Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[Cl-].[CH3:25][CH2:26][N:27]1[C:33](=[O:34])[C:31](=[O:32])[N:30]([C:35]([NH:37][C@@H:38]([C:45]([NH:47][C@@H:48]2[C:51](=[O:52])[N:50]3[C@@H:53]([C:58]([O-:60])=[O:59])[C:54]([CH3:57])([CH3:56])[S:55][C@H:49]23)=[O:46])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:29][CH2:28]1.[Na+].C(Cl)(Cl)Cl.CS(C)=O>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[CH3:25][CH2:26][N:27]1[C:33](=[O:34])[C:31](=[O:32])[N:30]([C:35]([NH:37][C@@H:38]([C:45]([NH:47][C@@H:48]2[C:51](=[O:52])[N:50]3[C@@H:53]([C:58]([OH:60])=[O:59])[C:54]([CH3:56])([CH3:57])[S:55][C@H:49]23)=[O:46])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:29][CH2:28]1
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C(=O)[O-])c2ccccc2)C(=O)C1=O
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C(=O)O)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Yield: 26.12 %

Procedure:
Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Sodium piperacillin (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and a cloudy solid was obtained in 26.12% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=30-40° C. Thermal data determined by thermalgravimetric analysis (TGA): Tonset5%=165° C. and Tonset=177° C.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:19][C:20](=[O:21])[CH3:22]
Reactant: CC(C)=O
Reactant: Cc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C=Cc1ccccc1C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
In a 250 ml single neck flask was charged 12.0 g (100 mmoles,1.0 eq) of o-tolualdehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.8 g of 4-(o-tolyl)-3-buten-2-one as a faintly yellow oil in 86.3% yield.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].CN([CH:24]=[O:25])C>C1COCC1>[Cl:13][C:14]1[C:15]([F:20])=[CH:16][N:17]=[CH:18][C:19]=1[CH:24]=[O:25]
Reactant: Fc1cnccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cncc(F)c1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
To a solution of diisopropylamine (6.4 mL, 45.6 mmol) in THF (50 mL) at −30° C. was added n-butyllithium (2.5 M in hexanes, 18.2 mL, 45.6 mmol) over 15 minutes and the resulting mixture stirred for 15 minutes then cooled to −78° C. A solution of 4-chloro-3-fluoro-pyridine (5.0 g, 38.0 mmol) in THF (10 mL) was added dropwise over 15 minutes then the resulting mixture was stirred at −78° C. for 18 hours. DMF (3.5 mL, 45.6 mmol) was added and the reaction was warmed to room temperature. The mixture was quenched with ammonium chloride (sat. aq., 300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in cyclohexane) to afford the title compound as a pale orange solid (5.1 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 10.47 (s, 1H), 8.88 (s, 1H), 8.70 (s, 1H).
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@:10]1([CH3:26])[C:22]([O:24][CH3:25])=[O:23])C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)=O.CO.[Pd]>[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:8][C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@:10]2([CH3:26])[C:22]([O:24][CH3:25])=[O:23])(=[O:51])=[O:50])=[CH:45][CH:44]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@@]1(C)CN(C(=O)OC(C)(C)C)CC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Solvent: CO
Product: COC(=O)[C@@]1(C)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
(3S,4R)-1-tert-Butyl 3-methyl 4-(benzyl((R)-1-phenylethyl)amino)-3-methylpiperidine-1,3-dicarboxylate (4.777 g, 10.24 mmol) was taken up in 100 mL of 4.4% formic acid in methanol. Palladium on Carbon (10%, 1.059 g) was added and the reaction mixture was stirred under a nitrogen atmosphere for 2 h at room temperature. Filtration through celite gave a colorless solution that was concentrated to give a colorless oil. The oil was combined with 4-(benzyloxy)benzene-1-sulfonyl chloride (4.377 g, 15.48 mmol) and equivalent volumes of CH2Cl2 and saturated sodium bicarbonate, and the resultant biphasic mixture was stirred vigorously overnight. The organic layer was separated and the remaining aqueous phase was washed with CH2Cl2 (3×). the organic extracts were combined, dried over Na2SO4 and concentrated to give a beige solid that was purified by chromatography on silica gel eluting with 30% ethyl acetate/hexanes to give (3S,4R)-1-tert-butyl 3-methyl 4-(4-(benzyloxy)phenylsulfonamido)-3-methylpiperidine-1,3-dicarboxylate as a white solid (4.523 g, 8.72 mmol, 85%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.14 (s, 3 H) 1.37-1.48 (m, 11H) 1.78 (s, 1H) 2.02-2.05 (m, 3H) 2.51 (s, 1H) 3.08-3.16 (m, 1H) 3.65 (s, 3H) 4.48 (s, 1H) 5.11 (s, 2H) 5.65 (d, J=9.60 Hz, 1H) 7.01-7.06 (m, 2H) 7.31-7.43 (m, 6H) 7.78-7.82 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)=[C:10]([F:22])[CH:9]=2)[CH2:4][CH2:3]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH2:36][CH2:37][C@H:38]1[CH2:43][CH2:42][Si@H:41]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40][CH2:39]1>[Cu]I.C1COCC1>[CH2:44]([Si@H:41]1[CH2:42][CH2:43][C@H:38]([CH2:37][CH2:36][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)=[C:10]([F:22])[CH:9]=3)[CH2:4][CH2:3]2)[CH2:39][CH2:40]1)[CH2:45][CH2:46][CH3:47]
Reactant: Fc1ccc(-c2ccc(C3CCC(Br)CC3)cc2F)cc1F
Reactant: CCCC[Si@H]1CC[C@H](CCBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)c(F)c3)CC2)CC1

Procedure:
36.9 g (0.1 mol) of 4-(4-bromocyclohexyl)-2,3',4'-trifluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 26.3 g (0.1 mol) of trans-1-(2-bromoethyl)-4-n-butyl-4-silacyclohexane. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-butyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,3',4'-trifluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 34.3 g (yield 72.6%) of the trans isomer.
Reaction SMILES: OCC1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@H:7]1[NH:15][CH3:16].Br[CH2:22][CH2:23]Br.C(N(CC)CC)C.[Br-].C([NH+](CC)CC)C.C([O:42][CH2:43][CH3:44])C>>[OH:42][CH2:43][C:44]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[N:5]1[CH2:23][CH2:22][N:15]([CH3:16])[C@@H:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C@@H:6]12
Reactant: CN[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1CO
Reactant: CCOCC
Reactant: BrCCBr
Agent: CC[NH+](CC)CC
Agent: [Br-]
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccccc2CO)[C@@H]2c3ccccc3C[C@H]21
Yield: 54 %

Procedure:
A solution of trans 1-(2-hydroxymethylanilino)-2-methylaminoindane (1.16 kg; 4.3 moles) in 1,2-dibromoethane (7 l, 17.1 moles) and triethylamine (2.5 l; 34 moles) was added dropwise to stirred 1,2-dibromoethane (13 l; 31.9 moles) at ca. 100° over a period of 1.5 h. This was followed by triethylamine (2.5 l; 34 moles) added dropwise over 30 min. The reaction was cooled to 50° and diethyl ether (80 l) was added with good stirring. After stirring for 1 h the precipitated triethylammonium bromide was filtered off and the resulting solution concentrated in vacuo to ca 3.5 l. Addition of ethyl acetate (2.5 l) assisted crystallisation of the required product. Filtration and trituration (pet. ether) afforded the title compound as a white crystalline solid (687 g; 54%) m.p. 166-7°.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:29](=[O:36])[N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH:50]1[C:62]2[CH:61]([CH2:63]OC(ON3C(=O)CCC3=O)=O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1>C(Cl)Cl>[CH:50]1[C:62]2[CH:61]([CH2:63][O:5][C:6]([NH:8][C@H:9]([C:29](=[O:36])[N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:10][C:11]3[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:16]=3)=[O:7])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)CCCCCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCCCCc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (S)-6-(4-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)hexanoate (Compound SP426) (5.65 g, 11.24 mmol) was dissolved in DCM (30.0 ml), trifluoroacetic acid (15.0 ml, 195 mmol) was added and the mixture was stirred for 30 minutes at room temperature, after which the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in dioxane (40 ml) and a 10% aqueous sodium carbonate solution (80 ml), N-(9-fluorenylmethoxycarbonyloxy)-succinimide (3.68 g, 10.90 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made acidic by adding a 5 N aqueous HCl solution and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound SP427 (6.39 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.O>[CH3:25][S:26]([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(Nc2ncc(Br)cn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1ccc(Nc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)ethanol 18 (6.22 mmol) in DCM (30 mL) is added triethylamine (9.33 mmol) and methanesulfonyl chloride (7.47 mmol). The reaction mixture is stirred at rt for 1.5 h. The reaction is diluted with H2O (10 mL) and washed with Na2CO3 solution (3×10 mL). The organic layer is washed with brine, dried over MgSO4 and concentrated to afford 4-(5-bromopyrimidin-2-ylamino)phenethyl methanesulfonate 19. 1H NMR (400 MHz, CD2Cl2) δ 8.36 (s, 2H), 7.65 (bs, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.79 (s, 3H). MS (m/z) (M+1)+: 372.0, 374.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.[Cu]I.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>[F:40][C:38]1[CH:37]=[CH:36][C:35]([CH2:41][C:42]([O:44][CH3:45])=[O:43])=[C:34]([C:32]#[C:33][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)[CH:39]=1
Reactant: C#Cc1cc(F)ccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(F)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.252 g, 0.552 mmol), methyl 2-(2-ethynyl-4-fluorophenyl)acetate (A50) (0.106 g, 0.552 mmol), PPh3 (0.007 g, 0.03 mmol), CuI (0.005 g, 0.03 mmol) and PdCl2(PPh3)2 (0.019 g, 0.028 mmol) in DMF (3 mL) and Et3N (1.0 mL) was heated under microwave irradiation for 20 minutes at 120° C. The resulting mixture was diluted with EtOAc (100 mL) then washed with water (100 mL), brine (25 mL) and dried over MgSO4. The volatiles were evaporated in vacuo and the residue was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound A51 as a yellow solid (0.158 g, 47%); 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J=1.0 Hz, 1H), 7.75 (s, 1H), 7.62-7.55 (m, 2H), 7.38-7.27 (m, 2H), 7.25-7.19 (m, 2H), 7.14 (td, J=8.3, 2.7 Hz, 1H), 4.36-4.20 (m, 2H), 3.92 (s, 2H), 3.72 (s, 3H), 2.82 (t, J=12.8 Hz, 2H), 2.66 (td, J=8.5, 4.2 Hz, 1H), 1.89-1.78 (m, 2H), 1.70-1.54 (m, 2H), 1.51 (s, 9H). LCMS-A: rt 1.852 min; m/z 613 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1CO.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reaction time: 0.33 h

Procedure:
A suspension of ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 2 (1 eq) in a mixture of tetrahydrofuran-methanol (0.15M) and 1N aqueous sodium hydroxide (2 eq) was heated at ca 50° C. with stirring for 20 minutes. After cooling, the mixture was diluted with water and acidified with 1N aqueous HCl. After stirring for 45 minutes, the precipitate was filtered, washed well with water and dried to afford the title acid as a cream-colored solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+].[N:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]2=[C:16](C(O)=O)[CH:15]=1>O>[Br:1][C:16]1[CH:15]=[N:14][N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cnn2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Brc1cnn2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
N-Bromosuccinimide (3.06 g, 17.22 mmol) and sodium hydrogen carbonate (4.34 g, 51.66 mmol) were added to a solution of pyrazolo[1,5-a]pyridine-3-carboxylic acid (Preparation 22b, 2.81 g, 17.22 mmol) in NN-dimethylformamide (40 mL) and the resulting mixture was stirred at room temperature for 4 h before being poured over 100 mL of water. The resulting suspension was extracted twice with ethyl acetate and the combined organic layers were dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (8:2 hexane/ethyl acetate) to yield the title compound (2.58 g, 76%).
Reaction SMILES: CN(C)CCCN=C=NCC.[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]([OH:23])=O.[CH3:24][O:25][C:26](=[O:53])[C@@H:27]([NH:32][C:33]([N:35]1[CH2:41][CH:40]([OH:42])[C@@H:39]([NH:43][C:44](=[O:51])[C@@H:45]([NH2:50])[CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:38][CH2:37][C@H:36]1[CH3:52])=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1>CN(C=O)C.CCOC(C)=O>[CH3:24][O:25][C:26](=[O:53])[C@@H:27]([NH:32][C:33]([N:35]1[CH2:41][C@H:40]([OH:42])[C@@H:39]([NH:43][C:44](=[O:51])[C@@H:45]([NH:50][C:21]([C:13]2[O:12][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=2)=[O:23])[CH2:46][CH:47]([CH3:48])[CH3:49])[CH2:38][CH2:37][C@H:36]1[CH3:52])=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC[C@H]1C
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)N1C[C@H](O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)c2cc3ccccc3o2)CC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (214 g, 1.12 mmol) was added to a solution of benzofuran-2-carboxylic acid (166 g, 1.02 mmol), (S)-2-({1-[(2R,5S)-5-((S)-2-Amino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepan-1-yl]-methanoyl}-amino)-4-methyl-pentanoic acid methyl ester (430 mg, 0.93 mmol), diisopropylethylamine (240 mg, 0.32 ml, 1.86 mmol), hydroxybenztriazole (151 mg, 1.12 mmol) in DMF (5 ml) and was stirred at RT overnight. The reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 ml), washed with cold aq. 1N HCl, aq. sat. NaHCO3, and brine, and then dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 2% to 3% MeOH/CH2Cl2) to yield the title compound (478 mg, 84% for two steps): electrospray MS: 572.4
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6]1[C:11]([CH2:12][NH:13][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1.[H-].[Na+].C(Cl)(Cl)(Cl)Cl.[C:25](Cl)(Cl)=[O:26].C(Cl)(Cl)=O.CC(C)=O.N>O>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][N:13]([CH3:14])[C:25]2=[O:26])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cl
Reactant: CNCc1cccnc1Nc1cccc(F)c1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: CN1Cc2cccnc2N(c2cccc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of 2.3 g of 2-(m-fluoroanilino)-3-methylaminomethylpyridine was added 0.96 g of approximately 50% sodium hydride and the mixture was stirred at room temperature for 30 minutes. To this was added 10 g of approximately 30% carbon tetrachloride-phosgene solution, dropwise under ice-cooling, and the resulting mixture was stirred for 1 hour. After an excess of the phosgene was decomposed with 10% acetone-ammonia solution, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether solution was applied on a column of alumina and then eluted with ether. The eluate was concentrated and left to give 1.3 g of 1-(m-fluorophenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 189° - 192° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])=[CH:4][C:3]=2[O:2]1.O.[C:16]([OH:20])(=[O:19])[CH:17]=O>C(O)(=O)C.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](/[CH:10]=[CH:11]/[C:12](=[O:14])/[CH:13]=[CH:17]/[C:16]([OH:20])=[O:19])=[CH:4][C:3]=2[O:2]1
Reactant: CC(=O)/C=C/c1ccc2c(c1)OCO2
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)/C=C/C(=O)/C=C/c1ccc2c(c1)OCO2

Procedure:
A solution of 15 g (78.8 mmol) of (E)-4-[3,4-(methylenedioxy)phenyl]but-3-en-2-one and 7.2 g (78.8 mmol) of glyoxylic acid monohydrate in 20 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/ether yielded (E,E)-6-[3,4-(methylenedioxy)phenyl]-4-oxo-2,5-hexadienoic acid of melting point 170°-173°.
Reaction SMILES: [C:1]([C:3]1[C:8](Cl)=[CH:7][C:6]([Cl:10])=[CH:5][N:4]=1)#[N:2].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C[O-].[Na+]>C1COCC1>[NH2:2][C:1]1[C:3]2=[N:4][CH:5]=[C:6]([Cl:10])[CH:7]=[C:8]2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CS
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc2cc(Cl)cnc2c1N
Reaction time: 2 h
Yield: 25.3 %

Procedure:
The product from Example 27A (3.46 g, 20 mmol) and methyl thioglycolate (1.8 mL, 20 mmol) were combined in 40 mL THF. To the solution was added 1.08 g NaOMe (20 mmol) After 1.5 h, and additional 1.08 g NaOMe was added, and then after an additional 2 h, the reaction was quenched in 5% aq. NaHCO3 and extracted with diethyl ether. The organic extracts were dried (MgSO4), evaporated, and the product was purified by silica gel column chromatography to yield 1.23 g (25%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 3H), 6.20 (br s, 2H), 8.04 (d, 1H), 8.54 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]1([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][NH2:37])=[CH:31][CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([CH:27]=[CH:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][NH:37][C:2]3[N:3]=[C:4]([NH2:20])[C:5]4[N:6]=[CH:7][N:8]([C:18]=4[N:19]=3)[C@@H:9]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]3[OH:11])=[CH:33][CH:34]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCc1ccc(C=CC2CCCCC2)cc1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(NCCc2ccc(C=CC3CCCCC3)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Reaction of 2-chloroadenosine with p-(cyclohexylvinyl)phenylethylamine in the manner described e.g. in Example 14 gives 2-[2-(p-cyclohexylvinyl-phenyl)-ethylamino]-adenosine, [alpha]D25 =-26.4° in DMSO, m.p. 161°-164°.