Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@H:5]([N:36]([C:38]([C@@H:40]([NH:44][C:45]([C@@H:47]([N:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])=[O:46])[CH:41]([CH3:43])[CH3:42])=[O:39])[CH3:37])[C@H:6]([O:34][CH3:35])[CH2:7][C:8]([N:10]1[C@H:14]([C@H:15]([O:32][CH3:33])[C@H:16]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])[CH3:17])[CH2:13][CH2:12][CH2:11]1)=[O:9])[CH3:4].C([NH:61][C@H:62]([C:64]([OH:66])=[O:65])[CH3:63])(OC(C)(C)C)=O.[OH:67][CH2:68][CH2:69][CH2:70][NH-:71].FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH2:2][C@@H:3]([C@H:5]([N:36]([C:38]([C@@H:40]([NH:44][C:45]([C@@H:47]([N:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])=[O:46])[CH:41]([CH3:43])[CH3:42])=[O:39])[CH3:37])[C@H:6]([O:34][CH3:35])[CH2:7][C:8]([N:10]1[C@H:14]([C@H:15]([O:32][CH3:33])[C@H:16]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])[CH3:17])[CH2:13][CH2:12][CH2:11]1)=[O:9])[CH3:4].[OH:67][CH2:68][CH2:69][CH2:70][NH-:71].[NH2:61][C@H:62]([C:64]([OH:66])=[O:65])[CH3:63]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Agent: [NH-]CCCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Auristatin F-hydroxypropylamide Boc-L-Alanine (112 mg, 0.115 mmol, prepared as described in Example 49) was taken up in dichloromethane (3 mL) and excess trifluoroacetic acid was added. The mixture was stirred at 23° C. for 1 hour and the solvent removed under high vacuum. The resulting oil was taken up in dichloromethane (1.5 mL) and precipitation from diethyl ether (30 mL to give the title compound as white solid (96.2 mg, 85%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+](=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27])=[N-]>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[F:20][C:17]([F:19])([F:18])[CH2:16][N:15]([C:12]1[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:21])([F:22])[F:1])=[CH:14][CH:13]=1)[CH:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27]
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)N(CC(F)(F)F)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
The product from step 1 (500 mg, 1.47 mmol), dimethyl diazomalonate (220 mg, 1.4 mmol, prepared via Synthetic Comm., 17 (14), 1709-16 (1987)), and rhodium acetate (65 mg, 0.015 mmol) were combined and dissolved in CH2Cl2 (12 mL). The resulting mixture was heated at reflux over 1.5 h, cooled to room temperature, and concentrated in vacuo. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded the title compound as a colorless oil (626 mg, 95%). MS (ES+) m/z 472 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[N:16]=[CH:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19](Br)=[CH:20][C:11]=3[C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[N:16]=[CH:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19]([C:33]4[CH:32]=[CH:31][C:30]([CH2:29][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:35][CH:34]=4)=[CH:20][C:11]=3[C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A degassed mixture of tert-butyl-{3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-carbamate (229 mg, 0.631 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (207 mg, 0.946 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (51.5 mg, 6.31 μmol, 10.0 mol %) in 1,4-dioxane (12.4 mL) and 2M aqueous cesium carbonate (1.32 mL) was heated under reflux for 5 h. The mixture was allowed to cool to room temperature, diluted with DCM and water, and filtered to remove the precipitate. The filtrate layers were separated and the aqueous phase was extracted with DCM, and the combined organic phase concentrated in vacuo. The resultant residue was dissolved in 20% methanol in DCM and absorbed onto silica gel for purification by flash chromatography (silica, 11 g column, Biotage, 1-20% methanol in DCM) to afford the title compound as a beige solid (86.9 mg, 30%). 1H NMR (DMSO-D6, 400 MHz): 11.96 (s, 1H), 9.55 (s, 1H), 8.99 (d, J=1.9 Hz, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.57 (d, J=7.8 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.35 (m, 4H), 1.55-1.45 (m, 4H), 1.52 (s, 9H), 1.39 (m, 2H). LCMS (Method D): RT=9.11 min, M+H+=458.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[CH2:16][S:15][C:14](=[S:17])[N:10]3[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[CH3:18][I:19]>>[I-:19].[CH3:18][S:17][C:14]1[S:15][CH2:16][C@@H:9]2[CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]=3[CH2:11][N+:10]=12
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1C(=S)SC[C@@H]1C2
Product: CSC1=[N+]2Cc3cc([N+](=O)[O-])ccc3C[C@H]2CS1
Product: [I-]
Reaction time: 15 h

Procedure:
(S)-7-Nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (16 g.) is dissolved in methyl iodide (800 cc.). After 15 hours at a temperature of about 20° C., the crystals which have appeared are filtered off, washed with diethyl ether (2 × 30 cc.) and then dried at 20° C., under reduced pressure (1 mm.Hg). (S)-3-Methylthio-7-nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (23.3 g.) is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[OH:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[N:6]=[C:5]2[C:19]([N:28]1[CH2:27][CH2:26][C:25]2[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=2[OH:23])[CH2:29]1)=[O:20]
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccc(F)cc13)C2
Yield: 29.6 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 97 (29.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.66 and 2.91 (2t, 2H), 3.52 and 4.02 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.44 and 4.90 (2s, 2H), 6.32-6.92 (m, 2H), 7.40-7.46 (m, 1H), 7.61-7.78 (m, 2H), 8.03-8.10 (m, 1H), 8.15-8.38 (m, 3H), 8.69 and 8.73 (2s, 1H); MS (ESI) m/z 448 ([M+H]+).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([OH:43])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=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][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:44]1[CH:49]=CC=C[CH:45]=1.[C:50](Cl)(=O)[O:51]C1C=CC=CC=1.C(Cl)(Cl)Cl>ClCCl.O>[CH3:45][N:44]([CH3:49])[C:50]([O:43][CH:21]([CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:51]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
3-Octadecyl-1-tritylglycerol (2.6 g, 4.43 mmol) and 0.7 g (8.86 mmol) of pyridine were dissolved in 9 ml of dichloromethane, and 0.69 g of phenyl chlorocarbonate was added dropwise. The solution was stirred at room temperature for 30 minutes, and then stirred with 25 ml of chloroform and 25 ml of water. The aqueous layer was discarded and the organic layer was washed with 1% sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in 13 ml of dichloromethane, and dimethylamine gas was bubbled into the solution. The solution was concentrated to dryness under reduced pressure and the residue was purified by column chromatography on silica gel (20 g) using n-hexane-ethyl acetate (9:1) as the eluent to give 2.92 g (100%) of colorless needles, melting at 57.5°-58.0° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[C:14]1([C:5]2[O:6][C:7]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[C:3]([CH2:2][C:20]#[N:21])[N:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1nc(-c2ccccc2)oc1-c1cccnc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1nc(-c2ccccc2)oc1-c1cccnc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 4-(chloromethyl)-2-phenyl-5-(pyridin-3-yl)oxazole (197 mg, 728 μmol) in DMSO (4 mL) was added at RT potassium cyanide (56.9 mg, 873 μmol). Stirring was continued for 1 h and the reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (2×20 mL) and brine (1×20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 168 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (80 mg, 306 μmol, 42.1%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]=2[CH2:29][CH2:28]1.[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>CN(C=O)C>[CH3:1][C:2]1[N:6]([C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]=2[CH2:29][CH2:28]1
Reactant: BrCc1ccccc1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CC2CCc3c(c4ccccc4n3Cc3ccccc3)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
A solution of 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-4H-carbazol-4-one (500 mg) in dry DMF (3 ml) was added dropwise to a stirred suspension of sodium hydride (73% dispersion in oil; 38 mg) in dry DMF (1 ml) under nitrogen. After 20 min. benzyl bromide (0.14 ml) was added and the mixture was stirred for 3 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 850 mg) which was purified by FCC (column made up in ethyl acetate:hexane:triethylamine 79:20:1) eluting with ethyl acetate:hexane (4:1) to give the title compound (265 mg) as a solid, m.p. 78°-80°.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]2[CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=[C:2]12.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>ClCCl.O>[S:1]1[CH2:5][CH2:4][N:3]2[CH:6]=[C:7]([CH:9]=[O:10])[N:8]=[C:2]12
Reactant: CCOC(=O)c1cn2c(n1)SCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=Cc1cn2c(n1)SCC2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
Ethyl 2,3-dihydroimidazo[2,1-b]thiazole-6-carboxylate (4.2 g; 21.21 mmol) was dissolved in dry dichloromethane (150 ml) and cooled to −70° C. under a stream of dry argon. This solution was treated with a solution of diisobutylaluminium hydride in toluene (1.5M, 26.9 ml, 2 equivalents) over 40 minutes at −70° C. The reaction mixture was stirred at −70° C. for a further 0.5 h. Water (10 ml) was added and the mixture stirred at ambient temperature for 0.5 hr. The mixture was acidified with 5M HCl, filtered through a celite pad and the pad further washed with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to dryness. Chromatography on silica gel, eluting with ethyl acetate, gave the title compound (1.4 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[O:13][C:12]1=[O:20]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N:11]2[N:15]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[O:13][C:12]2=[O:20])[CH:4]=1
Reactant: CC(C)(C)c1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)o1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1nn(-c2cc(N)ccc2Cl)c(=O)o1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
Electrolytic iron powder (93.5 g) was suspended in 5% acetic acid (187.2 ml), and the suspension was heated to 80° C. A solution of 3-(2-chloro-5-nitrophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (47.21 g) in acetic acid (167.5 ml) and ethyl acetate (167.5 ml) was added thereto. The resultant mixture was heated at a temperature of 70° C. for 3 hours. The reaction mixture was subjected to filtration on celite while hot. The filtrate was extracted with ethyl acetate, and the extract was washed with water and sodium bicarbonate solution and dried. Removal of the solvent under reduced pressure gave 3-(5-amino-2-chlorophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (38.28 g). m.p., 126.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:20])C(=O)C1>C(#N)C>[Cl:20][C:9]1[C:10]([CH3:12])=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)cc1O
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(C)cc1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of methyl 2-hydroxy-4-methylbenzoate (2 g, 12.04 mmol) in acetonitrile (30 mL) was added NCS (1.688 g, 12.64 mmol). The solution was stirred at 100° C. for 2 hours and then cooled. The solvent was removed in vacuo. The residue was redissolved in DCM (20 mL), washed with water (10 mL) and NaHCO3 solution (15 mL), dried over MgSO4 and the solvent removed in vacuo. Purification by column (Si, Isolute, 5% EtOAc/Cyclohexane) gave the title product as a solid (2.42 g, 100% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH2:35]N=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(O)C>CN(C=O)C>[CH2:34]([O:14][C:13](=[O:15])[C@@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:35]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
In DMF (50.0 ml), 5-t-butoxycarbonylamino-(2S)-(9H-fluoren-9-ylmethoxycarbonylamino)-pentanoic acid (2.50 g) was dissolved. The solution was added with WSCI hydrochloride (1.21 g) and HOBt (0.84 g) and the whole was stirred at room temperature for 1.5 hours. The solution was added with ethanol (1.0 ml) and the whole was stirred at room temperature for additional 17 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.22 g) as a white solid.
Reaction SMILES: [C:1](=[O:20])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:1]([O:2][CH:3]3[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH2:8]3)=[O:20])[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CN1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)OC3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 1-methylpiperidin-4-yl 4-nitrophenyl carbonate (1.81 g, 6.44 mmol) and DIPEA (0.76 mL, 4.4 mmol) in DMF (20 mL) was added 4-(4-methylphenyl)piperazine (1.53 g, 6.14 mmol). The reaction mixture was stirred at room temperature for 3 hours, the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (250 mL) and washed with 1M aq Na2CO3 (5×150 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give 1-methyl-piperidin-4-yl 4-(4-methylphenyl)piperazine-1-carboxylate (1.54 g, 79%) as a cream solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2.[CH2:15](OC(OCC)OCC)C.[N-:25]=[N+:26]=[N-:27].[Na+]>C(O)(=O)C>[N:1]1([CH:2]2[CH:7]3[CH:3]2[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]3)[CH:15]=[N:27][N:26]=[N:25]1
Reactant: CC(C)(C)OC(=O)N1CC2C(N)C2C1
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2n1cnnn1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
To a solution of tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (7.3 g, 25.3 mmol) and triethylorthoformate (24 mL, 152 mmol) in acetic acid (200 mL) was added sodium azide (9.9 g, 152 mmol) and the resulting mixture was set under inert atmosphere. The mixture was heated at 100° C. for 4 h and then cooled to RT at which time the volatiles were removed in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with aqueous sodium bicarbonate solution, followed by brine. The organics were dried over sodium sulfate, filtered, and concentrate to dryness under vacuum. The residue was placed in the refrigerator overnight and the next day a solid white precipitate was observed. The precipitate was triturated with hexane and the solvent was carefully decanted to give the title compound 3.2 g (50.3%) as a white solid. ESI-MS calculated for C11H17N5O2: Exact Mass: 251.28. Found 252.28.
Reaction SMILES: [CH2:1](NC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.[BH3-]C#N.[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27]>CO>[CH2:1]([NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:31])=[C:24]([Cl:23])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(NCc2ccccc2)cc1Cl
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Benzylaniline (3.69 g, 34.8 mmol), AcOH (1.11 mL), and NaBH3CN were added to a solution of 3-chloro-4-fluoroaniline (5.07 g, 34.8 mmol) in MeOH (200 mL) containing molecular sieves. The resulting mixture was stirred at 23° C. for 18 h. Sieves were removed by filtration and the filtrate was concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and CH2Cl2 (50 mL, 2×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (SiO2, 0-12% EtOAc/hexanes gradient) to give N-benzyl-3-chloro 4-fluoroaniline (7-1) 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 6.93 (dd, J=8.8, 5.8 Hz, 1H), 6.62 (dd, J=6.1, 3.1 Hz, 1H), 6.44 (ddd, J=8.9, 3.7, 3.1 Hz, 1H), 4.27 (s, 2H), 3.98 (brs, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CN(C)C=O>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: COc1ccc(S)cc1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2nc(C(=O)NCC(=O)O)c(O)c3ccccc23)cc1
Temperature: 125 °C

Procedure:
To a solution of 100 mg of [(1-Chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid, (U.S. Pat. No. 6,093,730, disclosed as N-((1-Chloro-4-hydroxyisoquinoline-3-yl)carbonyl)glycine), in 1 ml N,N-dimethylformamide was added 1 ml of 4-methoxybenzenethiol. The solution was heated at 120 to 130° C. in a sealed tube for 72 h. The solution was then concentrated under vacuum. The resultant residue (76 mg) was purified by chromatography on silica gel using a gradient of 0 to 15% methanol in dichloromethane with 0.5% acetic acid to elute the product. 6 mg of product was obtained; MS (+) m/z 385.05 (M+1)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](O)=[O:22].CCCP(=O)=O.C(N(C(C)C)C(C)C)C>O1CCCC1.C(OCC)(=O)C>[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21]([NH:15][C:13]1[CH:12]=[CH:11][N:10]2[CH:16]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[N:14]=1)=[O:22]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)ccn1
Reaction time: 18 h
Yield: 17.8 %

Procedure:
A mixture of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (156 mg, 0.766 mmol, 1 eq.), 2-methylisonicotinic acid (116 mg, 0.842 mmol, 1.1 eq.), propylphosphonic anhydride in ethyl acetate 50% (1.13 ml, 1.91 mmol, 2.5 eq) and ethyldiisopropylamine (0.535 ml, 3.06 mmol, 4 eq) in tetrahydrofuran (10 ml) is stirred for 18 hours at roomtemperature. The solution is then refluxed for 4 hours. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium bicarbonate, with water, dried over magnesium sulfate and the solvent is removed in vacuo. Purification of the residue by chromatography on a 12 g RediSep silica cartridge using dichloromethane+5% methanol as eluent affords 2-methyl-N-(2-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-isonicotinamide (45 mg, 17.8%) as a yellow solid. MS: m/e=330.2 (M+H+)