Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[BH4-].[Na+].[Cl-].[NH4+]>CCOCC.CO>[O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1cccc2c1OCC2
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: OCc1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,3-Dihydro-benzofuran-7-carbaldehyde (1.50 g, 10.20 mmol) was dissolved in ether, then cooled to 0° C., NaBH4 (400 mg, 10.57 mmol) in MeOH (5.00 mL) was added. The resulting reaction mixture was stirred for 30 min, then saturated ammonium chloride was added. The mixture was extracted with ether, and the combined organic phases were washed with brine, then dried over magnesium sulfate and concentrated to afford the desired alcohol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[C:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH:31][C:28]1[CH:29]=[N:30][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][CH:27]=1)=[O:8])([O-:3])=[O:2]
Reactant: Nc1cnc(-c2ccccc2)nc1
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cnc(-c2ccccc2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)benzoic acid (1.096 g, 4.38 mmol, 1.50 equiv) in dichloromethane (20 mL), 2-phenylpyrimidin-5-amine (500 mg, 2.92 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (838 mg, 4.39 mmol, 1.50 equiv), and 4-dimethylaminopyridine (713 mg, 5.84 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The reaction was diluted with 100 mL of water and the resulting mixture was extracted with 3×50 mL of dichloromethane. The organic layers were combined, washed with 1×100 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE:EA:CH2Cl2 (20:1:0-3:1:1). The product was obtained as 150 mg (11%) of a yellow solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.O>ClCCl>[OH:3][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CCCCCCCCCCCCCCC
Reactant: COC(=O)C=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC=CCC(O)C(=O)OC
Temperature: 25 °C

Procedure:
Methyl glyoxalate (8.80 g, 0.1 mol, 1.0 eq) and 1-hexadecene (44.80 g, 0.2 mol, 2.0 eq) are dissolved in dry dichloromethane (200 ml, freshly distilled from calcium hydride) under a nitrogen atmosphere. Stannic chloride (3.51 ml, 0.03 mol, 0.3 eq) is added dropwise with stirring and cooling at 0° C. (ice/water bath). After half an hour the reaction mixture is allowed to warm to room temperature and stirred for a further 21 hours before being neutralised with triethylamine (4.2 ml, 0.03 mol, 0.3 eq) with a further 5 minutes stirring. Water (50 ml) and dichloromethane (100 ml) are added, the organic layer is separated, washed in turn with water (50 ml) and brine (50 ml), dried over anhydrous magnesium sulphate and evaporated. The crude oil is purified by short path distillation (bp 220-230° C./0.7 mm Hq) to furnish the ester product as a colourless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](O)([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[OH-].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C=CCC(O)(CC=C)c1ccc(OC)c(Br)c1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC(CC=C)c1ccc(OC)c(Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a 250 mL RBF were added 4-(3-bromo-4-methoxyphenyl)hepta-1,6-dien-4-ol (4.85 g, 16.32 mmol), triethylsilane (5.21 mL, 32.6 mmol), and CH2Cl2 (50 mL). The flask was flushed with N2. BF3.Et2O (2.275 mL, 17.95 mmol) was added via syringe at −78° C. The resulting reaction mixture was stirred at −78° C. for 1 hr and was then allowed to warm to 0° C. briefly. 50 mL 10% KOH was added at 0° C. and the reaction mixture was extracted with 50 mL EtOAc/Hexane (1:1). The organics were washed with 30 mL brine, dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography, eluted with 10% EtOAc/Hexane to give 2-bromo-4-(hepta-1,6-dien-4-yl)-1-methoxybenzene (3.6 g) as colorless oil. 1H NMR (500 MHz, CDCl3:) δ 7.38 (s, 1H), 7.06 (d, 1H), 6.85 (d, 1H), 5.66 (m, 2H), 4.99 (d, 4H), 3.91 (s, 3H), 2.66 (m, 1H), 2.42 (m, 2H), 2.33 (m, 2H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:25]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:14](=[O:16])[NH:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 0.67 h

Procedure:
120 g of carbobenzoxy-L-alanine are dissolved in 800 ml of absolute tetrahydrofuran, treated dropwise while cooling with ice with 70 g of thionyl chloride and stirred for 40 minutes while cooling with ice. There is then rapidly added dropwise thereto a suspension of 100 g (0.38 M) of 2-amino-5-nitro-2'-fluorobenzophenone in 400 ml of absolute tetrahydrofuran and the mixture is stirred at room temperature for 24 hours. The solution obtained is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is dissolved in a small amount of methylene chloride and treated with ether. There is obtained (S)-benzyl-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl}carbamate. A further recrystallisation from methylene chloride/ether yields a product which melts at 158°-160° C. and shows a rotation of [α]25D =-23.4° (in methylene chloride; 1%). The mother liquors are purified on a 600 g silica gel column using methylene chloride as the eluting agent, an additional amount of the aforementioned product being obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CC(OC([N:28](C(OC(C)(C)C)=O)[C:29]1[NH:30][C:31]([C:35](O)=[O:36])=[C:32]([Cl:34])[N:33]=1)=O)(C)C.ClC1N=C(NC(OC(C)(C)C)=O)NC=1C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:95]([OH:101])([C:97]([F:100])([F:99])[F:98])=[O:96]>CN(C=O)C>[F:98][C:97]([F:100])([F:99])[C:95]([OH:101])=[O:96].[NH2:28][C:29]1[NH:30][C:31]([C:35]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]3[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:4]=2[F:20])=[O:36])=[C:32]([Cl:34])[N:33]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)O)[nH]1
Agent: CC(C)(C)OC(=O)Nc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
A mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.041 g, 0.131 mmol), a 50:50 mixture of 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-chloro-1H-imidazole-5-carboxylic acid and 4-chloro-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-imidazole-5-carboxylic acid (0.047 g, 0.131 mmol), HATU (0.060 g, 0.157 mmol) and DIPEA (0.027 ml, 0.157 mmol) in DMF (1.5 mL) was stirred at RT overnight. The reaction mixture was extracted between EtOAc and water. The organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated and the crude product was dissolved in dichloromethane (2 mL) and TFA (0.5 ml, 6.49 mmol) was added. The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.007 g, 6.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.56 (dd, 1H), 7.41-7.52 (m, 3H), 6.66 (s, 1H), 3.73 (s, 2H), 1.88 (br. s., 2H). ES MS: m/z 454 (M+1)
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Cl)[CH:19]=1>O.CCOC(C)=O.CN1CCCC1=O.C1(C)C=CC=CC=1>[N+:3]([C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[N:16][CH:17]=1)([O-:5])=[O:4]
Reactant: Clc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(Oc2cncc(Cl)c2)c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
The title compound was prepared using methods described in U.S. Pat. No. 3,576,616. Briefly, to a 16.5M solution of KOH (2.2 g, 39.6 mmol) in water was added 3-nitrophenol (5 g, 36 mmol) followed by N-methylpyrrolidinone (11 mL) and toluene (3.6 mL). The resulting mixture was heated to 110° C. and water was removed azeotropically using a Dean-Stark trap. Excess toluene was removed and collected in the trap followed by the addition of N-methylpyrrolidinone (18 mL) and 3,5-dichloropyridine (10.66 g, 72 mmol, Aldrich) and the mixture was stirred for 5 hr at 160° C. The temperature was then increased to 200° C. and the mixture was stirred for an additional 15 hr. The crude reaction mixture was cooled, water (100 mL) was added followed by EtOAc (100 mL). The mixture was filtered through a pad of Celite®, the phases were separated, and the aqueous phase was extracted 3× with EtOAc (100 mL). The organic phases were combined and washed twice with water (100 mL), once with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was purified by chromatography (10-25% EtOAc in hexanes as eluant) to provide 3.8 g (42%) of product as an orange solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([N:34](C)[CH:35]([CH3:62])[CH2:36][O:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[C:45]([N:47]1[CH2:61][C:50]2=[C:51]3[N:56]([N:57]=[C:49]2[CH2:48]1)[C:55]([CH3:58])=[C:54]([Cl:59])[C:53]([CH3:60])=[N:52]3)=[O:46])C=C.SC1C=CC=CC=1C(O)=O>C1COCC1.CC(=O)OCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:59][C:54]1[C:53]([CH3:60])=[N:52][C:51]2[N:56]([N:57]=[C:49]3[CH2:48][N:47]([C:45]([C:39]4[CH:40]=[CH:41][C:42]([F:44])=[CH:43][C:38]=4[O:37][CH2:36][CH:35]([NH:34][CH3:31])[CH3:62])=[O:46])[CH2:61][C:50]3=2)[C:55]=1[CH3:58]
Reactant: C=CCN(C)C(C)COc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)c1ccccc1S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(C)COc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Reaction time: 0.17 h
Yield: 12.9 %

Procedure:
A mixture of Pd(dba)2 (5.2 mg; 0.01 mmol; 0.05 eq.) and 1,4-bis(diphenylphosphino)butane (3.8 mg; 0.01 mmol; 0.05 eq.) in THF (1 mL) was stirred for 10 minutes then added to a solution of {2-[2-(allyl-methyl-amino)-propoxy]-4-fluoro-phenyl}-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]inden-2-yl)-methanone (85 mg; 0.18 mmol; 1 eq.) in THF (3 mL) followed by 2-mercapto-benzoic acid (31 mg; 0.20 mmol; 1.1 eq.) and the reaction mixture was stirred at 60° C. for 2 hours. The solution was diluted with EA, washed with 0.1M NaOH, dried over sodium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (10 mg, 13%) as a yellow solid. 1H NMR (DMSO-d6) δ 8.25 (s, 1H), 7.39 (ddd, J=8.4, 6.8, 3.2 Hz, 1H), 7.11 (dd, J=11.4, 2.3 Hz, 1H), 6.99-6.80 (m, 1H), 4.84 (d, J=8.8 Hz, 2H), 4.55 (d, J=15.8 Hz, 2H), 4.02 (d, J=5.5 Hz, 2H), 2.97-2.86 (m, 1H), 2.84 (s, 1.5H), 2.81 (s, 1.5H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.25 (d, J=1.7 Hz, 3H), 0.96 (dd, J=6.5, 2.4 Hz, 3H). HPLC (max plot) 99.7%, Rt 2.82 min. UPLC/MS: (MS+) 432.3 ([M+H]+).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].[Br-].[Li+].IC.[C:23](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.COCCOC>[CH3:23][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1]
Reactant: CCOC(=O)c1cc2cccnc2[nH]c1=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cccnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
2.2 g (10 mmol) of ethyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in a mixed solvent of N,N-dimethylformamide (50 mL) and 1,2-dimethoxyethane (15 mL), and under a nitrogen gas stream, 0.45 g (11 mmol) of 60% sodium hydride (oily) was added thereto at room temperature. The mixture was further stirred for 30 minutes at room temperature. 3.5 g (40 mmol) of lithium bromide was added to the above mixture under ice cooling, and the resulting mixture was stirred for 30 minutes at room temperature. 3.9 g (27.5 mmol) of iodomethane was further added to the mixture at room temperature, and the resulting mixture was stirred for 6 hours at 60° C. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, an aqueous solution of sodium hydrogen carbonate, and brine in this order, and was dried and concentrated. The residue was washed with diisopropyl ether, and thus 1.66 g (yield: 71%) of the title compound was obtained as a light purple solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(F)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluorobenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.75 (m, 12 H) 1.99 (m, 3 H) 2.19 (s, 3 H) 2.79 (m, 2 H) 3.74 (m, 1 H) 4.01 (t, J=14.0 Hz, 2 H) 4.68 (m, 1 H) 7.67 (d, J=8.6 Hz, 1 H) 7.72 (d, J=12.4 Hz, 1 H) 7.99 (t, J=8.2 Hz, 1 H) 8.20 (d, J=7.3 Hz, 1 H) 8.23 (s, 1 H) 9.08 (s, 1 H). [M+H] calc'd for C26H32F3N7O2, 532; found 532.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.C[O:33][C:34](=O)[C@H:35]([CH2:37][C:38]1C=CC=C[CH:39]=1)N>CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH:8][C:34](=[O:33])[CH2:35][CH2:37][CH:38]=[CH2:39]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: C=CCCC(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC

Procedure:
Following General Procedure A and using N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) using General Procedure A, followed by removal of the BOC-group using General Procedure Y) and pent-4-enoic acid (Aldrich), the title compound was prepared as a solid (mp=125.5-126.5° C.). The reaction was monitored by tlc (Rf=0.32 in 50% EtOAc/hexanes; 0.51 in 10% CH3OH/CH2Cl2) and the product was purified by flash chromatography using 10% CH3OH/CH2Cl2 as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][CH2:4][C:3]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1c(Cl)cccc1[N+](=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(Cl)c1CNC1CCN(Cc2ccccc2)CC1

Procedure:
15 g 2-chloro-6-nitro-benzaldehyde and 4-amino-1-benzylpiperidine in 150 mL toluol were refluxed for 3 h. The toluol was removed and the residue was dissolved in 300 mL methanol. 6.6 g sodium borohydride was added and the reaction was refluxed over night. The solvent was removed, water and dichlormethane were added and the layers were separated. The organic layer was washed with water, dried and filtered to yield 29 g of the desired product.
Reaction SMILES: C(O[CH2:5][C@@H:6]([C@@H:12]1[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C(=O)C)[C:18]=2[CH3:27])=[N:13]1)[O:7]S(C)(=O)=O)(=O)C.CO.[C:30]([NH:34][C:35]([C@@H:37]1[CH2:46][C@H:45]2[C@H:40]([CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:39][NH:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>O>[C:30]([NH:34][C:35]([C@@H:37]1[CH2:46][C@H:45]2[C@H:40]([CH2:41][CH2:42][CH2:43][CH2:44]2)[CH2:39][N:38]1[CH2:5][C@H:6]([C@@H:12]1[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=2[CH3:27])=[N:13]1)[OH:7])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(=O)OC[C@H](OS(C)(=O)=O)[C@@H]1COC(c2cccc(OC(C)=O)c2C)=N1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(O)cccc1C1=N[C@H]([C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)CO1
Temperature: 50 °C
Reaction time: 5.5 h

Procedure:
The crude product of Example 3, (2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2methanesulfonyloxyethane, 18′ (1.98 kg, 3.30 mol) was suspended in a mixed solvent of methanol (6.50 L) and water (6.50 L), and (3S, 4aS, 8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide, 642 g, 2.62 mol) and potassium carbonate (1.36 kg, 9.81 mol) were successively added, which was followed by stirring at 50° C. for 5.5 hours. Water (6.50 L) was added to cool the reaction mixture to room temperature and the resulting crystals were collected by filtration. These crude crystals were again suspended in water (6.50 L), stirred, washed and collected by filtration. The obtained crystals were re-suspended in methyl isobutyl ketone (10.0 L) and the suspension was subjected to azeotropic dehydration. The resulting slurry was cooled to room temperature and crystals were collected by filtration to give 902 g (1.07 mol) of the title compound, as colorless crystals.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]\[S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:2].CN1CCOCC1.C(Cl)(Cl)=O.[N-:38]=[N+:39]=[N-:40].CN(C)C(=[NH2+])N(C)C>ClCCl.C1(C)C=CC=CC=1>[CH3:2][C:1]1[N:4](/[CH:5]=[CH:6]\[S:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:40]=[N:39][N:38]=1
Reactant: CC(=O)N/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1nnnn1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
(Z)-1-Acetamido-2-triphenylmethylthioethene (1.07 g) in dry dichloromethane (30 ml) containing N-methylmorpholine (3.5 ml, 3.22 g) was cooled to -30° and treated with phosgene in toluene (8.4 ml, 12.5% w/w). After warming to room temperature and stirring for 30 minutes tetramethylguanidinium azide (600 mg) in dichloromethane (6 ml) was added. After 45 min. a further quantity of tetramethylguanidinium azide (300 mg) in dichloromethane was added. After a further 45 min. the reaction mixture was washed with water (2×300 ml), followed by saturated brine. After drying (MgSO4) the dichloromethane was evaporated in vacuo. Toluene (30 ml) was added and evaporated in vacuo (2×) and the residual material was crystallised from ethyl acetate/hexane to give (Z)-1-(5-methyltetrazol-1-yl)-2-triphenylmethylthioethene (827 mg), m.p. 208°-210°, νmax. (CHCl3) 1600, 1490, 1445, 1410 cm-1., δ(CDCl3) 2.54 (3 H, s), 6.15 (1H, d, J 9 Hz), 6.59 (1H, d, J 9 Hz), 7.35 (15 H, s) p.p.m. (Found: C, 71.65; H, 5.20; N, 14.41%. C23H20N4S requires C, 71.9; H, 5.21; N, 14.6%).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[N:13]=2)=[CH:8][CH:7]=1)([OH:3])=[O:2].O[N:30]1[C:51](=[O:52])[NH:50][C@H:49]2[C@@H:31]1[CH2:32][S:33][C@H:34]2[CH2:35][CH2:36][CH2:37][CH:38](N1C(=O)CCC1=O)[C:39](=[O:41])O.CO.CCOCC>CN(C=O)C>[C:39]([NH:13][CH2:14][CH2:19][NH-:20])(=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[C@@H:49]2[C@@H:31]([NH:30][C:51]([NH:50]2)=[O:52])[CH2:32][S:33]1.[C:1]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[N:13]=2)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Agent: CCCn1c(=O)c2[nH]c(-c3ccc(OCC(=O)O)cc3)nc2n(CCC)c1=O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: [NH-]CCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Compound 6d (24.1 mg, 0.056 mmol) was suspended in 1 ml DMF. N-Hydroxysuccinimido-d-biotin (Sigma, 23.6 mg, 0.069 mmol) was added with stirring. A solution formed after several minutes, and a precipitate appeared soon thereafter. After one day methanol (1 ml) and ether were added. The precipitate was collected and dried (yield 26.6 mg, 73%).