Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.N1C=CN=C1>>[CH:26]1([N:31]2[C:21](=[O:22])[C:5]3[C:4]4[C:19]5[C:8](=[CH:7][CH:6]=3)[C:9]3[C:20]6[C:13]([CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=6[C:18]=5[CH:1]=[CH:2][C:3]=4[C:24]2=[O:23])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCC1
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: c1c[nH]cn1
Product: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1C1CCCC1)c54
Temperature: 145 °C

Procedure:
0.30 g (0.93 mmol) of perylene-3,4-dicarboxylic anhydride is mixed with 0.24 g (2.80 mmol) of cyclopentylamine and 3 g of imidazole, and the mixture is heated under nitrogen at 145° C. for 4 h. The reaction product is removed from the flask by washing with ethanol, and the mixture is then treated with 10% hydrochloric acid and boiled until no more ethanol is present. The precipitated product is filtered off with suction, boiled in potassium carbonate solution and the solid residue is filtered off with suction and washed with hot dist. water. 60 mg (20%) of perylene-3,4-dicarboxylic anhydride can be recovered by acidifying the filtrate with conc. hydrochloric acid. The red residue is recrystallized 3 times by extraction with methanol and then dried in a drying cabinet at 120° C. Yield 0.22 g (61%) of dark-red small needles showing a strong red solid fluorescence, m.p. >315° C. Rf (CHCl3 /silica gel)=0.18. UV (CHCl3): λmax (ε)=506 (31013), 485 (31425) 355 (3050), 336 (3000), 319 (2680), 264 (34268), 256 (sh., 18100). Fluorescence (CHCl3): λmax (Irel)=541 (1), 572 (sh., 0.49).
Reaction SMILES: CN([CH:4]=[O:5])C.[H-].[Na+].[CH:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=1.[NH4+].[Cl-]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[I-].CCOCC>[CH2:14]([O:5][CH2:4][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Methyl glycoside alcohol 20 (160 mg, 0.32 mmol) was dissolved in THF (0.32 M, 1.0 mL). Then DMF (0.10 mL) was added as a co-solvent. The solution was cooled to 0° C., and NaH (60% dispersion in mineral oil, 19 mg, 0.48 mmol) was added all at once and stirred for 20 minutes. BnBr (0.060 mL, 0.48 mmol) was then added all at once, followed by the addition of TBAI (10 mg). The reaction was allowed to warm to r.t. and stirred overnight. After diluting with Et2O (20 mL), a saturated solution of NH4Cl (10 mL) was slowly added to quench the reaction. The aqueous layer was extracted with EtOAc (2×10 mL). The organic extracts were combined and dried with MgSO4. After filtration and evaporation of the volatiles under reduced pressure, chromatography (20:1→4:1 hexanes:EtOAc) gave benzyl ether I as a colorless oil (160 mg, 84%).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=O.N12CCCC1=NCCC2>CO>[S:8]1[C:4]2[S:5][CH:6]=[CH:7][C:3]=2[CH:1]=[C:9]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CSc1sccc1C=O
Agent: C1CN=C2CCCN2C1
Solvent: CO
Product: COC(=O)c1cc2ccsc2s1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of methyl (3-formylthiophene-2-ylthio)acetate (19.31 g, 91 mmol) in methanol (150 mL) was added 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (1 mL, 1 g, 8.05 mmol) and the stirred reaction flask was immediately immersed in an ice-water bath. Stirring was continued for 30 minutes and the mixture was filtered to give a tacky solid product which was washed with a little cold (-20° C.) methanol. The solvent was evaporated in vacuo from the mother liquor and the residue was partitioned between ether and aqueous sodium bicarbonate. The water layer was washed with ether twice, and the combined ether extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo to give an oil which solidified when triturated with a little cold (-20° C.) methanol. This was combined with the original solid product to give a total of 14.55 g of methyl thieno-[2,3-b]thiophene-2-carboxylate, m.p. 101°-105° C. Recrystallization from methanol gave product with m.p. 106°-107° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C@H:10]([CH2:12][CH:13]=[CH2:14])[CH3:11].CC(O)C.C(=O)=O.[Li]CCCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1.CCCCCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([B:27]([OH:32])[OH:28])=[C:3]([O:9][C@H:10]([CH2:12][CH:13]=[CH2:14])[CH3:11])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Reaction time: 0.75 h
Yield: 101.5 %

Procedure:
A solution of (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene (0.66 mL, 2.55 mmol, 1 equiv) in THF (13 mL) was cooled to −78° C. (IPA/dry ice). nBuLi (1.9 mL of a 1.6 M solution in hexane, 3.06 mmol, 1.2 equiv) was added slowly. No color change observed. After 45 min, triisopropyl borate (0.70 mL, 3.06 mmol, 1.2 equiv) was added. The reaction was stirred 30 min. 1 N HCl (5 mL) was added and the reaction was removed from the cold bath. After 10 min, the reaction was added to water and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to provide the crude boronic acid (0.58 g, 100%) as a viscous pale yellow oil. Purity is ˜80%. The crude boronic acid was for used as is for the Suzuki coupling. 1H NMR (500 MHz, CDCl3) δ 7.85 (t, J=8.0 Hz, 1H), 6.74 (td, J=8.3, 2.2 Hz, 1H), 6.66-6.62 (m, 1H), 5.87 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.24-5.18 (m, 2H), 4.63-4.54 (m, 1H), 2.60-2.45 (m, 2H), 1.43 (d, J=6.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCCCCCNc1ccc(F)c(C(=O)OC)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCN(c1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of methyl 2-fluoro-5-(hexylamino)benzoate (800 mg; 3.16 mmol) in anhydrous DCM (50 mL) were added 4-bromobenzenesulfonylchloride. (807 mg; 3.16 mmol) and TEA (0.53 mL). The reaction mixture was stirred overnight at 25° C. under N2 atmosphere. Then the mixture was poured into a saturated solution of NaHCO3 and extracted with DCM (2×200mL). The combined organic layers were washed with a saturated solution of NH4Cl followed by brine, dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure to give a brown cream. Purification by flash chromatography using silicagel (c-Hex/EtOAc, 95:5 then 90:10):gave 1.0 g (67.4%) of the title compound as a colorless cream. HPLC, Rt: 5.23 min (purity=97.13%). LC/MS,. M+(ESI): 272.1. 1H NMR (CDCl3) δ: 7.63 (m, 2H), 7.52 (m, 1H), 7.43 (d, J=9.2 Hz, 2H), 7.25 (m, 2H), 7.13 (t, J=9.2 Hz, 1H), 3.91 (s, 3H), 3.49 (t, J=6.97 Hz, 2H), 1.25 (m, 8H), 0.85 (t, J=6.8 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([NH:26][C:27](=[O:41])[C:28]2[CH:33]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:31]=[CH:30][C:29]=2[OH:40])[CH:14]=1>>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:26][C:27](=[O:41])[C:28]2[CH:33]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:31]=[CH:30][C:29]=2[OH:40])[CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCOCC2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccco2)ccc1C(=O)O)c1cc(N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to the obtained tert-butyl 4-(furan-2-yl)-2-(2-hydroxy-5-(morpholin-4-yl)benzamido)benzoate (0.085 g), followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and water and 2-propanol were added to the residue. After adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.064 g of 4-(furan-2-yl)-2-(2-hydroxy-5-(morpholin-4-yl)benzamido)benzoic acid as a yellow solid.
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:10](CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:15][S:16]([NH2:10])(=[O:18])=[O:17].[CH3:15][S:16]([NH2:7])(=[O:18])=[O:17].[C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: CS(N)(=O)=O

Procedure:
A mixture of 4-(7-methyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo- 2,3-d!pyrimidin-6-yl)phenylamine (EXAMPLE 188, 206 mg) in 40 ml of dichloromethane is cooled in an ice-water bath and treated with 0.15 ml of triethylamine followed by 0.05 ml of methanesulfonyl chloride. Three additional portions of methanesulfonyl chloride, 0.02 ml, 0.01 ml and 0.01 ml, are added in sequence over the next hour. The mixture is poured onto water, treated with aqueous saturated sodium bicarbonate and extracted with three portions of dichloromethane. The combined organic extracts are dried and concentrated to give a solid which is combined with previously isolated material (from a 50 mg run) and chromatographed over silica eluting with methanol/chloroform (3/97) to give the desired material which is recrystallized from hot acetonitrile to give the title compound, mp 245-248; NMR 7.49-7.47, 7.31-7.28, 6.42, 3.78-3.69, 3.64, 3.58-3.52, 3.36, 1.97-1.85δ.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:13]([CH3:16])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CCN(CC)CC>C(Cl)Cl>[CH:26]1([NH:31][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
To a mixture of (2R,3R)-2-(tert-butoxycarbonylamino)-3-methylpentanoic acid (0.5 g, 2.162 mmol, HATU (0.986 g, 2.59 mmol) and cyclopentanamine (0.427 mL, 4.32 mmol) in DCM (10 mL) was added Et3N (0.603 mL, 4.32 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound (0.56 g, 87%). 1H NMR (400 MHz, CDCl3) δ 0.82-0.89 (m, 3 H) 0.92 (t, J=7.45 Hz, 3 H) 1.32-1.41 (m, 6 H) 1.44 (s, 9 H) 1.55-1.77 (m, 3 H) 1.84-2.04 (m, 2 H) 2.99 (d, J=4.29 Hz, 1 H) 3.96 (dd, J=8.72, 5.43 Hz, 1 H) 4.21 (dt, J=13.89, 6.95 Hz, 1 H) 5.02 (br. s., 1 H) 5.93 (br. s., 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].CCN(C(C)C)C(C)C.[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23](Cl)=[O:24])=[N+:19]=[N-:20].[OH-].[Na+]>ClCCCl>[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:8])[CH3:1])[CH3:7])=[O:24])=[N+:19]=[N-:20]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CNCCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred ice cold solution of N1,N1,N3-trimethylpropane-1,3-diamine (5.0 g, 1 equiv, 43.0 mmol) and DIEA (11.2 mL, 1.5 equiv, 64.5 mmol) in anhydrous DCE (200 mL) was added 3-azido-3-methylbutanoyl chloride (6.95 g, 43.0 mmol) in small portions. The reaction was stirred and left at 0° C. for 1 h. Aqueous NaOH (5N, 4 equiv, 34.5 mmol) was added to the reaction mixture. The solvent and DIEA was removed via rotovap to give an oily aqueous mixture. The contents of the flask was poured into a separatory funnel and extracted with DCM (2×100 mL). The organic layer was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (8.71 g, 84.0%). This material was used without further purification. 1H NMR (D2O, 400 MHz): δ 1.34 (t, J=7.2, 3H), 1.43 (s, 6H), 2.11-2.15 (m, 2H), 3.09 (s, 3 H), 3.35 (s, 2H), 3.41 (dt, J=7.2, 4H). LRMS (ESI+) for C11H23N5O (241.2); Found: 241 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9].Cl[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([CH3:35])[N:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:35][C:30]1[N:29]=[C:28]([N:24]2[CH2:25][CH2:26][CH:21]([N:10]([CH2:8][CH3:9])[C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][CH2:23]2)[CH:33]=[C:32]([CH3:34])[N:31]=1
Reactant: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: Cc1cc(Cl)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CCN(C(=O)OCc1ccccc1)C1CCN(c2cc(C)nc(C)n2)CC1
Reaction time: 14 h
Yield: 63 %

Procedure:
A mixture of benzyl ethyl(piperidin-4-yl)carbamate trifluoroacetate (4.14 mmol, 1.0 eq), 4-chloro-2,6-dimethylpyrimidine (0.706 g, 4.97 mmol, 1.2 eq) and K2CO3 (1.14 g, 8.28 mmol, 2.0 eq) in acetone (20 ml) was stirred for 14 hours at boiling temperature. After monitoring by TLC, the mixture was concentrated, diluted with DCM (200 ml), washed with water (80 ml) and sat. NaCl solution (80 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2.0% MeOH in DCM). Yield: 63% (960 mg, 2.60 mmol)
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:9]=1)(O)=[O:6]>C(Cl)(Cl)Cl>[Cl:3][C:5]([C:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:9]=1)=[O:6]
Reactant: Cc1c(C(=O)O)cn(-c2ccnc3ccccc23)c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)Cl)cn(-c2ccnc3ccccc23)c1C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
10 mL (137 mmol) of sulphinyl chloride are added at a temperature in the region of 20° C. under an argon atmosphere to 1.1 g (4.1 mmol) of 3-carboxy-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole dissolved in 20 mL of chloroform. After stirring at the reflux point of the solvent for 1.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 20 mL of chloroform and is then brought back to dryness to give 1.17 g (4.1 mmol) of 3-chlorocarbonyl-4,5-dimethyl-1-(quinol-4-yl)-1H-pyrrole in the form of a brown-yellow solid which is used directly in the following step.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N+](=CP(=O)(OC)OC)=[N-].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH:27]([CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])[O:26][C:25]2=[O:41])=[CH:20][C:19]=1[F:42])#[CH:17]>C1COCC1>[F:42][C:19]1[CH:20]=[C:21]([N:24]2[CH2:28][CH:27]([CH2:29][N:30]3[C:31](=[O:40])[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38]3=[O:39])[O:26][C:25]2=[O:41])[CH:22]=[CH:23][C:18]=1[C:16]#[C:17][CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: C#Cc1ccc(N2CC(CN3C(=O)c4ccccc4C3=O)OC2=O)cc1F
Agent: COP(=O)(C=[N+]=[N-])OC
Agent: [K+]
Solvent: C1CCOC1
Product: CC#Cc1ccc(N2CC(CN3C(=O)c4ccccc4C3=O)OC2=O)cc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of potassium t-butoxide (17 mL of a 1.0 M solution in THF) was added a −78° C. THF (4 mL) solution of dimethyl diazomethylphosphonate (2.53 g, prepared according to the procedure described in J. Org. Chem. 1971, 36, 1379-1385). The mixture was stirred at −78° C. for 10 minutes then a −78° C. solution of Example 3A (5.19 g) in THF (100 mL) was added via cannula over 20 minutes. The reaction mixture was stirred for 24 hours, gradually warming to room temperature. The mixture was quenched with 1:1 saturated ammonium chloride/water (200 mL) and extracted with dichloromethane (50 mL). The aqueous layer was extracted with 4:1 THF/dichloromethane (250 mL), and the combined extracts were washed with 1:1 saturated sodium bicarbonate/water (200 mL) and 1:1 brine/water (200 mL). The organic extracts were dried over MgSO4, filtered, and concentrated to provide crude product. The crude product was purified by flash column chromatography on silica gel eluting with 4:1 hexanes/acetone to provide the desired product. MS (ESI(+)) m/e 379 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.9 (m, 2H), 7.77 (m, 2H), 7.45 (dd, J=2.4, 9 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.25-7.35 (dd, J=2.4, 8.7 Hz, 1H), 4.97 (m, 1H), 4.07-4.18 (m, 2H), 3.8-4.01 (m, 2H), 2.09 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:18]([O:20][CH3:21])=[O:19])[CH:2]=1.[ClH:22]>>[ClH:22].[N:1]1[C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:18]([O:20][CH3:21])=[O:19])[CH:2]=1
Reactant: COC(=O)c1cnc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: COC(=O)c1cnc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
A round-bottom flask containing 7-tert-butyl 3-methyl 5,6-dihydro-1,7-naphthyridine-3,7-(8H)-dicarboxylate (0.470 g, 1.61 mmol) and hydrochloric acid (6.03 mL, 24.1 mmol, 4.0 M in 1,4-dioxane) was stirred at rt for 1 h. The solution was then completely evaporated to yield methyl 5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate hydrochloride (0.440 g, 100%). LC-MS: (FA) ES+ 193; 1H NMR (Methanol-d4, 400 MHz) δ9.26 (s, 1H), 8.87 (s, 1H), 4.83 (s, 2H), 4.03 (s, 3H), 3.69 (m, 2H), 3.43 (t, J=5.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(-n2nnnc2Cl)cc1
Temperature: 65 °C
Yield: 87 %

Procedure:
5-Chloro-1-phenyl-1H-tetrazole (500 g, 2.78 mol) was carefully added in one portion to stirred white fuming nitric acid (91.5% HNO3, 2.5 L). The internal temperature of the mixture increased steadily to 65° C. then fell. An aliquot was removed and partitioned between water and dichloromethane. TLC analysis (80:20 hexanes/ethyl acetate) indicated consumption of starting material. The mixture was carefully poured into stirred ice (3 L), water (2 L) and dichloromethane (2 L). The layers were separated and the aqueous was extracted with dichloromethane (2 L). The combined organic phase was washed with 5% aqueous sodium bicarbonate solution (1 L), dried (MgSO4), filtered, and concentrated to a solid. The solid was mixed with 90:10 hexanes/ethyl acetate (3 L) and heated to 65° C. The mixture was cooled overnight (2-5° C.). Filtration afforded a white crystalline solid (544 g, 87%). 1H NMR (CDCl3, 300 MHz) δ 8.51 (d, 9.5 Hz, 2 H), 7.91 (d, 8.8 Hz, 2 H); mp 96.5° C.; Rf =0.2 (K).
Reaction SMILES: [C:1]1([CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([F:20])[F:19])[C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N.[H][H]>[Ni].CO>[C:1]1([CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([F:19])[F:20])[CH2:12][NH2:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCCCC(F)F)c1cccc2ccccc12
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC(CCCCC(F)F)c1cccc2ccccc12
Yield: 76.6 %

Procedure:
A mixture of 2-(naphth-1-yl)-7,7-difluoroheptanenitrile (413 mg, 1.51 mmol), Raney nickel (413 mg) and ammonia (0.9 g) in methanol (20 ml) was hydrogenated under 340 kPa (50 psi) hydrogen overnight at room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (40 ml) and the ethyl acetate extract was washed with brine (30 ml), dried (sodium sulfate) and concentrated in vacuo. The residue (400 mg) was purified by column chromatography on silica gel (100 g), eluting with 85:15 ethyl acetate/methanol to yield the title compound as an oil (321 mg, 77% yield). 1H NMR (300 MHz, CDCl3) δ1.35 (c, 6H), 1.78 (c, 4H), 3.08 (c, 2H), 3.61 (c, 1H), 5.52, 5.71, 5.9 (3t, total 1H), 7.37 (d, 1H), 7.5 (m, 3H), 7.75 (d, 1H), 7.88 (d, 1H), 8.16 (d, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:23])([CH2:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:5][C:4]=1[NH2:24].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][C:35](O)=O)=[CH:29][CH:28]=1)#[N:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(O)(=O)C>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH:33][CH2:34][C:35]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([CH2:17][C:18]4[NH:22][N:21]=[N:20][N:19]=4)([C:10]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[O:11])[CH3:23])=[CH:5][C:4]=3[N:24]=2)=[CH:31][CH:32]=1)#[N:26]
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CNc1ccc(C(C)(Cc2nnn[nH]2)C(=O)N2CCCC2)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(C)(Cc3nnn[nH]3)C(=O)N3CCCC3)ccc21

Procedure:
Prepared analogously to Example 1g/h from 2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one, 4-cyano-phenylglycine/O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and subsequently treating with glacial acetic acid.
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])=[O:13])(=O)C1C=CC=CC=1>O.[OH-].[NH4+]>[SH:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])=[O:13]
Reactant: C[C@H](NC(=O)CCSC(=O)c1ccccc1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: C[C@H](NC(=O)CCS)C(=O)O
Reaction time: 1 h
Yield: 70.7 %

Procedure:
N-(3-benzoylthiopropanoyl)-L-alanine (4.2 g) is dissolved in a mixture of water (7.5 ml) and concentrated ammonium hydroxide (6 ml). After one hour, the mixture is diluted with water, filtered and the filtrate is extracted with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness in vacuo. The residue is crystallized from ethyl acetate-hexane to yield 1.87 g of N-(3-mercaptopropanoyl)-L-alanine, m.p. 79°-81°.