Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:3](=[O:24])[CH:2]([NH:1][C:33]([O:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:34])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCCC2)c2ccccc21
Reaction time: 2 h

Procedure:
The amine was dissolved in anhydrous tetrahydrofuran (9 ml) under an atmosphere of nitrogen, at room temperature, and triethylamine (249 μl) was added dropwise. A solution of 4-nitrophenyl chloroformate (363 mg) in anhydrous tetrahydrofuran (9 ml) was then added, and the reaction mixture stirred for a further 2 h. After this time the undissolved solid was filtered off, washed with tetrahydrofuran, and the filtrate evaporated in vacuo. The residue was azeotroped with toluene (2×20 ml) and ether (20 ml). The resultant solid was then triturated in anhydrous ether to afford the title compound (420 mg) as a white solid. TLC (silica, petrol (60/80):ethyl acetate 2:1) Rf=0.7. 1H NMR (360 MHz, CDCl3) δ 0.77 (3H, d, J=6.6 Hz), 0.83 (3H, d, J=6.6 Hz), 1.40-1.87 (12H, m), 2.06-2.17 (1H, m), 2.98-3.02 (1H, m), 3.48 (1H, dd, J=13.8 and 5.0 Hz), 4.32 (1H, dd, J=13.8 and 9.3 Hz), 5.10 (1H, d, J=8.4 Hz), 6.92 (1H, d, J=8.2 Hz), 7.26-7.39 (4H, m), 7.53 (1H, dd, J=8.5 and 8.5 Hz), 7.61 (1H, m), 8.21 (2H, d, J=9 Hz).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[O:13])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][NH:27][N:26]=1>>[CH3:24][C:25]1[C:29]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12]([C:14]4[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=4)=[O:13])=[N:10][C:5]3=[CH:4][CH:3]=2)=[CH:28][NH:27][N:26]=1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: COC(=O)c1ccc(C(=O)Nc2nc3ccc(-c4c[nH]nc4C)nc3s2)cc1
Yield: 17 %

Procedure:
The titled compound (yield=17%, yellow solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1C (Example 3) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.58 (s, 3H) 3.91 (s, 3H) 6.56 (br. s., 1H) 7.76 (d, J=8.59 Hz, 1H) 8.12 (d, J=8.59 Hz, 4H) 8.25 (d, J=8.59 Hz, 2H) 13.15 (br. s., 1H); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31]N(C)C=O.IC>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]=[C:22]4[N:26]([CH3:31])[C:25]([CH3:28])([CH3:27])[CH2:24][S:23]4)=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N2CCN(c3ccc(NC4=NC(C)(C)CS4)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1ccc(N2CCN(c3ccc(N=C4SCC(C)(C)N4C)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 37 parts of 4,5-dihydro-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4,4-dimethyl-2-thiazolamine, 5 parts of a sodium hydride dispersion 50% and 376 parts of N,N-dimethylformamide was stirred for 2 hours at 70° C. After cooling to room temperature, 14.1 parts of iodomethane were added slowly to the reaction mixture. The whole was stirred for 1 hour at room temperature. The reaction mixture was diluted with water. The precipitated product was filtered off, washed with water and 2-propanol and purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (96:4 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 4-[4-(4-methoxyphenyl)-1-piperazinyl]-N-(3,4,4 -trimethyl-2-thiazolidinylidene)-benzenamine (int. 9). The second fraction was collected and boiled in 2-propanol. After cooling, the product was filtered off and dried, yielding 19.5 parts (51.0%) of 4,5-dihydro-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-N,4,4-trimethyl-2-thiazolamine; mp. 166.6° C. (int. 10)
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1)=[CH2:14].[Cl-].[Na+]>O.C(O)C>[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[CH:17][CH:16]=1)=[CH2:14]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C=Cc1ccc(CC(C(=O)OCC)C(=O)OCC)cc1
Yield: 70.1 %

Procedure:
Into a flask containing 100 ml of dry ethanol were fed 2.43 g (0.106 mole) of metallic sodium, 50.77 g (0.317 mole) of diethyl malonate and 16.12 g (0.106 mole) of p-vinylbenzyl chloride in dry nitrogen gas atmosphere. The mixture was subjected to reaction at the reflux temperature for 3 hours. 100 ml of pure water was added to the reaction mixture to dissolve the sodium chloride (NaCl) generated by the reaction. Extraction was carried out with three 100 ml-portions of methylene chloride to obtain a methylene chloride solution of the product, i.e., diethyl 2-(p-vinylbenzyl)malonate.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].O=[CH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>CCO>[O:15]=[C:9]1[NH:8]/[C:7](=[N:16]\[N:17]=[CH:19]\[CH2:20][CH2:21][C:22]([OH:24])=[O:23])/[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: O=CCCC(=O)O
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Solvent: CCO
Product: CCCCCn1/c(=N/N=C/CCC(=O)O)[nH]c(=O)c2[nH]cnc21
Yield: 96.6 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (1.0 g, 4.2 mmol) and 4-oxobutanoic acid (3.4 g, 15% in water, 5.1 mmol) in EtOH (70 ml) was refluxed for 1.5 hours. Evaporation of solvent gave the desired product (1.3 g, 96%) as a yellowish solid. LCMS calculated for C14H21N6O3 (M+H): 321.1. found: 321.1.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]([O:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH:7]([CH2:8][CH2:9][CH3:10])[CH3:6])[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(C)OC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(C)OC1CCC(=O)N1C(=O)c1ccccc1
Yield: 65.3 %

Procedure:
12.4 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3.2 g of 5-(2-pentyloxy) pyrrolidin-2-one in 130 cm3 of tetrahydrofuran. The mixture is maintained at this temperature for 20 minutes, then a solution of 2.62 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. The solution is returned to ambient temperature, concentrated and chromatographed on silica (eluent: hexane-ethyl acetate 7-3). 3.35 g of expected product is obtained.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2ccc(N)cc2)c1
Yield: 53.9 %

Procedure:
The title compound (200 mg) was prepared from 4-bromoaniline (300 mg, 1.74 mmol) and 3-ethoxyphenylboronic acid (380 mg, 2.29 mmol) as a colourless liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.33 (d, J 8.5, 2H), 7.26-7.22 (m, 1H), 7.06 (d, J 7.9, 1H), 7.01 (s, 1H), 6.75 (dd, J 5.8, 8.1, 1H), 6.60 (d, J 8.5, 2H), 5.20 (s, 2H), 4.04 (q, J 7, 2H), 1.16 (t, J 7, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:10]2[C:15]([C:16]=1[NH2:17])=[C:14]([CH3:18])[C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[N:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:10]2[C:15]([C:16]=1[N:17]=[C:29]=[O:31])=[C:14]([CH3:18])[C:13]([C:19]([F:21])([F:20])[F:22])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(C(F)(F)F)ccc2c1c(N)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1c(C(F)(F)F)ccc2c1c(N=C=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1

Procedure:
To a solution of 3-amino-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1E (1.74 g, 4.39 mmol) in anhydrous toluene (50 mL) was added triphosgene (0.44 g, 1.48 mmol) and triethylamine (0.89 g, 8.81 mmol). The reaction mixture was heated at reflux for 3 hours. Toluene (50 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 3-isocyanato-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1F which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[S:22](=[O:36])(=[O:35])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[N:29]=[CH:28]2)[C:15]([O:17][CH3:18])=[O:16])[CH3:11]>>[Cl:1][C:2]1[C:3]([N:23]([CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[N:29]=[CH:28]3)[S:22]([C:21]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[CH2:10][CH3:11])(=[O:36])=[O:35])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: CCc1cc(C(=O)OC)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1
Product: CCc1cc(C(=O)OC)ccc1S(=O)(=O)N(Cc1ccc2c(cnn2C)c1)c1ncc(Cl)cc1Cl

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 3-ethyl-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]([CH2:8][O:9][CH3:10])=[CH:6][CH:7]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]([CH2:8][O:9][CH3:10])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: COCc1ccc(Cl)cc1C(=O)OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)OC
Reaction time: 1 h

Procedure:
A sample of methyl 4-chloro-α-methoxy-o-toluate (10 g.) is added in small portions at 15°-20° to a solution of potassium nitrate (4.9 g.) in concentrated sulfuric acid. When the addition is complete, the mixture is stirred for 1 hour at 10°-15°, the poured onto ice and the precipitated solid (12.8 g.) collected by filtration. A sample of the damp product is recrystallized from 90% ethanol. After recrystallization, the solid mp is 77°-81°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[Li+].[OH-]>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-amino-4,5-dichlorobenzoate (2.1 g, 9.41 mmol) was dissolved in THF (15 mL) and water (30 mL) was added. LiOH (0.79 g, 18.8 mmol) was added the mixture was stirred overnight at rt. The product was precipitated by addition of 10% aq. HCl (30 mL) and isolated by suction filtration. The white solid was dried under vacuum (1.6 g, 81%). 1H NMR (400 MHz, DMSO-d6): 7.78 (s, 1H), 7.01 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-])=O)[CH:10]=3)=[N:8][C:4]=2[CH:3]=1>[Zn].C(O)(=O)C>[Cl:22][C:21]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH2:17])[CH:10]=3)=[N:6][C:5]=2[CH:20]=1
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1N

Procedure:
The product from Step A (3.09 g, 9.14 mmol) was added to glacial acetic acid (250 mL). Zinc (21.68 g, 331.7 mmol) was gradually added with stirring. After stirring 1.5 hours, zinc was filtered from the mixture and the solution was concentrated to a dark oil. Methylene chloride (100 mL) was added to the oil and the desired product crystallized out overnight (0.3154 g), mp>300° C.
Reaction SMILES: C(O)=O.[CH2:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([NH:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:11]([CH3:29])=[C:12]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[C:20]3Cl)=[O:16])[CH:13]=1)[CH3:5]>Cl.[Pd].CO>[CH2:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([NH:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:11]([CH3:29])=[C:12]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[CH:20]3)=[O:16])[CH:13]=1)[CH3:5]
Reactant: CCOCc1cc(NCCN2CCCC2)c(C)c(NC(=O)c2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Agent: [Pd]
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: CCOCc1cc(NCCN2CCCC2)c(C)c(NC(=O)c2ccc3c(=O)[nH]ncc3c2)c1
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-amide formic acid salt (55 mg, 0.104 mmol), 10% wet Pd/C (catalytic), 1 drop of conc. HCl and MeOH (4 mL) was evacuated and flushed (×3) with hydrogen. The reaction was stirred under a hydrogen balloon for 2.5 h. The reaction was filtered through celite, rinsed with MeOH and concentrated to yield 1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-amide (43 mg) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ: 1.16 (t, 3H), 1.93 (m, 4H), 2.00 (s, 3H), 2.53 (m, 4H), 3.47 (m, 6H), 4.39 (s, 2H), 5.23 (bs, 1H), 6.53 (s, 1H), 6.62 (s, 1H), 8.34 (s, 2H), 8.48 (s, 1H), 8.50 (s, 1H), 10.25 (s, 1H), 12.80 (s, 1H) ppm; m/z (M+1) 450.38.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:13]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCBr
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 0.17 h
Yield: 79 %

Procedure:
In a 10 liter-reaction vessel, 143 g (6.2 mol(M)) of metal sodium which had been cut small was added to 3.1 liters of anhydrous ethanol and dissolved therein. To the solution, 1025 g (6.4M) of diethyl malonate was added dropwise in 30 minutes at 40°-50° C. and 1200 g (6.2M) of n-octylbromide was further added thereto in 10 minutes at 40°-50° C., followed by heat-refluxing for 3 hours. After the reaction, about 2.5 liters of ethanol was distilled off from the reaction mixture. 2.5 liters of water was added to the residue and 2 liters of benzene was further added thereto to effect extraction. After the benzene layer was washed with saturated aqueous solution of common salt until the benzene layer showed neutrality, the resultant mixture was dried with anhydrous sodium sulfate, followed by distilling-off of benzene to obtain 1333 g of a crude product of diethyl 2-octylmalonate (Yield: 79%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15].[Li]CCCC>>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: C=C(C)c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Product: CC(CN1CCN(c2ccccc2)CC1)c1ccccc1

Procedure:
According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and 2.22 mmol (=0.26 g=0.29 ml) of α-methylstyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (3:1) gives the product 1-phenyl-4-(2-phenylpropyl)piperazine as a light-yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=1)[N:5]=2.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CS(C)=O>[N:11]1([C:8]2[N:7]=[C:6]([C:17]3[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=3)[N:5]=[C:4]3[C:9]=2[N:10]=[C:2]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:3]3[CH2:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCOCC4)n(CC4CCOC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]-N-methylpyrimidin-2-amine (100 mg, 0.23 mmol), morpholine (61 μl, 0.70 mmol), and dimethyl sulfoxide (1 ml) was stirred at 150° C. for 3 hours. The mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (56 mg, 50%) as a light brown solid.
Reaction SMILES: O[CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@H:25]([CH2:42][C:43]3[CH:52]=[C:51]([CH3:53])[C:46]4[NH:47][C:48](=[O:50])[O:49][C:45]=4[CH:44]=3)[C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[C:39]([OH:41])=[O:40])[CH2:30][CH2:29]3)=[O:27])=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:54]=[CH:55][CH:56]=[CH:57][C:11]=2[NH:10]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:42][C:43]3[CH:52]=[C:51]([CH3:53])[C:46]4[NH:47][C:48](=[O:50])[O:49][C:45]=4[CH:44]=3)[C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[C:39]([O:41][CH2:2][C:3](=[O:4])[N:5]([CH3:7])[CH3:6])=[O:40])[CH2:32][CH2:33]3)=[O:27])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:54]=[CH:55][CH:56]=[CH:57][C:11]=2[NH:10]1
Reactant: CN(C)C(=O)CO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)OCC(=O)N(C)C)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 mg (0.06 mmol) 2-hydroxy-N,N-dimethyl-acetamide were added to a solution of 34 mg (0.05 mmol) (R)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 18 mg (0.06 mmol) TBTU and 8 μL triethylamine in 2 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:50]([C:52]2[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][CH:53]=2)=O)=O)=[CH:44][CH:43]=1>>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:50]([C:52]3[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][CH:53]=3)=[N:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([C:8]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:11]5[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=5[N:9]=4)[CH:20]=3)[N:25]=2)=[CH:44][CH:43]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(Br)cc4)c(-c4ccc(Br)cc4)nc3c1)n2C1CCCCC1

Procedure:
Prepared as described for Compound 406 using 4,4′-dibromobenzil in place of benzil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:19])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:19])=[CH:6][CH:5]=1
Reactant: Cc1cc2ccccc2n1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2ccccc2n1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a stirred suspension of the above nitro compound ( 300 mg, 1.2 mmol) in EtOH (25 mL) and EtOAc (5 mL) was added solid ammonium formate (750 mg, 11.9 mmol) followed by 10% Pd—C (50 mg). The mixture was stirred for 2 h at room temperature, and then filtered through a short pad of diatomaceous earth and washed with EtOH/EtOAc. The filtrate was concentrated to give 1-(4-aminophenyl)-2-methylindol (0.22 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].Cl>N1C=CC=CC=1.O>[OH:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[CH:16][C:17]([OH:19])=[O:18])=[CH:7][C:6]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)O)cc([N+](=O)[O-])c1O

Procedure:
A solution of 1.0 g of 5-nitrovanillin and 4.0 g of malonic acid in 10 ml of pyridine was heated for 50 h at 80° C. The reaction mixture was diluted with water, acidified with hydrochloric acid, filtered, washed with water and dried. Yield 0.44 g (36%). The 1H-NMR spectrum was inaccordance with the structure alleged.