>>[Cl:37][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:9]([C:7]3[N:8]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:38])[N:24]=2)[CH:35]=[C:34]([F:36])[C:31]=1[C:32]#[N:33]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C1CC1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C2CC2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (1.41 mmol, 400 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.41 mmol, 395 mg). The product was purified by flash-chromatography. Yield 249 mg. 1H-NMR (400 MHz; CDCl3): δ −0.01 (s, 9H), 0.93 (t, 2H), 0.99 (d, 4H), 1.23 (d, 3H), 1.88-1.95 (m, 1H), 3.52 (t, 2H), 4.29-4.40 (m, 2H), 4.47-4.54 (m, 1H), 5.33 (s, 2H), 6.59 (d, 1H), 7.35 (d, 1H), 7.49-7.51 (m, 2H), 7.58 (d, 1H), 7.72 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[CH:10]([C:13](O)=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[CH:10]([C:13]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-carboxylic acid (120 mg) in DMF (dry) (3.5 mL) were added methanesulfonamide (101 mg), EDCI (203 mg) and DMAP (130 mg). The mixture was stirred at room temperature overnight.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14](/[C:17](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:18](\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH2:19][CH3:20])=[CH:13][CH:12]=1>>[C:21]1(/[C:18](/[CH2:19][CH3:20])=[C:17](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)\[C:14]2[CH:15]=[N:16][C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Reactant: OCCN1CCCCC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN2CCCCC2)nc1)c1ccccc1
Yield: 83.1 %

Procedure:
Following the same procedure as described in example 3, 2-(piperidin-1-yl)ethanol (385 mg, 10 eq) was reacted with (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenyl but-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) to give the desired product (106 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.16-7.21 (m, 2H), 7.01-7.15 (m, 6H), 6.88 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 2H), 5.63 (d, J=8.0 Hz, 1H), 4.25 (t, J=5.6 Hz, 2H), 2.73 (t, J=5.6 Hz, 2H), 2.40-2.62 (m, 6H), 1.63-1.75 (m, 4H), 1.44-1.56 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); m/z=429 [M+1]+.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][CH:12]1[CH2:25][CH2:24][O:23][C:22](=[O:26])[CH2:21][CH:20]=[CH:19][CH2:18][CH2:17][C:16]#[C:15][CH2:14][CH2:13]1>C(O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:11][CH:12]1[CH2:25][CH2:24][O:23][C:22](=[O:26])[CH2:21][CH:20]=[CH:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1
Reactant: CC1CCC#CCCC=CCC(=O)OCC1
Agent: [Pd]
Agent: CC1CC/C=C\CC/C=C/CC(=O)OCC1
Agent: CC1CCC#CCC/C=C/CC(=O)OCC1
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CC1CCC=CCCC=CCC(=O)OCC1
Reaction time: 5 h

Procedure:
Quinoline (27.5 μL, 0.232 mmol) and 10% Pd/BaSO4 (4.90 mg, 0.0461 mmol) were added to a stirred solution of (4E)-12-methyloxacyclotetradec-4-en-8-yn-2-one (256 mg, 1.16 mmol) in ethanol (20 mL). The reaction flask was flushed with argon followed by hydrogen, and the reaction mixture was stirred under hydrogen atmosphere at room temp. and ambient pressure. After 5 h, GC-monitoring indicated complete conversion, upon which the catalyst was filtered off through a pad of Celite and washed with ethanol. The solvent was removed under reduced pressure, and the resulting residue purified by chromatography on silica gel [30 g; pentane-Et2O (20:1); Rf=0.60 in pentane-Et2O (5:1)] to furnish (4E,8Z)-12-methyloxacyclotetradeca-4,8-dien-2-one (223 mg, 86%) as a colourless odoriferous liquid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[F:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][CH:41]=[C:40]2[CH2:46][CH2:47][CH2:48][C:49](O)=[O:50]>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:40]2[C:39]3[C:43](=[CH:44][CH:45]=[C:37]([F:36])[CH:38]=3)[NH:42][CH:41]=2)[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCc2c[nH]c3ccc(F)cc23)CC1
Reaction time: 24 h

Procedure:
A mixture of the diastereoisomers of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (465 mg, 2 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (830 mg, 3 mmol.) was added to a solution of 4-(5-fluoro-1H-indol-3-yl)butanoic acid (443 mg, 2 mmol.) in abs. methanol (10 ml), and stirring was carried out for 24 h at RT. For working up, the mixture was concentrated, water (5 ml) was added to the solid residue, and the pH was adjusted to 11 with 2M NaOH. Extraction was carried out with EE (5×10 ml), and the combined extracts were washed with 1M NaOH (2×3 ml), dried, filtered and concentrated. The residue was a diastereoisomeric mixture of the bases of the target product, which was separated by flash chromatography on silica gel (50 g) and purified (eluant: 700 ml of ethanol/EE 1:1). 260 mg (0.59 mmol.) of the non-polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)butanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide were obtained in the form of a light-yellow viscous oil; the oil was dissolved in 2-butanone (7 ml), and chlorotrimethylsilane (113 μl, 0.89 mmol.) was added thereto. There immediately formed a white precipitate, which was deposited in a tacky manner on the wall of the flask. The solvent was reduced to about 3 ml in vacuo and, after addition of ether (3 ml), vigorous stirring was carried out at RT for 1 h. The solid that formed was filtered off with suction, washed with ether (3×1.5 ml) and dried in vacuo. The hydrochloride of the non-polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)butanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide was thus obtained in the form of a hygroscopic solid in a yield of 272 mg.
Reaction SMILES: C(O)(=O)CCCCC(O)=O.C(#N)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17].[C:19]([O:29][CH3:30])(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].CO>>[C:16]([CH:15]([CH2:14][CH2:13][CH3:12])[C:24]([O:26][CH3:27])=[O:25])#[N:17].[C:24]([O:26][CH3:27])(=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:29][CH3:30])=[O:28]
Reactant: N#CCCCCC#N
Agent: O=C(O)CCCCC(=O)O
Solvent: CO
Solvent: COC(=O)CCCCC(=O)OC
Product: CCCC(C#N)C(=O)OC
Temperature: 220 °C
Reaction time: 5 h

Procedure:
Into a 2-liter, stainless autoclave were introduced 73.0 g (0.500 mole) of adipic acid, 432.0 g (4.000 moles) of adiponitrile and 26.1 g (0.150 mole) of dimethyl adipate. After purging with nitrogen, the content was stirred at 220° C. for 5 hours. After cooling the reaction mixture 320.0 g (10.000 moles) of methanol was added and the resulting mixture was stirred at 220° C. for 1 hour. By distilling the reaction mixture, there were obtained 114.2 g (0.810 mole) of methyl cyanovalerate and 26.8 g (0.154 mole) of dimethyl adipate.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14]#[C:15][C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=[C:10]([N:23]2[CH2:27][C@@H:26]([O:28][CH3:29])[C@H:25]([OH:30])[CH2:24]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([C:8]1[C:13]([C:14]#[C:15][C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][N:18]([CH3:33])[CH2:17]2)=[CH:12][CH:11]=[C:10]([N:23]2[CH2:27][C@@H:26]([O:28][CH3:29])[C@H:25]([OH:30])[CH2:24]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(C#CC3(O)CCCNC3)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@@H]1CN(c2ccc(C#CC3(O)CCCN(C)C3)c(Cc3ccccc3)n2)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a mixture of 94.0 mg of 3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]-3-pyridyl]ethynyl-3-piperidinol (Example 1), 34.6 μl of an aqueous solution of 37% formaldehyde and 1.5 ml of dichloromethane was added 73.4 mg of sodium triacetoxyborohydride under ice-cooling, followed by stirring at room temperature for 30 minutes. The organic layer was separated by adding water and ethyl acetate to the reaction mixture, and then it was washed with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by NH-silica gel column chromatography with 5% methanol/ethyl acetate, to give 79.0 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc(Br)c3)n2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
3 g (0.01 mol) of 4-[3-(3-bromophenyl)-1H-pyrazol-4-yl]pyridine were dissolved in 50 ml of dry dimethylformamide and 3.9 g (0.012 mol) of cesium carbonate and 1.6 ml (0.012 mol) of p-methoxybenzyl chloride were added. The mixture was stirred at 70° C. for 2 hours and the solvent removed in vacuo. The residue was taken up with dichoromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated. Purification by column chromatography (dichloromethane-acetone 95/5) afforded 2 g (48% yield) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][N:20]1[CH:24]=[C:23]([C:2]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:22]=[N:21]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(-c2cncc(C)c2)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cncc(C)c2)ccc1-c1cnn(C)c1
Temperature: 130 °C
Reaction time: 0.58 h

Procedure:
A solution of methyl 2-bromo-5-(5-methylpyridin-3-yl)benzoate (2-3, 0.269 g, 0.88 mmol, 1.0 equiv), 1-methylpyrazole-4-boronic acid pinacol ester (0.274 g, 1.32 mmol, 1.5 equiv), 4M Cs2CO3 (0.769 mL, 3.08 mmol, 3.5 equiv) and PdCl2(dppf) (0.064 g, 0.088 mmol, 0.1 equiv) was made in DMF (4.5 mL) and stirred at 130° C. for 35 minutes. The reaction mixture was cooled and partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by normal phase column chromatography (0 to 5% MeOH in EtOAc) to afford the product (2-4) as a solid. ESI+ MS [M+H]+ C18H17N3O2O: 308.02 found, 308.36 required.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[S:12])[NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Ca+2]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:12][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[N:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CCOC(=O)c1sc(CNC(=O)OC(C)(C)C)nc1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a solution of 5.02 g of (tert-butoxycarbonylamino)acetothioamide in 75 ml of ethanol were added 3.92 ml of ethyl 2-chloroacetoacetate and 2.75 g of calcium carbonate, and the mixture was stirred at 50° C. for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 5:1 mixture of toluene and ethyl acetate to give 5.65 g (yield 71%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].IC.[CH3:18][Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:13]#[N:14])([CH3:18])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(C)(C#N)CC2C1
Yield: 53.9 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (4.2 g, 20.2 mmol) and iodomethane (11.5 g, 80.8 mmol) were dissolved in 100 mL of tetrahydrofuran followed by dropwise addition of lithium hexamethyldisilazide (80.8 mL, 80.8 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was reacted for 2 hours until MS showed the disappearance of the starting materials. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an oil. TLC showed that there are two adjacent spots, and then the oil was purified by silica gel column chromatography to obtain the bottom spot compound 5-cyano-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12b (2.411 g) as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12](=[O:22])[N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[C:15](I)[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.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.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[C:12](=[O:22])[N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[C:15]([C:30]#[C:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: CCCCn1cc(I)cc(C(=O)NCc2ccccc2)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCn1cc(C#Cc2ccccc2)cc(C(=O)NCc2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a solution of 1-butyl-5-iodo-2-oxo-1,2-dihydropridine-3-carboxylic acid benzylamide (3-067) (78 mg) in DMF (2.0 mL) were added PdCl2(PPh3)2 (15 mg), phenylacetylene (89 mg), CuI (11 mg), and triethylamine (48 mg) at room temperature. After stirred at 90° C. for 18 h, to the reaction mixture were added a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by the preparative thin-layer chromatography (toluene/acetone=7/1) to give 1-butyl-2-oxo-5-phenylethynyl-1,2-dihydropridine-3-carboxylic acid benzylamide (3-069) (65 mg, 89%) as an oil.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][S:8][C@H:3]12.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)=O>[NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][S:8][C@H:3]12
Reactant: CCOC(=O)C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=CO
Product: CCOC(=O)C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
A solution of 175 mg. of tert-butyl 7-amino-3-(2'-ethoxycarbonylvinyl)-3-cephem-4-carboxylate-p-toluenesulfonate in 20 ml. of 98-100 percent formic acid was stirred at room temperature for two hours. The excess formic acid was removed under reduced pressure and the residue was purged once with ethyl acetate and then taken up in ethyl acetate:water mixture. The pH of the mixture was adjusted to 8.0 with saturated sodium bicarbonate solution and the organic layer was separated and removed. The aqueous portion was cooled in an ice bath and the pH was adjusted to 3.5 with 5 percent hydrochloric acid. The precipitate which formed upon acid addition was collected, yielding 67 mg. of the title compound. It had a m.p. of 234°-237° C. (d), and the IR, UV [λmax. 324 mμ (ε = 14,800)] and elemental analysis were consistent with the assigned structure:
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:30]([O:32][C:33](=[O:62])[CH:34]([C:55]1[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=1)[CH2:35][C:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=2)[N:38]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:37]=1)[CH3:31].[CH2:63]([NH2:66])[CH:64]=[CH2:65]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:30]([O:32][C:33](=[O:62])[CH:34]([C:55]1[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=1)[CH2:35][C:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([NH:66][CH2:63][CH:64]=[CH2:65])=[CH:43][CH:42]=2)[N:38]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:37]=1)[CH3:31]
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Reactant: C=CCN
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCNc1ccc(-c2cc(CC(C(=O)OCC)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 46.9 %

Procedure:
To a mixture of Pd2(dibenzylideneacetone)3 (4 mg, 0.004 mmol, 1 mol %), 2-(di-tert-butylphosphino)biphenyl (6 mg, 0.02 mmol, 5 mol %) and K3PO4 (130 mg, 0.61 mmol, 1.5 equiv) was added a solution of 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (Example 77, Step C; 200 mg, 0.4 mmol) in toluene (0.6 mL) followed by allylamine (0.030 mL, 0.48 mmol, 1.2 equiv). The resulting mixture was stirred at 110° C. for 12 h and then cooled to room temperature. Ethyl acetate (2 mL) and water (3 mL) were added, and the resulting aqueous layer was back-extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3 mL), and then dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (90 mg, 47%). HPLC: Rt=3.19 (Method B). MS (ESI): mass calculated for C31H33N3O2, 479.26; m/z found, 480.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.29 (s, 1H), 7.27-7.04 (m, 7H), 6.96 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.5 Hz, 2H), 6.07 (s, 1H), 5.96-5.89 (m, 1H), 5.29-5.25 (m, 1H), 5.18-5.16 (m, 1H), 4.20-4.14 (m, 1H), 4.10-4.02 (m, 2H), 3.76-3.75 (m, 2H), 3.52-3.45 (m, 1H), 3.08 (dd, J=14.5, 6.0 Hz, 1H), 2.34 (s, 6H), 1.19 (t, J=7.1 Hz, 1H).