Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:20])[N:11]([CH2:21][C:22]([OH:24])=O)[CH:10]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:9]1)=O)(C)(C)C.[NH2:32][C:33]1[CH:34]=[C:35]2[C:48](=[CH:49][CH:50]=1)[CH2:47][C@:37]1([C:45]3[C:40](=[N:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]1=[O:46])[CH2:36]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:31][C:27]1[CH:26]=[C:25]([CH:10]2[N:11]([CH2:21][C:22]([NH:32][C:33]3[CH:34]=[C:35]4[C:48](=[CH:49][CH:50]=3)[CH2:47][C@:37]3([C:45]5[C:40](=[N:41][CH:42]=[CH:43][CH:44]=5)[NH:39][C:38]3=[O:46])[CH2:36]4)=[O:24])[C:12](=[O:20])[C:13]3([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]3)[NH:8][CH2:9]2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1CC(c2cccc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2(COCCOC2)NCC1c1cccc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.23 g (0.52 mmol) 2-(1-(tert-butoxycarbonyl)-3-(3-fluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)ethanoic acid, 0.15 mg (0.58 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.13 g (0.70 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 95 mg (0.7 mmol) HOBT, 0.08 ml (0.58 mmol) TEA and 2 ml DMF were stirred overnight at RT. The mixture was concentrated by rotary evaporation. The residue was combined with 15 ml of a 1.25M methanolic hydrochloric acid and stirred for 2 h at 50° C. The reaction mixture was evaporated down and purified by HPLC.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[CH:14][C:13]([C:16](=[O:29])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:3]1.F[P-](F)(F)(F)(F)F.[N:37]1(OC(N(C)C)=[N+](C)C)[C:41]2N=CC=[CH:45][C:40]=2N=N1.CCN(C(C)C)C(C)C.C(N)C#C>CN(C=O)C.CCOC(C)=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:9]([NH:37][CH2:41][C:40]#[CH:45])=[O:11])=[CH:12][C:13]([C:16]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)=[O:29])=[CH:14][N:15]=2)[CH2:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(C(=O)O)c1
Agent: C#CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCNC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (R)-2-(3-hydroxypyrrolidin-1-yl)-5-((4-(trifluoromethoxy)phenyl)carbamoyl)nicotinic acid (Stage 72.3, 1.50 g, 3.65 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.66 g, 4.38 mmol) and DIPEA (0.566 g, 4.38 mmol) in DMF (40 mL) was stirred at RT for 15 min and then propargylamine (0.35 mL, 5.47 mmol) was added. The mixture was stirred for 3 h and then treated with EtOAc, washed with sat. aq. solution of NaHCO3 and brine. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the residue was crystallized from TBME/EtOAc to afford the product as a colorless crystalline solid. m.p. 246-248° C., HPLC (Condition 4) tR=4.79 min, UPLC-MS (Condition 8) tR=0.89 min, m/z=449.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.01 (m, 2H), 3.15 (t, J=2.54 Hz, 1H), 3.24 (d, J=12.12 Hz, 1H), 3.43-3.69 (m, 3H), 4.03 (d, J=4.30 Hz, 2H), 4.33 (br. s, 1H), 4.96 (d, J=3.13 Hz, 1H), 7.34 (d, J=8.99 Hz, 2H), 7.79-7.90 (m, 2H), 8.04 (d, J=2.35 Hz, 1H), 8.75 (d, J=2.35 Hz, 1H), 8.96 (t, J=5.67 Hz, 1H), 10.20 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([C:17]([NH:19][C:20]3[C:24](/[CH:25]=[CH:26]/[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][N:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:21]=3)=[O:18])=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1.[H-].[Na+].[CH3:48]N(C)C=O.CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([C:17]([N:19]([CH3:48])[C:20]3[C:24](/[CH:25]=[CH:26]/[P:27](=[O:34])([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])=[CH:23][N:22]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:21]=3)=[O:18])=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Yield: 78 %

Procedure:
To a mixture of diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy)-3-methoxybenzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer as washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil compound. To remove remaining trifluoroacetic acid, water was added to the oil compound, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-{3-[(4-([2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzoyl)(methyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as a colorless oil (39.8 mg, yield 78%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CS(C)=O>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[C:20]([NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])[CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[C@@H](O)CN
Reactant: N#Cc1ccc(OCc2ccccc2)cc1F
Solvent: CS(C)=O
Product: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A solution of (R)-(−)-1-amino-propan-2-ol (389 g, 5.19 mol) in dimethyl sulfoxide (600 mL) was added to a solution of the product from Step A (786 g, 3.46 mol), basic alumina (786 g), and 4 Å molecular sieves (131 g). The stirred mixture was heated at 110-140° C. for 24 h, cooled and filtered, the filter-aide was washed with 10 L of 4:1 ether-ethyl acetate followed by 4 L of 3:2 ethyl acetate-hexane. The organic washes were extracted with water (5 L) and the aqueous phase was extracted with 25% ethyl acetate-hexane (4×2 L). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated to about 3 L and allowed to stand for 48 h. The precipitated solid was collected by filtration, washed with hexane, and vacuum-dried to provide the desired product in two crops (619 g and 86 g). The concentated supernatant was applied to a 5 kg silica gel pad and eluted with a gradient of 10-50% ethyl acetate-hexane to give, after concentration in vacuo, additional product (119 g): total yield was 791 g (81%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].O>O1CCOCC1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12]1
Reactant: N#Cc1ccccc1F
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCC(Oc2ccccc2C#N)CC1
Temperature: 50 °C
Yield: 30.5 %

Procedure:
To a mixture of 2-fluoro-benzonitrile (1.6 g, 13.2 mmol) and 1-methyl-piperidin-4-ol (1.52 g, 13.2 mmol) in dioxane (50 mL) was added NaH (60%)(634 mg, 15.8 mmol) in portion. The reaction was heated at 50° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using ethyl acetate/methanol (20:1-10:1) to give the title compound (870 mg, 31%). MS (DCI/NH3) m/z 217 (M+1)+. 1HNMR (400 MHz, DMSO-d6) δ ppm 1.63 (m, 2H) 1.86 (m, 2H) 2.11 (s, 3H) 2.18 (m, 2H) 2.48 (m, 2H) 4.55 (m, 1H) 7.00 (td, J=7.67, 0.61 Hz, 1H) 7.23 (d, J=8.59 Hz, 1H) 7.56 (td, J=10.13, 7.36, 1.84 Hz, 1H) 7.63 (dd, J=7.67, 1.84 Hz, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][CH:28]([CH3:31])[CH2:29][NH:30][CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: CC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)CNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.48 mmol), 2-methylpropane-1-amine (0.9 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and flash column chromatography (DCM/MeOH). Yield: 0.11 g, 74%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 214° C. MS m/z (rel. intensity, 70 eV) 299 (M+, 6), 86 (100), 256 (21), 57 (8), 70 (6). [α]=−58° (MeOH).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:37])[NH:15][CH2:16][C:17]([N:19]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:28][CH:20]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])[CH:10]=[CH:11][CH:12]=1)(=O)[CH3:5]>O.CO.N1C=CC=CC=1>[OH:3]/[N:2]=[C:4](/[C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:37])[NH:15][CH2:16][C:17]([N:19]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:28][CH:20]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])[CH:10]=[CH:11][CH:12]=1)\[CH3:5]
Reactant: CC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: C/C(=N\O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Yield: 35.5 %

Procedure:
0.5 g of hydroxylamine hydrochloride in solution in 6 cm3 of water is added to a solution of 3 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-acetylphenyl)ureido]acetyl}-5-phenylprolinate in 12 cm3 of methanol and 6 cm3 of pyridine. The reaction mixture is heated under reflux for 2 hours. After evaporation of the solvents under reduced pressure at a temperature in the vicinity of 45° C., the residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (95/5 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the vicinity of 40° C. After recrystallization in acetonitrile, 1.1 g of tert-butyl (E)-(2RS,5SR)-1-{2-{3-[3-(1-hydroxyiminoethyl)phenyl]ureido}acetyl}-5-phenylprolinate, melting at 118° C., are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:31][S:28]([C:24]1[CH:23]=[C:22]([NH:20][C:18]2[N:19]=[C:12]3[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)=[CH:16][CH:15]=[CH:14][N:13]3[N:17]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CS(=O)(=O)c1cccc(Br)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(S(C)(=O)=O)c4)nc23)cc1

Procedure:
(3-Methanesulfonyl-phenyl)-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-bromo-3-methanesulfonyl-benzene (75.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.089 g, 77%). MP=230-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, J=6.9 Hz, 1H), 8.47 (s, 1H), 8.26 (d, J=7.9 Hz, 2H), 8.12 (d, J=7.5 Hz, 2H), 7.74-7.69 (m, 2H), 7.58-7.50 (m, 2H), 7.17 (s, 1H), 7.12-7.07 (m, 1H), 3.11 (s, 6H). MS=443 (MH)+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([NH2:12])[CH3:11])=[N:8][CH:9]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.C(N(C(C)C)CC)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:12][C@H:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][N:8]=2)[CH3:11])[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Cl)nc1N[C@@H](C)c1ccc(F)cn1
Temperature: 110 °C
Yield: 60.9 %

Procedure:
A mixture of (S)-1-(5-fluoropyridin-2-yl)ethanamine dihydrochloride (prepared as described in WO2006/123113, 560 mg, 2.63 mmol), 2,4-dichloro-5-methylpyrimidine (620 mg, 2.63 mmol) and diisopropylethylamine (1.4 mL, 7.9 mmol) in n-butanol (1 mL) was stirred and heated for 45 min at 110° C. in a microwave oven. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic solution was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (427 mg, 61%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=O)[CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[CH3:18][NH:19][CH3:20].C=O.[C:23](O)(=O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([CH2:14][CH2:15][CH2:18][N:19]([CH3:23])[CH3:20])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: CNC
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCCc1ccc(OCC(=O)O)c(Cl)c1Cl

Procedure:
(2,3-Dichloro-4-acetylphenoxy)acetic acid (U.S. Pat. No. 3,453,312) (7.89 g, 0.03 mole), dimethylamine hydrochloride (2.34 g, 0.03 mole), paraformaldehyde (1.05 g, 0.033 mol. equiv.) and glacial acetic acid (1 ml) were combined and heated on a steam bath for two hours. The reaction mixture was treated with hot ethanol (50 ml) and then cooled. The white solid was separated by filtration, washed with ethanol, dried and recrystallized from a mixture of ethanol and ether to give [2,3-dichloro-4-(3-dimethylaminopropyl)phenoxy]acetic acid hydrochloride, m.p. 194°-196° C.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C(O)C.O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:19])[CH:14]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1cccnc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2C1C(=O)c1cccnc1
Yield: 18.5 %

Procedure:
To a solution of 2.1 g (0.090 mole) of sodium metal in 100 ml of ethanol, was added 10.0 g (0.075 mole) of 2-oxindole, followed by 13.6 g (0.090 mole) of ethyl nicotinate. The resulting slurry was heated under reflux for 3 hours and then the mixture was cooled and filtered. The residue was discarded, and the filtrate was evaporated in vacuo. The residue thus obtained was dissolved in ca. 150 ml of water, and the aqueous solution was washed with chloroform. To the aqueous solution was then added 5.8 ml of glacial acetic acid and the resulting mixture was cooled in an ice-bath. The solid was recovered by filtration and recrystallized from ethanol to give 3.3 g of the title compound as yellow needles, m.p. 169°-170° C. Analysis: Calcd. for C14H10N2O2 : C, 70.58; H, 4.23; N, 11.76%. Found: C, 70.66; H, 4.41; N, 11.73%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].I[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.C(N(CC)C(C)C)(C)C>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:6][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of 3-ethynylaniline (1.16 g, 9.87 mmol) and tert-butyl (3-iodophenyl)carbamate (3.0 g, 9.4 mmol) in THF (28 mL) was treated with bis(triphenylphosphine)palladium(II) chloride (330 mg, 0.47 mmol), copper(I) iodide (140 mg, 0.75 mmol) and N,N-diisopropylethylamine (3.27 ml, 18.8 mmol), and stirred at 25° C. overnight. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.42 g, 49%). LCMS for C19H21N2O2 (M+H)+: m/z=309.1.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][NH:21][O:22][CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH:1][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of Boc-Phe-OH 5.1 (2.0 g, 7.53 mmol) and N,O dimethylhydroxylamine (808 mg, 8.29 mmol) in DCM (38 ml) was added TEA (2.2 ml, 15.8 mmol) and HOBT (1.27 g, 8.29 mmol). After cooling to 0° C., EDCI (1.59 g, 8.29 mmol) was added in one portion, and the reaction was stirred overnight, warming to room temperature. The reaction was concentrated in vacuo, diluted with EthOAc (150 ml), and washed with H2O, 1 N KHSO4, 1 N NaHCO3 and brine. After drying over Na2SO4, filtering, and concentrating in vacuo, the residue was purified by flash chromatography to give the title compound as an oil in 88% yield. Rf=0.35 (50% EthOAc/hexane). 1H NMR (300 MHz, CDCl3) δ7.28 (d, 2H, J=7.4 Hz), 7.24 (t, 1H, J=6.8 Hz), 7.17 (d, 2H, 7.1 Hz), 5.18 (d, 1H, J=7.4 Hz), 4.9 (dd, 1H, J=7.0, 11.9 Hz), 3.66 (s, 3H), 3.16 (s, 3H), 3.05 (dd, 1H, J=6.0, 13.6 Hz), 2.87 (dd, 1H, J=7.0, 13.6 Hz), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[CH:5]2.[C:19](Cl)(=O)[CH3:20].[Sn](Cl)(Cl)(Cl)Cl.Cl.C(=O)(O)O.[NH2:33][NH:34][C:35]([NH2:37])=[NH:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[C:5]2[CH2:20][CH:19]=[N:33][NH:34][C:35](=[NH:36])[NH2:37]
Reactant: N=C(N)NN
Reactant: Clc1ccc(-c2cc3cc(Cl)ccc3[nH]2)c(Cl)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)O
Solvent: ClCCl
Product: N=C(N)NN=CCc1c(-c2ccc(Cl)cc2Cl)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 3 %

Procedure:
A solution of 5-chloro-2-(2,4-dichlorophenyl)-1H-indole (160 mg, 0.54 mmol) and acetyl chloride (80 μL, 1.2 mmol) in CH2Cl2 is treated with tin tetrachloride (1.0 M solution in CH2Cl2, 1 mL), shaken at room temperature for 6 h, quenched with saturated NaHCO3 and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo. The resultant residue is suspended in isopropanol and concentrated HCl (100 μL), treated with aminoguanidine bicarbonate (100 mg, 0.75 mmol), heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. This residue is purified by HPLC to afford the title compound, 7.0 mg (3% yield), identified by HPLC1 and mass spectral analyses; (M+H) 395; retention time 4.51 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].C(N(CC)C(C)C)(C)C.O>ClCCl>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9](=[O:10])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g of 2-aminopyridine is dissolved in 10 ml of dichloromethane and then 1.18 g of 4-nitrophenyl chloroformate are added, as are 1.85 ml of N,N-diisopropylethylamine. The reaction mixture is stirred for one hour at ambient temperature. 50 ml of water are added to the reaction mixture and then the medium is extracted with 50 ml of dichloromethane. The solvents are evaporated off and then the solid is used in the next stage without further purification.
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH2:12][CH:11]1[C:30](OC)=[O:31])=[O:9])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+].O1CCCC1>O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH2:12][CH:11]1[CH2:30][OH:31])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: COC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(CO)C2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Methanol (6 ml) is added dropwise taking 30 minutes under reflux by heating, while stirring, to a mixture of methyl 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (6.3 g), sodium borohydride (1.64 g) and tetrahydrofuran (80 ml). The reaction mixture is poured into water, followed by extraction with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off. Crystals obtained from the residue are recrystallized from ethyl acetate-ether to afford 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol (4.15 g) as colorless crystals, m.p. 119-120° C.