Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:6]=[CH:5][C:4]([N:7]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[C:31]4[C:39](=[CH:40][CH:41]=3)[NH:38][C:37]3[CH:36]=[C:35]5[C:42]([CH3:50])([CH3:49])[C:43]6[C:48]([C:34]5=[CH:33][C:32]4=3)=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:25][CH:24]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]([CH3:22])([CH3:21])[C:10]=3[CH:9]=2)=[CH:3][CH:2]=1.Br[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:2]=[CH:3][C:4]([N:7]([C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]([CH3:21])([CH3:22])[C:10]=3[CH:9]=2)[C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[C:31]4[C:39](=[CH:40][CH:41]=3)[N:38]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:37]3[CH:36]=[C:35]5[C:42]([CH3:49])([CH3:50])[C:43]6[C:48]([C:34]5=[CH:33][C:32]4=3)=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:27][CH:28]=2)=[CH:5][CH:6]=1
Reactant: Brc1ccccc1
Reactant: CC1(C)c2ccccc2-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccc5[nH]c6cc7c(cc6c5c4)-c4ccccc4C7(C)C)cc3)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccc5c(c4)c4cc6c(cc4n5-c4ccccc4)C(C)(C)c4ccccc4-6)cc3)cc21
Temperature: 45 °C

Procedure:
20.0 g (27.8 mmol) of biphenyl-4-yl-[4-(12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-7-yl)phenyl]-(9,9-dimethyl-9H-fluoren-2-yl)amine are dissolved in 500 ml of toluene with 4.39 ml (41.7 mmol) of bromobenzene and degassed. 1.94 ml (1.94 mmol/1 M in toluene) of tri-tert-butylphosphine, 249.8 mg of Pd(OAc)2 and 4.01 g (41.7 mmol) of NaOtBu are added (solids are degassed in advance), and the mixture is stirred under reflux for 5 h. The warm (45° C.) mixture is filtered through Alox B (activity grade 1), washed with water, dried and evaporated. The crude product is extracted with heptane/toluene in a Soxhlet extractor and crystallised from heptane, giving, after sublimation, 14.7 g (67%) of the product as a yellowish solid having a purity of 99.9%.
Reaction SMILES: [Br:1]C1C=C(N)C=CN=1.[C:9]([O:13][C:14]([N:16]1[C:24]2[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:19]=2[C:18]([CH3:27])([CH3:26])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(C)(C)C.BrC1C=C(N)C(I)=CN=1.BrC1C=C(NCC(C)=C)C(I)=CN=1.BrC1N=CC2C(C)(C)CNC=2C=1>>[C:9]([O:13][C:14]([N:16]1[C:24]2[CH:23]=[C:22]([Br:1])[N:21]=[CH:20][C:19]=2[C:18]([CH3:27])([CH3:26])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: Nc1ccnc(Br)c1
Agent: C=C(C)CNc1cc(Br)ncc1I
Agent: CC(C)C
Agent: CC1(C)CNc2cc(Br)ncc21
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Br)cc21

Procedure:
The title compound was prepared from 2-bromo-pyridin-4-ylamine using analogous methods to those outlined above for 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (Preparations 107-110). Colourless solid. 1H NMR (CDCl3) 8.00 (1H, s), 7.87 (1H, br s), 3.75 (2H, s), 1.59 (9H, br s), 1.39 (6H, s). MS: [M+H−tBu]+ 271, 273. Synthetic intermediates isolated in this process were as follows: 2-Bromo-5-iodo-pyridin-4-ylamine (pale orange solid, 1H NMR (DMSO-d6) 8.18 (1H, s), 6.78 (1H, s), 6.48 (2H, br s); MS: [M+H]+ 299, 301); (2-Bromo-5-iodo-pyridin-4-yl)-(2-methyl-allyl)-amine (pale orange oil, 1H NMR (DMSO-d6) 8.20 (1H, s), 6.52 (1H, s), 6.47 (1H, brt), 4.85 (1H, d), 4.74 (1H, d), 3.82 (2H, d), 1.68 (3H, s); MS: [M+H]+ 353, 355); 6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (colourless solid, 1H NMR (DMSO-d6) 7.70 (1H, s), 6.73 (1H, br s), 6.47 (1H, s), 3.30 (2H, d), 1.26 (6H, s); MS: [M+H]+ 227, 229).
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]([N:7]([CH3:9])[CH3:8])=[CH:5][CH:4]=1.[Si:12]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:25](=O)[CH2:24][CH2:23]2)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[Si:12]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:25][CH:24]=[C:23]2[C:3]1[CH:11]=[CH:10][C:6]([N:7]([CH3:9])[CH3:8])=[CH:5][CH:4]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CN(C)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(=O)CC2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)c1ccc(C2=CCc3cc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)cc32)cc1
Temperature: 60 °C

Procedure:
Magnesium (124 mg, 5.1 mmol) is covered with 1 ml of distilled THF and heated at 60° C. with stirring. A solution of 4-bromo-N,N-dimethylaniline (1.02 g, 5.1 mmol) in 5 ml of distilled THF is added dropwise over the course of 20 min. The reaction mixture is heated at reflux of the THF for 1 h. A solution of 5,6-di(tert-butyldimethylsilyloxy)indan-1-one (2 g, 5.1 mmol) in 10 ml of distilled THF is added dropwise at room temperature over the course of 5 min to this yellow-green solution. The mixture is brought to reflux for 20 h. The reaction mixture, which is violet in colour, is hydrolyzed by saturated aqueous ammonium chloride solution, then extracted with ethyl acetate. The organic phase is washed with saturated aqueous NaCl solution, then dried over MgSO4. The solvent is evaporated under reduced pressure. The desired product is purified by chromatography with an eluent: 9:1 hexane/ethyl acetate, and is obtained in the form of an oil (0.9 g; 36%)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].I[C:37]1[CH:38]=[N:39][N:40]2[CH:45]=[C:44]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[CH:43]=[N:42][C:41]=12.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:44]2[CH:43]=[N:42][C:41]3[N:40]([N:39]=[CH:38][C:37]=3[C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:45]=2)=[CH:51][CH:50]=1
Reactant: COc1ccc(-c2cnc3c(I)cnn3c2)cc1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cncc(-c2cnn3cc(-c4ccc(OC)cc4)cnc23)c1
Temperature: 80 °C

Procedure:
A mixture of ethyl 5-bromonicotinate (500 mg, 2.17 mmol, 1 equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (662 mg, 2.61 mmol, 1.20 equiv), potassium acetate (639 g, 6.51 mmol, 3.00 equiv), and 1,1′-bis (diphenylphophino)-ferrocene)dichloropalladium (89 mg, 0.11 mmol, 0.050 equiv) in DMF (5 mL) was heated at 80° C. for 16 hours. The mixture was partitioned between water (100 mL) and ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated. A solution of the residue, 3-iodo-6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine (2-1, 254 mg, 0.723 mmol, 0.333 equiv), tetrakis(triphenylphosphine)palladium (50 mg, 0.043 mmol, 0.020 equiv) in a mixture of aqueous 2M sodium carbonate solution (1 mL) and dioxane (10 mL) was heated at reflux for 16 hours. The reaction was then partitioned between water (50 mL) and ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was suspended in methanol and filtered to give ethyl 5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]nicotinate (2-2) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.50 (d, 1H, J=2.2 Hz), 9.12 (d, 1H, J=2.2 Hz), 8.96 (t, 1H, J=2.2 Hz), 8.88 (d, 1H, J=2.2 Hz), 8.8.3 (d, 1H, J=2.4 Hz), 8.54 (s, 1H), 7.56 (d, 2H, J=8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 4.48 (q, 2H, J=7.3 Hz), 3.90 (s, 3H), 1.46 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:5]([CH:21]=C)[CH:4]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:32].[Na+].Cl>O1CCOCC1.O.[Os](=O)(=O)(=O)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[O:32])[C:6]2[CH:7]=[CH:8][N:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:13])=[O:14])[C:10]=2[CH:11]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(OC)cc2c1ccn2S(=O)(=O)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C=O)c2ccn(S(=O)(=O)c3ccccc3)c2c1
Yield: 144.5 %

Procedure:
6-Methoxy-1-(phenylsulfonyl)-4-vinyl-1H-indole (0.27 g, 0.9 mmol; Intermediate 33) was dissolved in dioxane (24 mL) and 2,6-lutidine (0.2 mL, 1.7 mmol) was added. Osmium tetraoxide (0.011 g, 0.04 mmol) was added and after 15 min of stirring did the mixture change colour to black. Sodium periodate (0.74 g, 3.4 mmol) dissolved in water (8 mL, warmed to dissolve) was added and a precipitation started to form. After 1 h of stirring at rt was the mixture portioned between 2N HCl and dichloromethane. The organic layer was dried (Na2SO4) and concentrated to give 0.41 g of the crude product. MS (ESI+) for C16H13NO4S m/z 316 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([CH3:39])[C:29]=1[N:30]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[N:31]1)[O:6][CH:7]([C:11]1[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:16])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].O1CCCC1.CO.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([CH3:39])[C:29]=1[N:30]1[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[N:31]1)[O:6][CH:7]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[CH:25][CH:26]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(OC)c1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(OC)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
To a flask containing ethyl 3-(4-(1-(3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoate (37.0 mg, 0.0700 mmol) was added tetrahydrofuran (0.170 mL), methanol (0.170 mL), and 1 N sodium hydroxide (0.170 mL, 0.170 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 2 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude material. The crude material was azeotrophed three times with methylene chloride and then dried in vacuo for 18 h to provide (+/−)-3-(4-(1-(3-methoxy-5-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido) propanoic acid (26.0 mg, 74%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.66 (s, 1H), 7.39 (d, J=82 Hz, 2H), 6.88 (t, J=6.0 Hz, 1H), 6.41-6.21 (m, 2H), 5.17 (dd, J=7.7, 5.2 Hz, 1H), 3.75-3.65 (m, 2H), 3.63 (s, 3H), 2.66 (t, J=5.9 Hz, 2H), 2.04-1.93 (m, 1H), 1.89 (s, 3H), 1.86-1.74 (m, 1H), 1.62-1.35 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). MS (M+1): 520.4.
Reaction SMILES: C(Cl)(Cl)Cl.C(O)(=O)C.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10]1.C1C(=O)N([Br:27])C(=O)C1>O>[Br:27][C:10]1[S:9][CH:13]=[CH:12][C:11]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)Cc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1ccsc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
In a 250 ml 3-neck flask containing 50 ml of CHCl3 and 50 ml of glacial acetic acid, 9.5 grams (0.0558 mol) of ethyl thiophene-3-acetate was added, followed by 9.93 grams (0.0558 mol) of NBS. The mixture was stirred at room temperature for 12 hours. The mixture became clear yellow solution after 1 hour and then was cooled down to room temperature, and poured into 200 ml deionized (DI) water. The organic portion was washed again with 100 ml of DI-water, and then finally washed with 100 ml of 5% aqueous sodium bicarbonate solution. After having been dried over magnesium sulfate, the solvent was filtered and the product was concentrated under vacuum. The resulting residue was vacuum distilled at 95° C. under 1 mm mercury (Hg) yielding 12.3 grams of ethyl 2-bromothiophene-3-acetate (88% yield). 1H NMR (CDCl3): 1.26 (t, 3H), 3.60 (s, 2H), 4.16 (q, 2H), 6.93 (d, 1H), 7.22 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:22]([NH2:24])[CH3:23]>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4]([NH:24][CH2:22][CH3:23])[N:3]=1
Reactant: CCN
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(Cl)nc(N)nc32)O[C@@H]1CO
Solvent: CC#N
Product: CCNc1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 70 °C
Yield: 59 %

Procedure:
2-Amino-9-(3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-6-chloro-9H-purine (0.23 g, 0.74 mmol) was dissolved in 20 mL anhydrous acetonitrile in a sealed tube. The solution was cooled to 0° C., saturated with ethylamine (Aldrich, lot #00115JV) and sealed. After heating at 70° C. for 16 hours, the reaction mixture was filtered and the filtrate evaporated to dryness. The residue was preloaded onto silica gel and eluted from a silica column using CHCl3 /MeOH (95:5, v/v). Combination and evaporation of appropriate fractions yielded 0.140 g (0.44 mmol, 59%) of product. mp=199°-201° C.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[C:14]2[O:13][C:12]3[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl>C(O)C.CN(C)C=O.O>[OH:19][CH:18]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[C:14]=3[O:13][C:12]=2[CH2:15][CH2:16][CH2:17]1
Reactant: O=C1CCCc2oc3c([N+](=O)[O-])cccc3c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=[N+]([O-])c1cccc2c3c(oc12)CCCC3O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Sodium borohydride (38 mg) was added to a solution of 6-nitro-1-oxo-1,2,3,4-tetrahydrodibenzofuran (231 mg) in a mixture of ethanol (1.5 ml) and N,N-dimethylformamide (1.5 ml). The mixture was stirred at ambient temperature for 20 minutes, diluted with water and acidified with 3.6% hydrochloric acid. The separated oil was extracted with ethyl acetate and the extract was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give 1-hydroxy-6-nitro-1,2,3,4-tetrahydrodibenzofuran (175 mg).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([O:39][C:40](=[O:49])[C@H:41]([CH3:48])[NH:42][C:43](=[O:47])[N:44]([CH3:46])[NH2:45])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:49])[C@H:41]([CH3:48])[NH:42][C:43](=[O:47])[N:44]([CH3:46])[NH:45][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[CH3:38]
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)[C@H](C)NC(=O)N(C)N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](C)NC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of acetylalanylalanylproline (3 mmole) and N-methylmorpholine (3 mmole) in dry tetrahydrofuran (110 ml) at -20° to -25° C. is added isobutyl chloroformate (3 mmole) and stirred at -20° C. for 10 minutes. A solution of 2-azaalanylalanine ethyl ester (3 mmole) in tetrahydrofuran (15 ml) is added dropwise. The resulting mixture is allowed to warm to room temperature over a period of 1 hour and stirred overnight. The precipitate is filtered off and the filtrate is concentrated to dryness. Chromatography on silica gel (70 gm) and elution with 8% methanol in chloroform gives acetylalanylalanylprolyl-2-azaalanylalanine ethyl ester.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[S:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[S:21][N:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)sn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 157a (60 mg, 0.10 mmol) in THF/i-propanol/water (4 mL/4 mL/1 mL) was added lithium hydroxide (24 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was dried with Na2SO4 and concentrated to afford a yellow solid, which was purified by reverse-phase prep-HPLC to afford 157 as a yellow solid (27 mg, 50%). MS-ESI: [M+H]+ 546.7. 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.60-8.54 (m, 3H), 7.90 (s, 1H), 7.78 (d, J=16.0 Hz, 1H), 7.55-7.50 (m, 2H), 7.04 (s, 1H), 4.89 (t, J=6.5 Hz, 1H), 4.43-4.41 (m, 2H), 3.61 (s, 3H), 2.48 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[N:2]1.Cl[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15]>C1(C)C=CC=CC=1>[N:17]([S:14]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][O:1][N:2]=1)(=[O:16])=[O:15])=[C:18]=[O:19]
Reactant: Oc1ccccc1-c1ccon1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)Oc1ccccc1-c1ccon1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution containing 30 g of 2-(isoxazol-3-yl)phenol [prepared by the procedure of R. Beugelmans and C. Morin, J. Org. Chem., 42, 1356 (1977)] in 200 ml of dry toluene was added slowly 26.3 g of chlorosulfonyl isocyanate while maintaining the temperature at 20° to 30° C. with external cooling. The resulting suspension containing a while solid was stirred at 25° C. for 1 hour, then heated at 100° to 110° C. for 1 hour. The resulting slightly cloudy solution was cooled to 25° C., filtered, and the filtrate was concentrated in vacuo to yield 45 g of the title compound as a crude oil. The IR spectrum showed an isocyanate absorption at 2220 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].CC([O-])=O.[Na+]>CC#N.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]>[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 25.7 %

Procedure:
A sealed tube was charged with the mixture of 338c (274 mg, 0.7 mmol), 210d (337 mg, 0.7 mmol), Pd(dppf)Cl2 (33 mg, 0.04 mmol), K3PO4.3H2O(372 mg, 1.4 mmol), and NaOAc (115 mg, 1.4 mmol) in CH3CN(20 ml). The system was evacuated and then refilled with N2. And the reaction mixture was heated at 110° C. under microwave irradiation for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 338d as a yellow solid (120 mg, 43%). MS: [M+H]+ 668.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39](OCC3C=CC=CC=3)=[O:40])[CH:34]=2)[CH:29]=[N:28][CH:27]=1.Cl>C1COCC1.CCOC(C)=O>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:39](=[O:40])[C:35]2[CH:34]=[C:33]([O:32][C:30]3[CH:29]=[N:28][CH:27]=[N:26][CH:31]=3)[CH:38]=[CH:37][N:36]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)c1cc(Oc2cncnc2)ccn1
Reactant: Cc1cccc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)c2cc(Oc3cncnc3)ccn2)n1
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
2-Amino-6-picoline (49 mg, 0.45 mmol, 2.0 eq) was dissolved in THF (0.55 mL) in a flame-dried round bottom flask. A 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (943 μL, 0.453 mmol, 2.00 eq) was added dropwise and the reaction was stirred for 5 min. Compound 8 (69 mg, 0.22 mmol, 1.0 eq) was added as a solution in THF (0.55 mL) and the reaction was stirred for 30 min. The reaction was diluted with EtOAc, neutralized with 1N HCl and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 45 mg (65%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 9.19 (s, 1H), 8.92 (s, 2H), 8.69 (d, J=5.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.82-7.75 (m, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.42 (dd, J=5.6, 2.6 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 2.43 (s, 3H); [M+1]+: 308.2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl.O>CO>[N+:9]([CH:12]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: 0 °C

Procedure:
Benzaldehyde (2, 52.35 g, 0.493 mol) and nitromethane (30.11 g, 0.493 mol) were dissolved in methanol (100 mL) in a two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel. NaOH (25.6 g, 0.641 mol) in ice/water (50 mL) was added dropwise to the solution keeping the temperature below 15° C. A fine slurry formed during the addition and methanol was added to allow stirring. After the addition the slurry was diluted with ice/water and the resulting clear solution was added dropwise to a solution of conc. HCl/H2O (200/300 ml); a yellow precipitate was formed during the addition. The precipitate was filtered on a buchner funnel, washed with water and crystallized from methanol obtaining pure 3 (58.78 g, 80%). Yellow needles. M.p. 57-58° C.