Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.CN(C)C=O>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccc(Cl)cc2)cn1)c1ccccc1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide (0.50 g, 2.01 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.01 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.22 g, 0.34 mmol) in dimethylformamide (10 mmol) was stirred at room temperature for 2 hours. Water (100 mL) was added and a thick oil was being formed. The water was decanted and the residue dissolved in dichloromethane, dried over sodium sulphate, filtered and evaporated in vacuo. Ethyl acetate was added and the solution was heated briefly (some of the compound does not dissolve). The solvent was decanted and heptane was added to it. After standing overnight, the crystals were isolated by suction, washed with heptane and dried in a vacuum oven at 45° C. Further purification by flash column chromatography (SiO2, ethyl acetate:heptane 50:50), yielded the title compound (0.41 g, 53% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13]O)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][N:38]2[C:37](=[O:39])[C:36]3=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]3[C:34]2=[O:44])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
To a solution of 3,5-dinitrobenzylic alcohol 6 (1.38 g, 6.94 mmol), triphenylphosphine (2.19 g, 8.33 mmol) and phthalimide (1.23 g, 8.33 mmol) in dry THF (40 mL) was added DIAD (1.64 mL, 8.33 mmol) under an N2 atmosphere. The resulting mixture was stirred at 25° C. for 48 hours after which solvents were evaporated under reduced pressure. The crude product mixture was triturated in EtOAc and filtered under reduced pressure to give the title compound 7 as a beige solid (1.33 g, 4.05 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 8.98 (t, J=2.0 Hz, 1H), 8.61 (d, J=2.0 Hz, 2H), 7.93-7.89 (m, 2H), 7.81-7.77 (m, 2H), 5.05 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 168.5, 168.4, 149.6, 141.3, 135.5, 132.5, 129.6, 124.7, 119.3, 41.2; HRMS (ESI) Calculated for C15H10N3O6 [M+H]+: 328.0564. Found: 328.0568. m.p.: 171° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]1(OB(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OB(O)Oc1ccccc1
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1
Reaction time: 20 h
Yield: 87 %

Procedure:
The compound is prepared by the reaction of 6-bromo-2-naphthol (500 mg, 2.24 mmol, 1 eq) with phenylboric acid (1 eq) according to method A within 20 h. Purification by column chromatography with hexane/ethyl acetate 7/3 as the eluent yields the desired product in a yield of 87%, 429 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:33]([N:35]([C@@H:47]([CH3:55])[CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[N:45]=[CH:44][CH:43]=[CH:42]2)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([NH:19][C@H:20]([C:33]([N:35]([C@@H:47]([CH3:55])[CH:48]([O:49][CH2:50][CH3:51])[O:52][CH2:53][CH3:54])[CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[CH:44][CH:43]=[CH:42]3)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:16])[CH3:12])=[O:9])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 79 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:56])[O:7][C:6](=[O:8])[N:5](COCC[Si](C)(C)C)[C:4]2[C:17]([CH2:21][O:22][CH:23]3[CH:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[O:47][CH3:48])=[CH:31][CH:30]=4)[CH2:27][CH2:26][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:24]3)=[CH:18][CH:19]=[CH:20][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][C:2]1([CH3:56])[O:7][C:6](=[O:8])[NH:5][C:4]2[C:17]([CH2:21][O:22][CH:23]3[CH:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[O:47][CH3:48])=[CH:31][CH:30]=4)[CH2:27][CH2:26][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:24]3)=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)OC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2NC(=O)OC3(C)C)cc1

Procedure:
Analogously to Example 228a, 0.45 g of tert-butyl 3-[4,4-dimethyl-2-oxo-1-(2-trimethylsilanylethoxymethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-8-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 4.47 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran) are reacted. The title compound is obtained as a yellowish oil. Rf=0.15 (9:1 dichloromethane-methanol); Rt=5.87.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6][C@@H:5]2[C:7]([CH2:13][O:14][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:8][C@@H:9]([C@H:10]3[CH2:12][O:11]3)[C@@H:4]2[O:3]1.[NH3:35]>CO>[NH2:35][CH2:12][C@H:10]([C@H:9]1[C@H:4]2[C@H:5]([O:6][C:2]([CH3:34])([CH3:1])[O:3]2)[C:7]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8]1)[OH:11]
Reactant: N
Reactant: CC1(C)O[C@H]2[C@H]([C@H]3CO3)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Solvent: CO
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CN)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Temperature: 100 °C

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4-((S)-oxiran-2-yl)-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (1-4) (2 g, 4.0 mmol, 1.0 equiv) was dissolved in a solution of ammonia in methanol (100 mL, 7 N). The mixture was heated in the microwave at 100° C. for 30 min. The reaction was concentrated to afford (S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (1-5) as an amber solid that was carried to the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.21-7.45 (m, 15H), 5.81 (2 s, 1H), 5.00 (t, 1H, J=5 Hz), 4.57-4.70 (2 d, 1H, J=5.5 Hz), 3.77 (d, 1H, J=14 Hz), 3.66 (d, 1H, J=14 Hz), 3.31 (m, 1H), 2.57-2.88 (m, 2H), 1.30 (s, 3H), 1.29 (s, 3H). LRMS m/z (M+H) 472.1 found, 472.2 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:10]=1.S(=O)(=O)(O)[OH:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]([NH2:20])=[O:24])=[CH:17][CH:16]=2)[N:10]=1
Reactant: N#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1

Procedure:
A solution of 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (1.0 g, 0.003 mol) in conc. sulphuric acid (10 mL) was heated to 70° C. for 15 h. The reaction mixture was quenched in ice water. The reaction mass was basified till pH˜6-6.5 with dilute NaOH. The obtained solid was filtered off, washed with water and suck dried to afford 0.300 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.36 (br s, 1H), 7.84 (t, 1H), 7.57 (d, 1H), 7.67 (d, 1H), 7.98 (m, 5H), 12.70 (br s, 1H); MS (m/z): 333.11 (M+H)+.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C([Li])(C)(C)C.N1C2C(=CC=CC=2)C=C1.CON(C)[C:30]([CH:32]([NH:41][C:42]([CH:44]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31].P(=O)(O)(O)O>CCOCC>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:30]([CH:32]([NH:41][C:42]([CH:44]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CON(C)C(=O)C(CCc1ccccc1)NC(=O)C(CC(C)C)NC(=O)OCc1ccccc1
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(CCc1ccccc1)C(=O)c1cc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
A mixture comprised of potassium hydride (0.29 g, 2.56 mmol, 67% in mineral oil) in anhydrous ether (5 mL) was cooled to 0° C. and then a solution comprised of 5-bromo-1H-indole (0.5 g, 2.56 mmol) in anhydrous ether (5 ml) was added. The mixture was stirred for 15 minutes and then cooled to −78° C. under nitrogen. A solution comprised of tert-butyllithium (3 mL in pentane, 5.08 mmol) in anhydrous ether (5 mL) was cooled to −78° C. and added to the indole mixture over 2 minutes. The mixture was stirred for 10 minutes and then a solution comprised of benzyl 1-[1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (0.3 g, 0.64 mM) in ether (10 mL) was added. The mixture was allowed to warm to room temperature and then poured into a cold solution at 0° C. of phosphoric acid (25 mL, 1 M in water). The aqueous layer was separated and extracted with ethyl acetate (25 mL). The organic layers were combined and washed with saturated sodium bicarbonate (25 mL), dried (MgSO4) and concentrated. The product was purified from the residue by flash chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes to provide benzyl 1-[1-(1H-indol-2-ylcarbonyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (112 mg, 0.21 mmol) as a white solid. MS (ESI) m/z=526(M+1); 1H NMR (CDCl3): δ 0.8-1.05 (d, J=4 Hz, 6H), 1.5 (s, 1H), δ 1.5-1.78 (m, 3H), δ 2.00 (m, 1H), δ 2.4 (m, 1H), δ 2.65 (m, 2H), δ 4.35 (m, 1H), δ 5.17 (s, 2H), δ 5.25 (d,J=6 Hz 1H), δ 5.75 (m, 1H), δ 6.55 (s, 1H) 7.05 (d, J=4 Hz, 1H), δ 7.1-7.45 (m, 10H) 7.7(d, J=4 Hz, 1H), δ 8.15 (d, J=4 Hz, 1H) 8.78 (m, 1H). (C32H35N3O4).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[CH:48]=[C:49]([CH:55]=[CH:56][CH:57]=1)[C:50]([O:52]CC)=[O:51].O.[OH-].[Li+].[OH-].[Li+].Cl>CN(C=O)C.C(N(CC)CC)C>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([NH:46][C:47]1[CH:48]=[C:49]([CH:55]=[CH:56][CH:57]=1)[C:50]([OH:52])=[O:51])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: N[C@@H](CCC(=O)Nc1cccc(C(=O)O)c1)C(=O)O
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) and HATU (150.4 mg, 0.40 mmol) were dissolved in 2 ml of DMF, and triethylamine (68.5 μl) was added to the solution. The mixture was then stirred for 10 minutes. Ethyl 3-aminobenzoate (49.2 mg, 0.33 mmol) was added to the mixture and stirred overnight. After liquid separation was effected with ethyl acetate and 1M aqueous sodium hydroxide solution, the organic layer was washed sequentially with 1M aqueous sodium hydroxide solution, 1M hydrochloric acid and aqueous saturated sodium chloride solution (brine), followed by drying over sodium sulfate. After the solvent was distilled off, the resulting residue was dissolved in 2 ml of THF, 1 ml of ethanol and 1 ml of water. Lithium hydroxide monohydrate (13.5 mg, 0.32 mmol) was added to the solution. After stirring for 5 hours, 4.5 mg of lithium hydroxide was added to the mixture and stirred overnight. After it was confirmed that the reaction was completed, pH of the reaction solution was adjusted to 2 with 1M hydrochloric acid and the solvent was distilled off. After 3 ml of TFA was added to the resulting residue, the mixture was stirred at room temperature for 5 hours and the solvent was removed by distillation. The mixture was then purified according to the purification step A to give the title compound.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[F:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[F:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:7][CH2:8][C@:4]([CH2:1][CH3:3])([OH:12])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Cc1c(F)ccc(C#N)c1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(F)c2C)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4-difluoro-3-methylbenzonitrile (279 mg) and lithium carbonate (220 mg), the title compound was obtained as pale-yellow oil (yield: 151 mg, yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21](O)=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].C1N=C[N:32](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-].O>CS(C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([NH2:32])=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:27])([F:28])[F:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-6-nitroquinazoline-8-carboxylic acid (40 mg, 0.09 mmol) in 1 mL of anhydrous DMSO, CDI (22 mg, 0.14 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 50° C. for 3 h. After cooling down to rt, NH4Cl (11 mg, 0.14 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at it overnight. The reaction mixture was poured into water. The yellow precipitate was collected as the desired product by filtration, followed by washed with water in 96% yield. 1HNMR (in DMSO): 4.90 (d, J=5.5 Hz, 2H), 7.66-7.72 (m, 2H), 7.93 (s, 1H), 8.19 (d, J=3.3 Hz, 1H), 8.72 (s, 1H), 9.17 (d, J=2.6 Hz, 1H), 9.53 (d, J=2.6 Hz, 1H), 9.87 (t, J=5.8 Hz, 1H), 10.22 (d, J=3.3 Hz, 1H). Mass: M+H+: 426.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:11][C:10]=1[CH:28]=[N:29][O:30][CH3:31]>ClCCl.FC(F)(F)C(O)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:11][C:10]=1[CH2:28][NH:29][O:30][CH3:31]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CONCc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triethylsilane (1.9 ml) was added dropwise to a solution of 3-(4-chloro-3-methoxyiminomethylphenyl)-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (3.6 g) in a mixture of 30 ml of dichloromethane and 50 ml of trifluoroacetic acid. After the mixture had been stirred for 20 hours at room temperature, the solvent was distilled off. The residue was taken up in 200 ml of dichloromethane, whereupon the organic phase was washed four times using 50 ml of water in each case, dried over sodium sulfate and finally concentrated. Crystallization using diisopropyl ether and petroleum ether gave the title compound (m.p. 83-85° C.).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8].[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C>CO>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([OH:8])[CH2:6][NH:5][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:24][CH:25]=2)=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(Oc2cnccn2)cc1
Reactant: NCC(O)c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC(CNCc1ccc(Oc2cnccn2)cc1)c1ccc(F)cc1
Reaction time: 8 h
Yield: 35.1 %

Procedure:
Sodium cyanoborohydride (0.62 mL, 1 M in THF) was added to a solution of 2-amino-1-(4-fluoro-phenyl)-ethanol (80 mg, 0.52 mmol), 4-(Pyrazin-2-yloxy)-benzaldehyde (103 mg, 0.52 mmol) and glacial acetic acid (0.5 mL), in methanol (3 mL) at RT and the flask was stirred overnight. The reaction mixture was concentrated in vacuo; the residue was quenched with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane (3×4 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated again in vacuo to yield 1-(4-fluoro-phenyl)-2-[4(pyrazin-2-yloxy)-benzyl amino]-ethanol as a white solid 62 mg, 35%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[O:9][CH2:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.[ClH:30]>C(O)C>[ClH:30].[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:10]2[O:9][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2=[O:18])=[CH:20]1
Reactant: CCOC(=O)C1=C(NC2CCCCC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(NC2CCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of ethyl 2-(cyclohexylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.019 g, 0.075 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.011 g, 0.075 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.079 mL, 0.16 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.0070 g, y. 22%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29]Cl)[C:24]=1[CH3:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO.C(OCC)(=O)C>[CH2:14]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:24]=1[CH3:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 32.2 %

Procedure:
To a liquid prepared by dissolving with stirring 6.7 g (0.045 mol, 0.95 eq.) of 2-mercaptobenzimidazole and 52.5 g (0.273 mol, 5.8 eq.) of a 28% sodium methoxide solution in 350 mL of methanol, a liquid prepared by dissolving the whole amount of 4-octyloxy-2-chloromethyl-3-methylpyridine in 180 mL of methanol was added at 27° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 14.9 g of an orange-colored oily matter. The orange-colored oily matter was recrystallized from ethyl acetate (5 vol.), to obtain 5.8 g of colorless crystals (HPLC: 98.8 Area %, yield 32.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:27]([NH:26][N:25]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1)[CH:22]([CH3:24])[CH3:23])(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1
Reactant: CC(C)NNC(=O)c1ccncc1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1ccncc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200.0 mg, 0.70 mmol), N′-isopropylisonicotino hydrazide (188.2 mg, 1.05 mmol) and HATU (399.2 mg, 1.05 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) for refinement and dried so that ivory (E)-tert-butyl 3-(3-(2-isonicotinoyl-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (108 mg, 34.4%).