Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C>C(O)C>[CH2:4]1[C:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:2][CH2:3]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21

Procedure:
A mixture of tryptamine hydrochloride (1.96 g, 10 mmol), ethyl 3-bromopyruvate (1.67 mL, 1.2 equiv) and decolorizing charcoal (0.5 g) in absolute ethanol was heated to reflux under nitrogen overnight. TEA was added and the reaction mixture was heated to reflux for another 7.5 hours. After cooling, charcoal was removed by filtration and washed with ethanol. The filtrate was concentrated under vacuum and diluted with water (20 mL). It was then extracted with EtOAc (3×30 mL) and the combined organic layers were washed with brine and dried over MgSO4. Evaporation of solvent and recrystallization from DCM-Hexane gave the title compound (1.17 g). 1H-NMR (CDCl3): δ 10.49 (1 H, br s), 7.79 (1H, d), 7.43 (1 H, d), 7.43 (1 H, d). 7.06 (2H, m), 5.27 (1 H, br s), 4.29 (2H, q) 3.58 (2H, m), 3.17 (2H, m), 1.36 (3H, t); MS (ES): 257 (MH+).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=2)[C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1.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>CN(C=O)C>[CH3:25][N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:17]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)=[N:27]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
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
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCOCC3)c2)n1
Yield: 47.8 %

Procedure:
3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (3.14 g, 9.5 mmol), 1-methyl-1H-pyrazol-3-amine (1.85 g, 19.0 mmol) and HATU (4.70 g, 12.35 mmol) were dissolved in DMF (12.5 mL) and DIPEA (3.31 mL, 19.0 mmol) added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL), extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a pale yellow gum (1.85 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23](OCC)=[O:24])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH:23]=[O:24])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cn(S(=O)(=O)c2cccc(C)c2)c(-c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(S(=O)(=O)n2cc(C=O)c(C)c2-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Under a nitrogen atmosphere, a solution (60 mL) of ethyl 4-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (2.48 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (13 mL) of diisobutylaluminum hydride in toluene was added dropwise over 15 min, and the mixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile solution (100 mL), tetra-n-propylammonium perruthenate (0.21 g), N-methylmorpholine N-oxide hydrate (1.31 g) and molecular sieves 4A powder (6.0 g) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (300 mL) was added to the residue, the suspension was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the title compound as a yellow oil (yield 1.76 g, 80%).
Reaction SMILES: [F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=3[CH3:23])[NH2:19])[C:3]=12.[OH:24][C:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([S:37]([F:42])([F:41])([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(#N)C>[F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([NH:19][C:31](=[O:32])[C:30]4[CH:34]=[C:35]([S:37]([F:42])([F:38])([F:39])([F:40])[F:41])[CH:36]=[C:28]([C:25]([OH:24])([CH3:27])[CH3:26])[CH:29]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])[C:3]=12
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)c(F)c12
Reactant: CC(C)(O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)c(F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
60 mg (0.195 mmol) of the compound of Example 83A and 60 mg (0.195 mmol) of the compound of Example 19A were dissolved in 2 ml of DMF, and 89 mg (0.234 mmol) of HATU and 41 μl (0.234 mmol) of N,N-diisopropylethylamine were added in succession. After about 16 h of stirring at RT, the reaction mixture was diluted with 1 ml of acetonitrile and separated into its components by preparative HPLC (Method 36). The product fractions were combined and freed from the solvent on a rotary evaporator. The residue was dissolved in a little methanol and the solution was passed through a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol) to convert the formate salt obtained after preparative HPLC into the free base. Evaporation and drying under high vacuum gave 42 mg (35% of theory) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:28][C:29]([NH2:32])([CH3:31])[CH3:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([NH:32][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[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(CC)CC
Product: CC(C)(C)NC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 3 h

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-1H-indole-2-carboxylic acid (36 mg, 0.10 mmol) and 2-methylpropan-2-amine (8.8 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) containing triethylamine (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N-tert-butyl-1H-indole-2-carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M+1)+; retention time 3.12 minutes.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:28])[C:14]=3[NH:18][C:19](=[O:27])[CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:9]=2)[CH2:3]1.[Si:29]([O:36][CH2:37][CH:38]=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:28][C:13]1[C:14]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:38][CH2:37][O:36][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:3]1)[CH:17]=[CH:16]2
Reactant: N[C@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 50(a), using N-[2-[(3S)-3-amino-1-piperidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide (Example 60) (200 mg), (tert-butyldimethylsilyloxy)acetaldehyde (0.086 mL) and sodium triacetoxyborohydride (0.212 g) to afford the sub-title compound (0.2 g).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[Na+].[Br:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=1.[S]>CS(C)=O.CC(N(C)C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:7][CH:21]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Br)cc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C1CC1c1ccc(Br)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
In a round-bottom flask, mixed trimethylsulfoxonium iodide (6.6 g, 30 mmol) in dimethyl sulfoxide (28 mL, KF=266 ppm H2O) and dimethylacetamide (12 mL, KF=249 ppm H2O). Added sodium tert-butoxide (2.7 g, 28 mmol) in one portion. Stirred the suspension for NLT 0.5 H at room temperature. Separately, mixed (E)-tert-butyl 3-(4-bromophenyl)acrylate 1 (5.66 g, 20 mmol) in dimethyl sulfoxide (20 mL) and heated to 50° C. Then, transferred the sulfur ylide mixture (slight suspension) by cannula (<10 min addition). The flask/cannula were rinsed into the reaction mixture with dimethyl sulfoxide (2-4 mL). Stirred the resulting yellow solution at 50° C., monitoring by HPLC for reaction completion (<1% pA of 1 after 0.5 h). Cooled the reaction mixture to <10° C. before quenching (exothermic) by slow addition with water (120 mL, product precipitates). The resulting product slurry was stirred at room temperature (1-2 h) and then filtered. The flask and wetcake were washed with water (˜70 mL total). The wetcake was dried under vacuum at 45° C. Isolated 4.44 g of an off-white solid (98% pA, 96 wt %) in 71% wt-adjusted yield. A sample of the isolated product was further purified by crystallization from methanol/water (1:1, 20 mL/g). 1H NMR (400 MHz, CDCl3) δ 1.16-1.21 (m, 1H), 1.47 (s, 9H), 1.50-1.55 (m, 1H), 1.77-1.81 (m, 1H), 2.37-2.41 (m, 1H), 6.95 (d, 2H, J=8.37), 7.37 (d, 2H, J=8.51). 13C NMR (100 MHz, CDCl3) δ 17.3, 25.4, 25.5, 28.4, 80.7, 119.7, 127.5, 131.1, 139.2, 171.7 with 4 peaks overlapping.
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[C:7]1([C:13]23[CH2:21][CH:17]4C[CH:19]([CH2:20]2)[C:15](C(=O)C)([CH2:16]4)[CH2:14]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][C:26]([OH:28])=[O:27]>O1CCOCC1.O>[C:7]1([C:13]23[CH2:14][CH:15]4[CH2:16][CH:17]([CH2:21]2)[C:25]([C:26]([OH:28])=[O:27])([CH2:19]4)[CH2:20]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)O
Reactant: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C12CC3CC1CC(c1ccccc1)(C3)C2
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a stirred mixture of NaOH (2.4 g, 60.0 mmol), H2O (16 mL), and 1,4 dioxane (2 mL) at ice bath temperature was added Br2 (0.56 mL, 10.4 mmol) and stirred for 15 minutes. The resulting hypobromite solution was added dropwise to a stirred solution of 1-(1-phenyltricyclo[3.3.1.03,7]non-3-yl)ethanone obtained from preparation I (1.0 g, 4.0 mmol) in 1,4-dioxane (6 mL) at ice bath temperature. After stirring the reaction mixture at r.t. for 1 h, it was again cooled to ice bath temperature and quenched by adding AcOH (3.6 mL, 60 mmol). The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-phenyltricyclo[3.3.1.03,7]nonane-3-carboxylic acid (0.62 g) in 64% yield. m/z (M+1) 243; 1H NMR (CDCl3) 300 MHz δ 7.40-7.25 (m, 4H), 7.25-7.18 (m, 1H), 2.90-2.86 (m, 1H), 2.54-2.48 (m, 1H), 2.38 (ddd, J=2.0, 2.0, 11.0 Hz, 1H), 2.20-2.05 (m, 4H), 1.98-1.78 (m, 5H), 1.70 (dd, J=2.8, 11.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH:31]=[C:30]3[C:21]([NH:22][C:23]4[C:28]([O:29]3)=[CH:27][CH:26]=[C:25]([C:32](O)=[O:33])[CH:24]=4)=[N:20][C:19]2=[O:35])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][CH2:51][NH2:52])[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].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>CN(C=O)C>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][CH2:51][NH:52][C:32]([C:25]2[CH:24]=[C:23]3[C:28]([O:29][C:30]4[C:21]([NH:22]3)=[N:20][C:19](=[O:35])[N:18]([CH:15]3[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17][CH2:16]3)[CH:31]=4)=[CH:27][CH:26]=2)=[O:33])[CH2:47][CH2:48]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(C(=O)O)ccc2O3)CC1
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
Product: CC(C)(C)OC(=O)NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(C(=O)NCCCN4CCN(C(=O)OC(C)(C)C)CC4)ccc2O3)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.1 %

Procedure:
A solution of 3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylic acid (6) (150 mg, 0.31 mmol, 1 equiv) and 4-(3-Amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.62 mmol, 2.0 equiv) in DMF (5 mL) was treated with HATU(235 mg, 0.62 mmol, 2.0 equiv) and Hunig's base. The resulting solution was stirred at RT for 6 h. When TLC and LCMS showed the reaction was complete, the reaction solution was concentrated in vacuo, and the residue was directly purified by column chromatography (SiO2, 0-10% MeOH/CH2Cl2 gradient elution) to afford the desired 4-[3-({3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carbonyl}-amino)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (106 mg, 220 mg, theoretical, 48%), which was treated with 4M HCl in dioxane to afford the final product 3-[1-(3-Amino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylic acid (3-piperazin-1-yl-propyl)-amide (8). For 7: C36H54N8O7, LCMS (EI) m/e 711(M++H). For 8: C26H38N8O3, LCMS (EI) m/e 511(M++H).
Reaction SMILES: [C:1]([C:7]#[N:8])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br.O.C(=O)(O)[O-:12].[Na+]>C(O)(=O)C>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1](=[O:6])[C:7]([NH2:8])=[O:12]
Reactant: CC(C)(C)C(=O)C#N
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)C(N)=O
Yield: 88 %

Procedure:
111.0 g (1 mole) of pivaloyl cyanide were added dropwise to 800 g of a 36% strength solution of hydrogen bromide in glacial acetic acid at room temperature, while stirring. When the addition had ended, the mixture was subsequently stirred at room temperature for 3 hours. 9 ml (0.5 mole) of water were then added dropwise at 20° to 25° C. and the mixture was subsequently stirred at room temperature for 1 hour. The reaction solution was then poured into an excess of saturated sodium bicarbonate solution. It was extracted three times with 200 ml of methylene chloride each time. The combined organic phases were washed with 200 ml of water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. After some time, the oil which remained crystallized completely. The recrystallization from petroleum ether gave 113.5 g (88% of theory) of trimethylpyruvic acid amide of melting point 69° to 70° C.
Reaction SMILES: [ClH:1].[P:2]([O-:57])([O-:56])([O:4][C:5](C(C)(C)C)(C(C)(C)C)[C:6]1[CH:11]=[C:10]([N:12](C(OC(C)(C)C)=O)[C:13]([NH2:22])=[N:14]C(OC(C)(C)C)=O)[CH:9]=[C:8]([N:30](C(OC(C)(C)C)=O)[C:31]([NH2:40])=[N:32]C(OC(C)(C)C)=O)[CH:7]=1)=[O:3]>CCOCC>[ClH:1].[ClH:1].[NH:12]([C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([NH:30][C:31]([NH2:40])=[NH:32])[CH:9]=1)[CH2:5][O:4][P:2](=[O:3])([OH:56])[OH:57])[C:13]([NH2:22])=[NH:14]
Reactant: CC(C)(C)OC(=O)N=C(N)N(C(=O)OC(C)(C)C)c1cc(N(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)cc(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c1
Agent: Cl
Solvent: CCOCC
Product: N=C(N)Nc1cc(COP(=O)(O)O)cc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65 %

Procedure:
1 M solution of HCl in ether (35 ml) was added to di-tert-butyl-3,5-Bis(N,N′-bis-Boc-guanidino)benzyl phosphate (0.45 gram, 0.57 mmol) and the resulting mixture was stirred at room temperature for 22-24 hours, during which a white precipitate was formed. The ether was thereafter decanted and the precipitate was washed 3-4 times with dry ether, evaporated and the residue was dried under high vacuum to give 0.13 grams (65%) of the final product.
Reaction SMILES: OC1(CCN2C(=O)CSC2CCCC2C=CC(C(O)=O)=CC=2)CCCCC1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34]O)=[O:33]>C(Cl)(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([OH:34])=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc(Cl)c1

Procedure:
A mixture of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (0.391 g., 1.0 mmol.), m-chloroperoxybenzoic acid (100%, 0.362 g., 2.1 mmol.), and chloroform (5 ml.) is refluxed for 30 minutes. The reaction mixture is evaporated in vacuo to give a solid residue which is applied to a silica gel column (18 g.) with chloroform. Elution with chloroform-acetic acid (25:1; v:v; 150 ml.) provides m-chlorobenzoic acid and impure material. Continued elution with the same eluant affords the title compound as a colorless viscous oil (0.273 g., 0.64 mmol., 64%), pmr (CDCl3) δ 3.75 (2H, s), 4.60 (1H, m), 7.26 (2H, d), 8.00 (2H, d).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].ClC1C=C(C=CC=1)OC1C2C=CC=CC=2CCNC1.ClCC#N.C(=O)(O)[O-].[Na+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:54]=[CH:55][CH:56]=1)[O:39][CH:40]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH2:44][CH2:43][N:42]([CH2:51][C:52]#[N:53])[CH2:41]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CN(C=O)C.C1COCC1.CCOCC>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH2:53][CH2:52][CH2:51][N:42]1[CH2:41][CH:40]([O:39][C:38]2[CH:54]=[CH:55][CH:56]=[C:36]([Cl:35])[CH:37]=2)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH2:44][CH2:43]1
Reactant: N#CCN1CCc2ccccc2C(Oc2cccc(Cl)c2)C1
Agent: Clc1cccc(OC2CNCCc3ccccc32)c1
Agent: N#CCCl
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCN1CCc2ccccc2C(Oc2cccc(Cl)c2)C1
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(m-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine of Example 4 (8.0 g, 0.029 mole), chloroacetonitrile (4.4 g, 0.058 mole) and sodium bicarbonate (10 g, 0.12 mole in DMF (100 ml) was stirred at 65° C. for 2.5 hours. The mixture was concentrated to an oil which was stirred with water and extracted with ether. The organic extracts were washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered and concentrated to an oil (8 g) which was extracted with boiling hexanes and concentrated to a light solid (5.4 g, 62%, m.p. 89°-95° C.). A solution of 1-(m-chlorophenoxy)-3-cyanomethyl-2,3,4,5-tetrahydro-3-benzazepine (5.1 g, 0.017 mole) in THF (50 ml) was dropped into a stirred suspension of LiAlH4 (2.6 g, 0.068 mole) in THF (100 ml). After stirring three hours at ambient temperature, the reaction mixture was cooled, diluted with ether, then quenched by dropwise addition of saturated NH4Cl. The mixture was filtered, and the organic filtrate was washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered and concentrated to an oil (3.7 g.) which was converted using the procedure of Example 1 to the dioxalate salt (5.5 g, 65%, d 150°-155° C.). This material was twice recrystallized from a 20:1 solution of ethyl acetate/methanol to yield 3-(2-aminoethyl)-1-(m-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine dioxalate, d 172°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:11]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH:18]([CH3:20])[CH3:19])[N:12]=1)=O.[NH2:22]/[C:23](=[C:26](\[NH2:29])/[C:27]#[N:28])/[C:24]#[N:25].CS(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:22]=[C:23]([C:24]#[N:25])[C:26]([C:27]#[N:28])=[N:29][C:9]=1[C:11]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CC(C)n1nc(C(=O)C(=O)c2ccccc2Br)ccc1=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2Br)ccc1=O
Yield: 56 %

Procedure:
A mixture of 1-(2-bromophenyl)-2-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-1,2-ethanedione (5.30 g) and (2Z)-2,3-diamino-2-butenedinitrile (1.65 g) in a solution of DMSO (0.25 ml) and toluene (25 ml) was refluxed for 8 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (85:15 v/v) to give 5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2,3-pyrazinedicarbonitrile as a solid (3.58 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15](=O)[NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[NH3:32]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:32][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: N
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 110 °C
Yield: 35.5 %

Procedure:
A mixture of 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, 2.4 mmol) and ammonia acetate (3.7 g, 20 eq.) in Xylene (2 mL) was heated in microwave at 110° C. for 2 hours. The mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (356 mg, containing 15% starting material, yield 35%). LCMS-ESI″: calc'd for C19H21BrN4O2: 417.30. Found: 418.9 (M+H+).