Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])(O)=O.[Na+].Cl[C:28]([O:30][CH3:31])=[O:29]>C1COCC1.O.CCOC(C)=O>[C:18]([NH:17][CH2:16][C@@H:14]1[O:13][C:12](=[O:21])[N:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH2:1][N:2]([C:28]([O:30][CH3:31])=[O:29])[CH2:3][CH2:4]3)[CH2:15]1)(=[O:20])[CH3:19]
Reactant: COC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N1CCc2cc(N3C[C@H](CNC(C)=O)OC3=O)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A mixture of N-[[(5S)-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Step 6, 450 mg, 1.55 mmol) and NaHCO3 (260 mg, 3.10 mmol) in THF (15.5 mL) under N2 is treated with methyl chloroformate (0.144 mL, 1.87 mmol) with vigorous stirring. A thick, white slurry results which is redissolved by the addition of H2O (approx. 2 mL). The mixture is stirred at ambient temperature for 1 hr and is then diluted with H2O (10 mL) and EtOAc (20 mL) and the layers are separated. The aqueous phase is reextracted with CH2Cl2 (20 mL), and the combined organic phase is washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product is chromatographed on silica gel (45 g, 230-400 mesh), eluting with MeOH/CHCl3 (2/98), and those fractions with an Rf=0.51 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 475 mg (88%) of the title compound as a glassy solid. 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 2H), 7.11 (m, 1H), 6.19 (m, 1H), 4.76 (m, 1H), 4.59 (s, 2H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.75 (s, 3H), 3.75-3.50 (m, 4H), 2.85 (m, 2M), 2.02 (s, 3H); MS (ESI+) for C17H21N3O5 m/z 348 (M+H)+; [α]25D=−20° (c 1.04, DMSO).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)Cn1ccnc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2nccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 10 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give desired product as a solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH:6][CH3:7].Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.O>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH3:7]
Reactant: Brc1nccs1
Reactant: CNCCCNC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNCCCN(C)c1nccs1
Temperature: 120 °C
Yield: 60 %

Procedure:
2.45 g (24.0 mmol) N,N3-dimethylpropane-1,3-diamine was added to 0.36 ml (4.0 mmol) 2-bromothiazole and heated to 120° C. for 1 h. After cooling to RT, dilution with water and chloroform took place. The phases were separated and the aqueous phase was extracted with chloroform. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. Column chromatography (SiO2, DCE/MeOH/25% aq. NH3-soln 4:4:1) was carried out on the residue, yielding 440 mg (2.4 mmol, 59%) N1,N3-dimethyl-N1-(thiazol-2-yl)propane-1,3-diamine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(OCC)(=O)C.C(Cl)Cl>[CH3:16][C:12]1[C:13]([C:1](=[O:3])[CH3:2])=[CH:14][C:15]2[C:6]([CH3:19])([CH3:5])[CH2:7][CH2:8][C:9]([CH3:18])([CH3:17])[C:10]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a 250 ml three-necked round bottomed flask fitted with a magnetic stirring bar and a reflux condenser containing acetyl chloride (2.3 g, 29.7 mmol) and 50 ml of DCM was added 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene 1b (5 g, 24.8 mmol) followed by slow addition (ca. 0.5 g portions) of AlCl3 (7.5 g, 56.2 mmol). The brown mixture was stirred for 30 min and then heated at reflux for 15 min. Additional AlCl3 (1-2 g) was necessary to effect the completion of the reaction. The cooled reaction mixture was poured into 200 ml of vigorously stirred ice water followed by acidification with 20% aqueous hydrochloric acid 50 ml and addition of 100 ml of ethyl acetate. Stirring was continued until the organic layer was yellow 15 min. The organic layer was extracted with ethyl acetate (2×100 ml), dried over MgSO4, filtered and concentrated in vacuo. Kugelrohr distillation (80-120° C., 3×10−4 torr) gave an analytically pure sample of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)ethanone 5.31 g (88%) as a white solid; m.p. 54-56° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[N:14]=[N:15][NH:16][N:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>CC#N>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[N:14]=[N:15][NH:16][N:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2nn[nH]n2)cc1C=O
Solvent: CC#N
Product: COc1cc(OC)c(-c2nn[nH]n2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 19 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-(2H-tetrazol-5-yl)-benzaldehyde (Ex-75A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 19% yield, mp 218° C. (dec). 1H-NMR (DMSO-d6) δ 8.58 (s, 1H), 8.20 (d, 2H), 8.03 (m, 3H), 7.85 (d, 1H), 6.90 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). MS m/z=422 ([M+CH3CN+H]+, 100%). HRMS m/z: calc. 381.1199, found 381.1184.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([C:14](N)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[OH-:36].[NH4+].[CH3:38]O>O>[CH3:38][O:36][C:14]([C:11]1([NH:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:15]
Reactant: CO
Reactant: NC(=O)C1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [NH4+]
Solvent: O
Product: COC(=O)C1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 120 h

Procedure:
To a solution of 1-Benzyl-4-(4-chloro-phenylamino)-piperidine-4-carboxylic acid amide (1.19 g 3.46 mmol) in methanol (10 ml) in a sealed tube was added toluene sulfonic acid (2.33 g, 12.11 mmol). The reaction was heated to 120° C., and stirred at that temperature behind a blast shield for 5 days. The reaction was then allowed to cool to room temperature at which time it was worked up by diluting with water, then by adding concentrated ammonium hydroxide until the pH≈8. The mixture was extracted three times with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The yellow oil was used crude (744 mg, 60%).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27](Cl)=[O:28]>O>[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: O=C(Cl)CSCC(F)(F)F
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CSCC(F)(F)F)[C@H]3SC2)s1
Temperature: 25 °C

Procedure:
7-Amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (3.96 g, 14 mmol) was reacted with trifluoroethylmercaptoacetyl chloride in the same manner as described in Example 1. After stirring at room temperature the solution was diluted with water (50 ml), washed with ether (3 × 150 ml), acidified to pH 2 with 3N HCl and extracted with ethyl acetate (3 × 150 ml). The extracts were washed with water dried, and concentrated. The product was collected and converted to its sodium salt by the procedure in Example 1.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[C:18]([OH:26])[CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[Cl:28]CCl.Cl>C(O)(C)C.C(N(CC)CC)C>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[CH:20]=[CH:19][C:18]([OH:26])=[C:17]([CH2:10][N:12]([CH3:24])[CH3:13])[C:16]2=[CH:15][C:14]=1[CH2:13]3)=[O:11].[ClH:28]
Reactant: ClCCl
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1
Temperature: 27.5 °C
Yield: 238.7 %

Procedure:
10-hydroxy-camptothecin (1.0 kg), dichloromethane (about 13 kg) and isopropanol (about 8 kg) were charged into a suitable reactor. N,N-dimethylmethyleneiminium chloride (0.3-0.5 kg) was added into the reactor. Triethylamine (0.04-0.2 kg) was then added into the resulting mixture at 20-35° C. and stirred at 20-35° C. for at least 12 hours. When the reaction was complete, a mixture of hydrochloric acid (32%, 0.06-0.3 kg) and isopropanol (about 5 kg) was added into the resulting mixture. After the addition was completed, the resulting mixture was stirred, filtered, and then washed with dichloromethane (about 3 kg). The wet solids were dried to give about 1.5 kg of crude topotecan HCl.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)[CH2:10][CH2:11][CH:12]=[O:13].[CH2:15]([C:22](O)=O)[C:16](CC(O)=O)=O.O.O.O.C([O-])(=O)C.[Na+].Cl>O>[CH2:1]([N:8]1[CH:10]2[CH2:9][CH2:22][CH:15]1[CH2:16][C:12](=[O:13])[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=CCCC=O
Reactant: O=C(O)CC(=O)CC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under N2, a solution of benzylamine (36.1 ml, 0.33 mol) in water (435 ml) was added within 45 min at 3 to 8° C. to a solution of 1,4-butane dialdehyde (1.15 equiv.), 1,3-acetone dicarboxylic acid (1.5 equiv.) and sodium acetate trihydrate (2 equiv.) in 330 ml water as described in Example 1, Step (a). The mixture was warmed up to 50° C. over 5 h and kept at this temperature for 2 h. After cooling to 20-25° C., 80 ml conc. HCl was added and the solution was washed with TBME (2×240 ml). The pH of the aqueous phase was adjusted to 7-8 with NaOH and the product layer was separated. The aqueous phase was extracted with TBME (3× with a total of 240 ml). The combined product phases were dried over Na2SO4 and concentrated as completely as possible under vacuum at 50°. Yield: 68.7 g (90% abs.). Assay (HPLC): 93% pure vs. standard.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]=[CH:10][C:11]([OH:13])=O)=[O:8])[CH:2]=1.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]=[CH:10][C:11]([N:14]2[CH2:21][CH2:20][CH2:19][C@H:15]2[C:16]([OH:18])=[O:17])=[O:13])=[O:8])[CH:2]=1
Reactant: O=C(O)C=CC(=O)c1cccnc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: O=C(C=CC(=O)N1CCC[C@H]1C(=O)O)c1cccnc1

Procedure:
As for Example 27, 3-(3-pyridylcarbonyl)acrylic acid (0.01 mole) is reacted with N,N'-carbonyldiimidazole (0.011 mole) in tetrahydrofuran and to the mixture is added 0.011 mole of L-proline. The mixture is refluxed 16 hours and the solvent removed under reduced pressure. The mixture is partitioned between dichloromethane and water containing acetic acid. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is removed in vacuo to yield 1-[3-(3-pyridylcarbonyl)acryloyl]-L-proline. The preceding compound is dissolved in carbon tetrachloride and 0.03 mole of thioacetic acid is added. The mixture is heated 3 hours and the solvent is removed in vacuo to give the product of the Example as a glass.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[O:47]1[CH2:52][CH2:51][N:50]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH2:49][CH2:48]1.[O-]CC.[Na+].Cl>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23]([N:24]5[CH2:25][CH2:26][N:27]([S:62]([C:59]6[CH:60]=[CH:61][C:56]([S:53]([N:50]7[CH2:51][CH2:52][O:47][CH2:48][CH2:49]7)(=[O:55])=[O:54])=[CH:57][CH:58]=6)(=[O:63])=[O:64])[CH2:28][CH2:29]5)=[O:30])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCN(S(=O)(=O)c2ccc(S(=O)(=O)N3CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
To a mixture N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.040 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.028 mL, 0.160 mmol) followed by 4-(morpholinosulfonyl)benzene-1-sulfonyl chloride (13.00 mg, 0.040 mmol) and the resulting solution stirred at room temperature for 24 h. The mixture was treated with sodium ethoxide (0.015 mL, 0.040 mmol) and stirred at room temperature for 1 h. The reaction was diluted with water and dichloromethane. The aqueous phase was acidified with 1N HCl and the product extracted into the organic phase. The organic phase was concentrated and the residue was triturated with methanol. The white solids were collected by filtration to give the title compound (2.2 mg, 7% yield). (M+H) calcd for C35H41FN7O10S2: 802.23; found: 802.84. 1H NMR (400 MHz, CDCl3) δ: 11.94 (1 H, s), 8.70 (1 H, s), 8.17 (1H, t, J=6.02 Hz), 7.91 (4 H, s), 7.31 (2 H, dd, J=8.41, 5.40 Hz), 6.96 (2 H, t, J=8.66 Hz), 4.51 (2 H, d, J=6.02 Hz), 4.04-4.22 (4 H, m), 3.67-3.80 (4 H, m), 3.44-3.65 (2 H, m), 2.88-3.20 (8 H, m), 2.50-2.67 (2 H, m), 2.46 (1 H, brs), 1.79-2.06 (4 H, m), 1.58-1.77 (2 H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:11]3[CH:23]=2)[CH:5]=[CH:6][CH:7]=1.[Br:24]N1C(=O)CCC1=O>O1CCOCC1>[Br:24][C:23]1[N:11]2[CH:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][NH:14][C:15](=[O:16])[C:10]2=[CH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(F)c3)cn21
Solvent: C1COCCO1
Product: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(F)c3)c(Br)n21

Procedure:
Ethyl [7-(3-fluorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]acetate (116 mg, 0.36 mmol) was dissolved in dry dioxane (15 ml) and reacted with N-bromo succinimide (72 mg, 0.40 mmol) overnight at room temperature. The crude was dried under vacuo and purified on silica gel with Ethyl Acetate/Hexane 3/2 to give the wanted compound in quantitative yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:6][N:5]=[C:4]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:3]=12.[CH3:30]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([N:13]([CH3:14])[CH3:15])=[O:12])[C:2]=2[CH3:30])[NH:19][CH:20]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)C)c3)c(Cl)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)C)c3)c(C)c12
Yield: 6.7 %

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-[4-Chloro-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (37 mg, 0.09 mmol), trimethylboroxine (15 μL, 0.11 mmol), tetrakis(triphenylphosphine)palladium (7 mg, 0.009 mmol), potassium carbonate (52 mg, 0.27 mmol), and dioxane (1 mL). The vial was purged with nitrogen, sealed, and irradiated in a Personal Chemistry Optimizer at 140° C. for 60 min. The reaction mixture was diluted with ethylacetate, filtered over Celite and concentrated. The crude product was purified by mass triggered reverse phase HPLC to afford the title compound (2.4 mg, 0.006 mmol, 7% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.74 (d, J=2 Hz, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.50 (t, J=8 Hz, 1H), 7.41 (dt, J1=9.5 Hz, J2=1.5 Hz, 1H), 7.37 (dt, J=7.5 Hz, J2=1.5 Hz, 1H), 7.33 (m, 4H), 7.26 (dd, J1=7 Hz, J2=2 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 6.97 (td, J=7.5 Hz, J2=1 Hz, 1H), 3.70 (s, 3H), 2.97 (bs, 3H), 2.93 (bs, 3H), 2.04 (s, 3H). MS: m/z 386.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:8]=2[NH:7][CH:6]=1)[CH3:3].[O:14]1[C:19]2=[CH:20][CH:21]=[C:22](N3CC=CCC3)[C:18]2=[CH:17][CH:16]=[CH:15]1.[C:29]1(C)[CH:34]=CC=C[CH:30]=1>>[O:14]1[C:15]2[CH:16]=[CH:17][C:18]([CH:3]3[CH2:34][CH:29]=[CH:30][CH2:1][N:2]3[CH2:4][C:5]3[C:9]4[C:8](=[N:13][CH:12]=[CH:11][CH:10]=4)[NH:7][CH:6]=3)=[CH:22][C:21]=2[CH:20]=[CH:19]1
Reactant: C1=CCN(c2ccc3occcc2-3)CC1
Reactant: Cc1ccccc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Product: C1=CCN(Cc2c[nH]c3ncccc23)C(c2ccc3occc3c2)C1
Temperature: 110 °C

Procedure:
A suspension of 7-azagramine (180 mg, 1.0 mmol) and 4-benzofuran-5-yl-1,2,3,6-tetrahydropyridine (200 mg, 1.0 mmol) in toluene (5 ml) was heated at 110° C. for 16 h. The resulting hot solution was filtered and allowed to cool. The title compound (180 mg) crystallised and was collected by filtration as a white, crystalline solid, m.p. 168°-70° C.; (Found: C, 75.02; H, 5.81; N, 12.28. C21 H19N3O.0.33.H2O requires C, 75.20; H, 5.91; N, 12.53); δH (DMSO-d6) 2.50 (2H, br s, tetrahydropyridinyl CH2, obscured by solvent), 2.69 (2H, br s, CH2), 3.11 (2H, br s, tetrahydropyridinyl CH2), 3.76 (2H, s, ArCH2N), 6.12 (1H, br s, CH=CR), 6.91 (1H, s, ArH), 7.03 (1H, m, ArH), 7.40 (2H, m, ArH), 7.51 (1H, m, ArH), 7.64 (1H, s, ArH), 7.95 (1H, m, ArH), 8.04 (1H, m, ArH), 8.20 (1H, m, ArH), and 11.47 (1H, br s, NH); m/z (CI+, NH3) 330 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](O)=[CH:5][C:4](=[O:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-:12].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][C:2]1[O:7][C:6]([CH2:11][OH:12])=[CH:5][C:4](=[O:9])[C:3]=1[O:10][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Reactant: Cc1oc(O)cc(=O)c1O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(C)oc(CO)cc2=O)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 54.5 %

Procedure:
To a suspension of 5 g of 6-methyl-5-hydroxy-2-hydroxy-4-pyrone in 60 ml of dimethylformamide were successively added 6.8 g of potassium carbonate and 6.2 g of p-methoxybenzyl chloride. The mixture was stirred at 60° C. for 6 hours. After the reaction mixture was concentrated, 200 ml of water and 400 ml of dichloromethane were added to the concentrate. The organic phase was washed with 200 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure. The concentrate was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (manufactured by Wako Pure Chemical Industry Co., Ltd.) (100 g) to give 5.3 g of the title compound.
Reaction SMILES: C(OC([N:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9][CH2:10][NH:11][CH2:12][C:13](OCC)=[O:14])=O)(C)(C)C.Cl.C(N(CC)CC)C>O1CCOCC1>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:13]2=[O:14])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Ethyl [(2-{(tert-butoxycarbonyl) [2-(4-nitrophenyl)ethyl]amino}ethyl)amino]acetate (0.50 g, 1.3 mmol) in dioxane (4 mL) was added 4N HCl in dioxane (3.2 mL, 13 mmol). The solution was stirred at 25° C. for 2 hours. LC showed complete removal of the Boc group. The volatiles were removed under vacuum, and the residue was redissolved in toluene and ethanol. To that solution was added triethylamine (0.73 mL, 5.2 mmol). The mixture was heated to reflux for 48 hours. LC at that point showed mostly product. The product was purified by silica gel chromatography (DCM: MeOH) to afford 1-[2-(4-nitrophenyl)ethyl]piperazin-2-one. LC-MS (IE, m/z): 250 [M+1]+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccccn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
LiHMDS (1.0M in THF, 62 mL, 6.2 mmol) was added dropwise to a stirred solution of pyridin-2-ylamine (3.1 g, 33 mmol) in anhydrous THF (50 mL) under a nitrogen atmosphere at −78° C. After 30 min stirring at −78° C., 2,4-difluoro-1-nitrobenzene (3.4 mL, 31 mmol) was added and stirring at −78° C. continued for 30 min. The reaction mixture was slowly warmed to RT and after 5 h quenched by addition of a saturated aqueous solution of NH4Cl (150 mL). The mixture was partitioned between EtOAc and water, then filtered through Celite®. The organic fraction was dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% DCM in cyclohexane) to afford the title compound as an orange solid (3.9 g, 54%). 1H NMR (CDCl3, 400 MHz): δ 10.48 (1H, s), 8.82 (1H, dd, J=12.32, 2.77 Hz), 8.38 (1H, dd, J=5.03, 1.87 Hz), 8.34-8.25 (1H, m), 7.70-7.64 (1H, m), 7.03-6.94 (2H, m), 6.68-6.61 (1H, m).