Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[C:17]([C:32]#[N:33])[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C-:34]#[N:35].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:34]#[N:35])=[C:17]([C:32]#[N:33])[C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: [C-]#N
Reactant: CCn1c2ccccc2c2cc(C=C(C#N)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C(C#N)=C(C#N)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc21
Reaction time: 0.17 h
Yield: 23.7 %

Procedure:
1.0 g (2.18 mmol) of N-ethyl-3-(2-cyano-2-(3,5-bis(trifluoromethyl)phenyl)ethenyl) carbazole and 10 ml of N,N-dimethylformamide as solvent were placed in a 200 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.11 g (2.25 mmol) of sodium cyanide and 1.0 ml of water, which was stirred for 10 minutes. Further, 1.0 g (2.25 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 100 ml of chloroform was added. To the resultant solution was added 50 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain 0.25 g of a brown solid. The yield of the synthesized compound was 24%, and its melting point was 180-182° C. The IR chart is shown in FIG. 19.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]([CH2:17][CH:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)[C:7]=2[CH:24]=1)[CH3:2].[CH2:25]=O.Cl>C(O)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]([CH2:17][CH:18]3[O:23][CH2:22][CH2:21][N:20]([CH3:25])[CH2:19]3)[C:7]=2[CH:24]=1)[CH3:2]
Reactant: C=O
Reactant: CCc1ccc2c(c1)N(CC1CNCCO1)c1ccccc1CC2
Agent: Cl
Solvent: O=CO
Product: CCc1ccc2c(c1)N(CC1CN(C)CCO1)c1ccccc1CC2
Reaction time: 8 h

Procedure:
A mixture of 3-ethyl-5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.3 g), 90% formic acid (0.7 g) and 37% formalin (0.58 ml) was stirred at 90°-100° C for 8 hours. After cooling, 4N hydrochloric acid was added to the reaction mixture. The resulting mixture was evaporated to dryness under reduced pressure. Water was added to the residue, neutralized with aqueous ammonia, and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 3-ethyl-5-(4-methyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 168°-170° C (oxalate).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:24])[O:4][N:3]=1.I[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:11](=[O:16])[C:10]3([CH3:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2c1cccnc1
Temperature: 140 °C

Procedure:
5-(3,5-Dimethyl-isoxazol-4-yl)-3-methyl-3-phenyl-1,3-dihydro-indol-2-one (100 mg, 0.314 mmol), 3-iodopyridine (71 mg, 0.346 mmol), copper (I) iodide (60 mg, 0.314 mmol), N,N′-dimethylethylenediamine (41.5 mg, 0.471 mmol), potassium carbonate (217 mg, 1.571 mmol) are added to a microwave vessel. Dioxane (5 mL) is added and the mixture heated to 140° C. for 30 minutes in a microwave reactor. A further 3-iodopyridine (35 mg, 0.173 mmol) and copper (I) iodide (12 mg, 0.063 mmol) are added. The mixture is again heated to 140° C. for 30 minutes in a microwave reactor. The reaction mixture is filtered. The filtrate is washed with dichloromethane. The volatiles are evaporated and the residue purified using reversed phase HPLC. This afforded the desired product.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[NH:16][C@@H:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC(OC2C=CC(NC(=S)N[C@@H](CC3C=CC=CC=3)C(NCCN3CCCC3)=O)=CC=2)=CC=1.Cl.O1CCOCC1.O(C1C=CC(N=C=O)=CC=1)C1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH2:28]([C@H:17]([NH:16][C:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[O:35])[CH2:18][NH:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCN1CCCC1
Agent: Cl
Agent: O=C(NCCN1CCCC1)[C@H](Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)N[C@H](CNCCN1CCCC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
(S)-2-[3-(4-Phenoxy-phenyl)-ureido]-3-phenyl-N-(2-pyrrolidin-1-yl-ethyl)-propionamide. To a solution of [(S)-2-phenyl-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (Example 9, step A) (0.1 g, 0.28 mmol) in CH2Cl2 (3 mL), a 4 M solution of HCl in dioxane (2.5 mL, 10 mmol) was added, and the mixture was stirred for 4 h at rt. The solvents were removed, and the residue was treated with CH2Cl2. The solvents were removed again under reduced pressure. The residue was dissolved in CH2Cl2 (3 mL), and TEA (0.07 g, 0.69 mmol) was added at 0° C. followed by 4-phenoxyphenylisocyanate (0.07 g, 0.33 mmol). The mixture was warmed to rt over a period of 4 h and then diluted with EtOAc (75 mL). The organic layer was washed with saturated NaHCO3 (25 mL) and brine (25 mL), and dried (Na2SO4). The solvent was removed, and the residue was purified by flash column chromatography using 0–20% MeOH (1% NH4OH)/CH2Cl2 to afford 0.03 g (25%) of the desired product. MS (electrospray): mass calculated for C28H32N4O3, 472.25; m/z found, 473.2 [M+H]+, 495.2 [M+Na]+. 1H NMR (400 MHz, DMSO-d6): 8.68 (s, 1H), 8.04 (t, J=5.5 Hz, 1H), 7.36–6.89 (m, 14H), 6.30 (d, J=8.3 Hz, 1H), 4.46 (m, 1H), 3.15 (m, 2H), 2.96 (dd, J=13.6, 5.6 Hz, 1H), 2.82 (dd, J=13.6, 7.7 Hz, 1H), 2.42–2.37 (m, 6H), 1.67–1.63 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH3:23])=[O:21]>ClCCl>[CH3:23][O:22][C:20](=[O:21])[NH:12][C:10]1[O:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc2oc(N)nc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2c(OC)cccc2o1
Reaction time: 3.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of 65 g (40 mmol) 4-methoxy-benzooxazol-2-yl-amine and 4.5 ml (56 mmol) pyridine in 250 ml dichoromethane at 0° C. was added dropwise a solution of 4.1 ml (49 mmol) methyl chloroformate in 50 ml dichoromethane and stirring continued for 3.5 hours. The mixture was then poured onto water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (dichloromethane) afforded 4.7 g (54%) (4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester as an off-white crystalline solid. EI-MS m/e (%): 222 (M+, 100), 190 (27), 163 (23).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([CH2:23][NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:17]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>C1COCC1.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([CH2:23][NH:24][CH2:25][CH2:26][CH3:27])[CH2:17]3)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NCC1Cc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNCC1Cc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2C1
Yield: 8.3 %

Procedure:
N-[5-(4-Isopropyl-benzenesulfonylamino)-indan-2-ylmethyl]propionamide (0.50 g, 1.25 mmol) was dissolved in 10 mL of THF and 4.2 mL (43.9 mmol) of a borane-THF complex was introduced dropwise. The resulting mixture was stirred at reflux for 1 h. The solution was cooled, 5 mL of 2 N HCl was added slowly, and the mixture was stirred at reflux for 2 h. The cooled solution was quenched with water, then NaOH (2N) and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and the filtrate was evaporated in vacuo to give product as a white solid which was further purified by column chromatography using (dichloromethane-MeOH, 7-12%) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (40 mg, 7%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH:21][CH3:22])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][N:21]([CH3:22])[CH2:24][CH2:25][O:26][C:27]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:28]=2[C:29]#[N:30])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCCBr
Reactant: CNCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CN(CCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1)CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.68 %

Procedure:
To a solution of N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N2-methylethane-1,2-diamine {Preparation Sd Step (1), 0.5 g, 1.56 mmol} in DMF (5 mL) was added TEA (0.234 g, 2.34 mmol) followed by 2-(2-bromoethoxy)-4-nitrobenzonitrile (0.423 g, 1.56 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound in silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 10% methanol in chloroform) to get 2-(2-((2-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)ethyl)(methyl)amino)ethoxy)-4-nitrobenzonitrile (0.3 g, 37.68%) as a dark brown solid. LC-MS (M+H)+=511.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.91-7.89 (1H, m), 7.85 (1H, s), 7.72-7.70 (1H, m), 7.14-7.10 (2H, m), 6.98-6.96 (2H, m), 4.42-4.39 (2H, m), 4.17-4.15 (1H, m), 3.66-3.56 (2H, m), 3.49 (3H, s), 3.35-3.26 (2H, m), 3.18-3.12 (4H, m), 2.78-2.63 (1H, m), 1.99-1.98 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:11](=[O:31])[N:10]2[CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(CC(=O)OC)[C@@H]1c1ccc(C#N)cc1

Procedure:
500 mg (1.164 mmol) of the compound from Example 5A were stirred together with 220 mg (1.397 mmol) of methyl bromoacetate and 322 mg (2.329 mmol) of potassium carbonate in 20 ml of DMF at 60° C. overnight. The solid was then filtered off, the filtrate was concentrated on a rotary evaporator, the residue was dissolved in dichloromethane and this solution was washed three times with water. The organic phase was separated off, dried over sodium sulphate, filtered and concentrated. The crude product was purified by chromatography on silica gel (mobile phase toluene/ethyl acetate 3:1). This gave 419 mg (72% of theory) of the desired product.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12]([CH:15]([C:17]3C4C(C5C=CC=C[C:29]=5[CH:30]=3)=CC=CC=4)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[C:32](F)(F)[C:33](O)=O>C(Cl)Cl>[CH2:30]1[C:29]2[C:13]([C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:7]=2[CH:8]=[C:10]2[C:11]=3[C:33]3[CH:32]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]3[CH:2]=[CH:1][CH:14]=[CH:13][C:9]=32)=[CH:12][CH:15]=[CH:17]1
Reactant: O=C(O)C(F)(F)F
Reactant: OC(c1cc2ccccc2c2ccccc12)c1cc2ccccc2c2ccccc12
Solvent: ClCCl
Product: C1=CCc2c3c(c4ccccc4c2=C1)=c1c(c2ccccc2c2ccccc12)=C3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Di-phenanthen-9-yl-methanol (24.5 g, 63 mmol) was suspended in CH2Cl2 (100 ml). Trifluoroacetic acid (40 mL) was added dropwise under an atmosphere of nitrogen over a period of 10 minutes, forming a yellow suspension. This was stirred at room temperature under nitrogen for 20 minutes after which time excess solvent was removed in vacuo. The resulting yellow solid was suspended in CH2Cl2 (100 mL) and reconcentrated (5 times). The residue was then washed with diethyl ether to give 1H-tetrabenzo[a,c,g,i]fluorene as a bright yellow solid (16.4 g, 45 mmol, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH3:2].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:6]([N:7]=[C:13]=[O:15])[C:5]=1[CH3:11])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1cccc(N)c1C
Solvent: Cc1ccccc1
Product: CCOc1cccc(N=C=O)c1C
Yield: 249.2 %

Procedure:
At room temperature, to a mixture of 3-ethoxy-2-methylaniline 33.0 g and toluene 400 mL was added triphosgene 25 g, and the resulting mixtures were stirred with heating reflux for four hours. The mixtures were concentrated under reduced pressure to give 1-ethoxy-3-isocyanato-2-methylbenzene 37.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6].[C:32](O)(=O)[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH2:32][C:33]4[CH:41]=[CH:40][C:39]5[O:38][CH2:37][O:36][C:35]=5[CH:34]=4)[CH2:26][CH2:27]3)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2ccc(CN3CCNCC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(CN3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-dichloro-N-[6-(4-piperazin-1-ylmethylphenoxy)pyridin-3-yl]benzamide (300 mg, 0.66 mmol) in DMF (10 mL) were added piperonylic acid (120 mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 0.73 mmol) and 1-hydroxybenzotriazole monohydrate (100 mg, 0.74 mmol) under ice cooling. The resulting reaction solution was stirred overnight at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 110 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[N:19][C:20]([NH:23][NH2:24])=[CH:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.FC1C=CC(C2N=C3N(C=2)C=CO3)=CC=1.[CH2:40]1C(=O)N(I)[C:42](=[O:43])[CH2:41]1.FC1C=CC(B(O)O)=CN=1.NN.[Si](OCCC=O)(C(C)(C)C)(C)C.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20]4[N:19]([C:40]([CH2:41][CH2:42][OH:43])=[N:24][N:23]=4)[CH:18]=2)[CH:14]=[CH:13][O:12]3)=[CH:2][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Agent: CC(C)(C)[Si](C)(C)OCCC=O
Agent: Fc1ccc(-c2cn3ccoc3n2)cc1
Agent: NN
Solvent: CO
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: OCCc1nnc2ccc(-c3c(-c4ccc(F)cc4)nc4occn34)cn12
Temperature: 65 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
The 6-(2,4-difluorophenyl)-5-(6-hydrazinylpyridin-3-yl)imidazo[2,1-b]oxazole (0.20 g, 0.65 mmol; prepared using A from 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole [prepared according to WO2004110990A2, Example 1, Steps 1-3] with NIS, C with 2-fluoropyridine-5-boronic acid [Asymchem], D with hydrazine) and 3-(tert-butyldimethylsilyloxy)propanal (0.12 g, 0.65 mmol; Toronto) were dissolved in MeOH (5.0 mL) and heated to about 65° C. for about 1 h. The MeOH was evaporated then DCM (5 mL) was added followed by iodobenzene diacetate (0.21 g, 0.65 mmol). The reaction was stirred for about 16 h and then evaporated. The resulting solid was dissolved in 1M TBAF in THF (5 mL). The reaction was allowed to stir for about 30 min. The THF was evaporated and the crude material was purified by reverse phase HPLC (Table 1, Method f). The fractions containing product were concentrated under reduced pressure and the resulting precipitate was filtered and dried under vacuum for about 16 h at about 60° C. to provide the title compound (0.033 g, 14%) as a white solid: LC/MS (Table 1, Method a) Rt=1.76 min; MS m/z: 364.1 (M+H)+.
Reaction SMILES: [ClH:1].C([O:4][C:5]([CH:7](C(OCC)=O)[CH2:8][CH2:9][CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][N:11]1[CH3:23])=[O:6])C.C>>[ClH:1].[C:5]([CH2:7][CH2:8][CH2:9][CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][N:11]1[CH3:23])([OH:6])=[O:4]
Reactant: CCOC(=O)C(CCC1c2[nH]c3ccccc3c2CCN1C)C(=O)OCC
Agent: Cl
Product: CN1CCc2c([nH]c3ccccc23)C1CCCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 79.8 %

Procedure:
25 ml of 5% hydrochloric acid were added to 1.08 g of 1,2,3,4-tetrahydro-1-[3,3-bis(ethoxycarbonyl)-propyl]-2-methyl-β-carboline, and the mixture was stirred at 80° C. for 5 hours. After the reaction was completed, the mixture was treated with activated charcoal powder and then condensed under reduced pressure. 930 mg of 1,2,3,4-tetrahydro-1-(3-carboxypropyl)-2-methyl-β-carboline hydrochloride were thereby obtained. Yield: 79.8%
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[OH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(C(O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98.7 %

Procedure:
A solution of 5-cyanoindole (2.84 g, 20 mmol) and benzaldehyde (4.24 g, 40 mmol) in MeOH (100 mL) was treated with powdered NaOH (0.8 g, 20 mmol) and stirred at rt for 4 days. The solvent was partially removed in vacuo and the residue diluted with CH2Cl2, washed with water (3×), and dried over Na2SO4, filtered and evaporated to a solid which was triturated with hexanes to provide 3-(hydroxyphenylmethyl)indole-5-carbonitrile as a light yellow solid (4.9 g, 98%).
Reaction SMILES: [CH2:1]([OH:19])[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].C(N(CC)CC)C.[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=1)[C:33](Cl)=[O:34])([O-:29])=[O:28].O>O1CCCC1.C(OCC)(=O)C>[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=1)[C:33]([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])=[O:34])([O-:29])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
In a 500-ml three-necked flask equipped with a stirrer was placed 200 ml of tetrahydrofuran (THF), and 13.5 g (0.050 mol) of stearyl alcohol and 8.4 ml of triethylamine were added thereto, followed by stirring at 0° C. Afterward, a solution obtained by dissolving 11.5 g (0.050 mol) of 3,5-dinitrobenzoyl chloride in 50 ml of THF was added dropwise to the flask over 30 minutes, and under this state, reaction was carried out for 6 hours. After the completion of the reaction, this solution was poured into 1 liter of water, and extraction was then made with 1.5 liters of ethyl acetate. In succession, the resultant organic layer was washed with 3N hydrochloric acid three times, a saturated sodium bicarbonate solution three times and water. The resultant ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. Next, the resultant crystal was recrystallized from ethyl acetate twice to obtain 18.1 g (0.039 mol) of stearyl 3,5-dinitrobenzoate. Its melting point was in the range of 75.9° to 76.7° C. The structure of this compound was confirmed by an infrared absorption spectrum (IR) and NMR.