Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[C:5]([NH:10][CH3:11])[C:4]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH:6]=[C:5]([NH:10][CH3:11])[C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: NCCOCCO
Reactant: CNc1cc(F)cc(NC)c1[N+](=O)[O-]
Product: CNc1cc(NCCOCCO)cc(NC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
0.01 mole (2 g) of 2-methylamino-6-methylamino-4-fluoronitrobenzene in 8 ml of 2-(2-aminoethoxy)ethanol was heated to 100° C. After 30 minutes the reaction medium was diluted with 20 ml of ice water and the desired product precipitated out. After filtering and vacuum drying in the presence of P2O5, it was recrystallized from isopropanol and then from ethyl acetate. The product melted at 132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18](O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cncc(Br)c2)C1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless oil. MS: 343.1 and 345.1 (M+H+).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH3:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]3[CH2:24][CH2:25][O:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])([CH2:28][CH3:29])[C:22]=3[NH:21][C:20]=12.[ClH:34].C(OCC)(=O)C.C(OCC)C.CCCCCC>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH3:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]3[CH2:24][CH2:25][O:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])([CH2:28][CH3:29])[C:22]=3[NH:21][C:20]=12.[ClH:34]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(N)O
Reaction time: 3 h

Procedure:
In 1 ml of dichloromethane, 421.5 mg (0.948 mmol) of the Boc-aminopropanol-etodolac obtained above was dissolved, and 3 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring for 3 hours. Diethyl ether and hexane were added thereto for precipitation, and the precipitate was dried under reduced pressure. The precipitate was purified by silica gel column chromatography to give 197.6 mg (55%) of the titled compound. The structure was identified by 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
3-(4-Chlorophenoxy)benzaldehyde (1.50 mL, 7.82 mmol, purchased from Acros Organics) in 30 mL absolute ethanol was treated with (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (1.12 mL, 7.82 mmol, purchased from Lancaster). After stirring at ambient temperature for 4 hours, the mixture was treated with NaBH4 (0.33 g, 8.60 mmol) in one portion. After stirring an additional 18 hours, the reaction mixture was concentrated under reduced pressure and the residue dissolved in diethyl ether and quenched by addition of a solution of 1N NaOH. The phases were allowed to separate and the aqueous phase was extracted with diethyl ether. The organic phases were combined, washed with water, brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 15% ethyl acetate/hexanes) to provide the title compound as a colorless oil (2.26 g, 79%). 1H NMR (300 MHz, CDCl3) δ6.85-7.37 (m, 12H), 3.75-3.95 (m, 3H), 2.65-2.9 (m, 2H), 1.4-2.1 (m, 5H); MS (ESI+) 364 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(F)cc2)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(F)cc5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (amine intermediate “P”) were reacted to give the title compound. LC/MS (M+H)+: 653. Ret. time: 2.06 min. (Condition L).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][C:30]#[C:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[ClH:41].C(O)C>O1CCCC1>[ClH:1].[ClH:41].[NH2:33][CH2:32][C:31]#[C:30][CH2:29][N:28]1[C:21]2[C:20]([NH:19][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:25][CH:24]=[N:23][C:22]=2[CH:26]=[CH:27]1
Reactant: CC(C)(C)OC(=O)NCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 60 °C
Reaction time: 16 h

Procedure:
tert-Butyl {4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-yl}carbamate (1.90 g) was dissolved in tetrahydrofuran (35 mL), 2N hydrochloric acid (18 mL) was added, and the mixture was stirred at 60° C. for 16 hrs. To the reaction mixture was added ethanol, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (802 mg) as a white powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH:13]([OH:15])[CH:12]([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[O:15]([C@H:13]1[CH2:14][N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:11][C@H:12]1[OH:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: OC1CN(Cc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@@H]1Oc1ccccc1
Temperature: 50 °C

Procedure:
A slurry of 2.4 g. (0.1 mole) of sodium hydride (4.2 g. of 57% oil dispersion, washed with ether to remove the oil) in 30 ml. of dimethylformamide was stirred while a solution of 19.3 g. (0.1 mole) of 1-benzyl-3,4-dihydroxypyrrolidine, cis isomer, (I) in 30 ml. of dimethylformamide was added dropwise. The mixture was heated at 50° C. for 1 hr., then a solution of 19.2 g. (0.2 mole) of fluorobenzene in 30 ml. of dimethylformamide was added in one portion. The mixture was heated at 90° C. for 18 hr., then cooled and concentrated under vacuum. The residue was dissolved in benzene and washed with water. The semicrystalline residue from the concentrated organic fraction was dissolved in cyclohexane and the solution was decanted from an insoluble oil (mostly I). The cyclohexane solution was treated with charcoal to remove residual I and then crystallized as fluffy, off-white needles (m.p. 88.5°-90° d.) which weighed 1.2 g. (4.5%).
Reaction SMILES: [NH:1](C(OC(C1C=C(OC)C=C(OC)C=1)(C)C)=O)[C@H:2]([C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:45]([OH:47])=[O:46])[CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[C@@H:28]([CH3:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1.[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73]>O.C(Cl)Cl>[NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:45]([OH:47])=[O:46])[CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[C@@H:28]([CH3:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:25])[CH2:3][S:4][C:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F:70][C:71]([C:72]([OH:74])=[O:73])([F:76])[F:75]
Reactant: COc1cc(OC)cc(C(C)(C)OC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)O)[C@@H](C)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)O
Reaction time: 1.5 h

Procedure:
8.8 g (10 mmoles) of Ddz-Cys(Trt)-Thr(But)-Ser(But)-OH are dissolved at room temperature in a mixture of 8.75 ml (0.1 mole) of trifluoroacetic acid, 1.75 ml of water and 165 ml of methylene chloride (=about 175 ml of a 5% strength solution of trifluoroacetic acid in methylene chloride, containing 1% of water). The mixture is left to stand at room temperature for 1.5 hours and is then neutralized with 8.85 ml (0.11 mole) of pyridine. The solution is concentrated and the residue is partitioned between ethyl acetate and water. The ethyl acetate phase is washed twice more with water and is dried over Na2SO4 and concentrated. The residue is dissolved in a small amount of ether and the solution is slowly added dropwise to petroleum ether.
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([F:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-].CO.[Cl-].[Na+]>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[C:13]([F:21])[CH:12]=2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid methyl ester (750 mg, 2.36 mmol) and methyl urea (437 mg, 5.90 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 14.5 mL, 7.08 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then partitioned between water (75 mL) and ethyl acetate (75 mL). An emulsion formed, and a saturated aqueous sodium chloride solution was added to break down the emulsion. The aqueous layer was further extracted with ethyl acetate (2×75 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a white semi-solid. The semi-solid was treated with a solution of 2/1 hexanes/ethyl acetate, and a white solid formed. The solid was filtered, washed well with hexanes, and dried to afford 1-[3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionyl]-3-methyl-urea (322 mg, 38%) as a white solid: mp 187-189° C.; FAB-HRMS m/e calcd for C17H20F4N2O2 (M+H)+361.1539, found 361.1549.
Reaction SMILES: [CH2:1]1[O:6][C:4](=[O:5])[NH:3][C@@H:2]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[Br:19][CH2:20][C:21](Br)=[O:22].CCOC(C)=O.CCCCCC>C1COCC1.C(OCC)(=O)C>[CH2:7]([C@@H:2]1[CH2:1][O:6][C:4](=[O:5])[N:3]1[C:21](=[O:22])[CH2:20][Br:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(Br)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CBr)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a solution of R-(−)-4-benzyl-2-oxazolidinone (15.0 g, 84.65 mmol) in THF (200 mL) was added nBuLi (2.5M in hexanes, 34 mL, 84.65 mmol) dropwise at −78° C. The solution was stirred at −78° C. for 30 min and then bromo acetyl bromide (18.65 g, 7.8 nL, 124.15 mmol) was added. The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that reaction was complete. It was diluted in ethyl acetate (200 mL) and the organic layer was washed with saturated aqueous NaRCO3 (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude brown oil (24.6 g). The crude product was purified by flash chromatography, eluent: 1:4 EtOAc-hexane, to furnish (4R)-4-benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-one as a colorless oil (19.9 g, 79.6%). Mass Spectrum (+ESI): 300, 299 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[N:30]2)[CH2:25][CH2:24]1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[N:30]4)[CH2:27][CH2:28]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: c1ccc2c(c1)nnn2C1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(n2nnc3ccccc32)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidin-4-yl-1H-benzotriazole, hydrochloride, 5 equivalent of diisopropylamine was added, praeparative HPLC (Method C) (7%, colourless crystals). HPLC-MS m/z=506.2 (M+1), Rt: 4.56 min.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[C:24]([OH:26])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O=S(Cl)[Cl:29]>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[C:24]([Cl:29])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1cccc(-c2ccccc2)c1C(=O)O
Product: CCCCCCCCCCOc1cccc(-c2ccccc2)c1C(=O)Cl

Procedure:
20 ml of SOCl2 was added to 4 g (1.13×10-2 mol) of decyloxybiphenylcarboxylic acid, and the mixture was heated at reflux for 3.5 hours. Excessive SOCl2 was evaporated to obtain decyloxybiphenylcarboxylic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCc1cccc(F)c1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCc1cccc(F)c1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(3-fluorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (71% yield). 1H NMR (400 MHz, CDCl3) δ 8.05, 7.93, 7.74, 7.64-7.56, 7.37-7.35, 7.26-7.24, 7.01-6.90, 4.10-4.03, 3.89-3.70, 3.36-3.33, 2.92.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH:19]=O)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][NH2:29])=[N:26][CH:27]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>O.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:26]3[CH:27]=[C:22]([F:21])[CH:23]=[CH:24][C:25]3=[N:28][N:29]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Solvent: Ic1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccc(F)cn34)nc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde (1.39 g, 4.83 mmol) and 5-fluoro-2-hydrazinylpyridine (1.28 g, 6.04 mmol) were combined in DCM (12.1 mL, 4.83 mmol) at ambient temperature and stirred for 15 minutes. The mixture was cooled to 0° C. followed by addition of iodobenzene diacetate (IBD; 1.87 g, 5.80 mmol). The reaction was warmed to ambient temperature and stirred overnight. Additional IBD (0.8 equivalents, 4.64 mmol) was added and the reaction was allowed to stir at ambient temperature for 48 hours total. The mixture was transferred to a separatory funnel, diluting with water and DCM. The organic phase was washed with saturated aqueous Na2SO3, followed by back extraction of the aqueous phase 2 times with DCM. The organics were combined and washed with brine, dried over Na2SO4, filtered and concentrated to a residue under reduced pressure, followed by purification by flash column chromatography to give the product (1.08 g, 57% yield). MS APCI (+) m/z 395.3 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24]>>[CH3:20][O:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:24]
Reactant: Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Temperature: 25 °C
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 13 except that the reaction mixture was stirred at ambient temperature rather than being heated to 100° C., 6-amino-4-(3'-chloroanilino)quinazoline was reacted with 2-methoxyacetyl chloride to give 6-(2-methoxyacetamido)-4-(3'-chloroanilino)quinazoline in 41% yield, m.p. 177°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:21]2[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(C)cc(=O)n(CCN3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 5 mL of chloroform, (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde was dissolved, thereto were added 135 mg of tert-butyl piperazine-1-carboxylate and 43.6 mg of acetic acid, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 231 mg of sodium triacetoxyborohydride, and stirred for 1 hour. Thereto was added an aqueous saturated sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60N manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate] to obtain 173 mg of a yellow oily substance, tert-butyl 4-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.S.[Na]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: S
Agent: [Na]
Solvent: O
Product: Nc1cc(Cl)ccc1Cl
Yield: 59 %

Procedure:
384 Parts of 2,5-dichloronitrobenzene and 200 parts of water were introduced into a stirring apparatus and reacted with 1,000 parts of 36% sodium hydrogensulfide solution in the same manner as described in Example 1. Then, the 2,5-dichloroaniline obtained as by-product was separated by steam distillation. After cooling to 20°C 806 parts of sodium sulfite (Na2SO3 . 7 H2O) were added and the pH was adjusted at 6 with 374 parts of 30% hydrochloric acid at a temperature within the range of from +10°C to 12°C within 2 to 3 hours while stirring. The precipitated solid reaction product was suction-filtered, dissolved in 1,000 parts of a 8% sodium hydroxide solution at 50° to 60°C to separate the sulfur and the disulfide; the solution was suction-filtered from the undissolved moiety and 4-chloro-2-aminothiophenol was precipitated from the filtrate at room temperature (20° C) with 242 parts of 30% hydrochloric acid.
Reaction SMILES: C(O[C:6](=O)[NH:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34](C=O)=[CH:33][CH:32]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:26][C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([N:7]=[CH:6][C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:38][CH:37]=3)[CH2:9][CH2:10]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NN1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CN2CCN(N=Cc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of tert-butyl[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 493 (40 mg, 0.11 mmol), 4-trifluoromethoxybenzaldehyde (24 mg, 0.13 mmol), trifluoroacetic acid (0.08 ml) and methylene chloride (1 ml) was stirred at room temperature for 3 hours. The mixture was added a saturated sodium hydrogencarbonate solution for neutralization followed by extraction with methylene chloride. The solution was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1) to afford N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethoxybenzylidene)amine (19 mg, yield 40%) as a white powder.