Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[OH:25])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])([O-])=O>[Fe].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[OH:25])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8]
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOC(=O)c1ccc(O)c(N)c1
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
A mixture of 10.5 g of dodecyl 3-nitro-4-hydroxybenzoate obtained in Step 1 above and 100 ml of acetic acid was heated at 70° C. under a nitrogen atmosphere and 10 g of reducing iron was added thereto over a 5 minute period with stirring. The reaction mixture was filtered and the filtrate was poured into 500 ml of ice water to deposit the crystals. The crystals were washed and dried to obtain 8.2 g (yield 85%) of the desired compound having a melting point of 86° to 89° C.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[S:34][C:35]([C:39](O)=[O:40])=[C:36]([CH3:38])[N:37]=3)[C:29]2=[O:42])=[CH:25][CH:24]=1.[CH:45]([C:48]1[S:49][CH:50]=[C:51]([CH2:53][NH2:54])[N:52]=1)([CH3:47])[CH3:46]>>[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[S:34][C:35]([C:39]([NH:54][CH2:53][C:51]4[N:52]=[C:48]([CH:45]([CH3:47])[CH3:46])[S:49][CH:50]=4)=[O:40])=[C:36]([CH3:38])[N:37]=3)[C:29]2=[O:42])=[CH:25][CH:24]=1
Reactant: CC(C)c1nc(CN)cs1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1csc(C(C)C)n1
Yield: 68 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (2-isopropylthiazol-4-yl)methanamine, the title compound was obtained as a colourless solid in 68% yield: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.45 (t, J=5.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.19-7.14 (m, 3H), 4.41-4.39 (m, 4H), 3.97 (t, J=9.0 Hz, 2H), 3.42 (t, J=9.0 Hz, 2H), 3.26-3.15 (m, 1H), 2.44 (s, 3H), 1.28 (d, J=6.0 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 163.6, 162.2, 160.4, 157.9, 155.5, 154.0, 133.0 (d), 130.4 (d), 118.4, 115.9, 113.8, 46.6, 42.4, 42.0, 32.9, 23.3, 17.5; MS (ES+) m/z 474.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:26]1C=C(C=C[CH:33]=1)C#N>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[CH:33][CH:26]=[C:22]([C:21]#[N:20])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Reactant: N#Cc1cccc(Br)c1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccc(C#N)c2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 3-Brombenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=344.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:11]([O:13][CH3:14])=[O:12]>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[CH3:14][O:13][C:11]([NH:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])=[O:12]
Reactant: COC(=O)Cl
Reactant: NCc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NCc1ccccc1N

Procedure:
The amine component employed is obtained starting from 2.0 g of 2-(aminomethyl)aniline, dissolved in 30 ml of methylene chloride, by reaction with 1.3 ml of methyl chloroformate in the presence of 3.1 ml of diisopropylethylamine at 5° C. After purification over 80 g of silica gel (mobile phase A), 2-(methoxycarbonylaminomethyl)aniline is obtained: Rf (A)=0.23; Rf (Z)=0.31.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)C=CC=CC=1.[F:17][C:18]1([F:34])[O:22][C:21]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][C:20]=2[O:19]1>>[N:13]1[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:34])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:30]2)=[O:16])=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Product: O=C(Nc1ccncc1)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1

Procedure:
The title compound was prepared from pyridin-4-yl-carbamic acid phenyl ester and 1-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.36-8.34 (d, J=6.8 Hz, 2H), 7.41-7.39 (d, J=5.8 Hz, 2H), 7.10 (s, 1H), 6.99 (s, 2H), 3.55-3.53 (m, 4H), 3.49 (s, 2H), 2.47-2.44 (m, 4H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([CH:17]=1)[CH:15]=O.[Sn](Cl)Cl>C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:9][C:10]1[CH:17]=[C:14]2[C:13](=[CH:12][CH:11]=1)[N:18]=[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH:4]=[CH:15]2
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)=O
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 70 °C
Yield: 14.1 %

Procedure:
Ethyl pyruvate (535.4 mg, 4.61 mmol) was added to 5-Bromo-2-nitro-benzaldehyde (1.01 g, 4.39 mmol) in ethanol (22 mL) at room temperature under argon. Then, tin(II)chloride (4.16 g, 21.95 mmol) was added to the reaction mixture, followed by the addition of zinc(II)chloride (2.99 g, 21.95 mmol), and finally activated 4 Å molecular sieve pellets (1.01 g). The mixture was heated at 70° C. in an oil bath for twenty hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added, and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with dichloromethane and subsequently a second silica gel chromatography purification eluting with 1:4 ethyl acetate:hexanes to give 173.6 mg (14%) of ethyl 6-bromo-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.55 (d, J=9 Hz, 1H), 8.42 (d, J=2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.11 (d, J=9 Hz, 1H), 7.98 (dd, J=9, 2 Hz, 1H), 4.42 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 280 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])([CH3:3])[CH3:2].[CH:12]1([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(N(CC)CC)C>[CH:1]([O:4][C:5](=[O:11])[CH2:6][C@@H:7]([C:8]([OH:10])=[O:9])[NH:22][CH2:21][CH2:20][CH2:19][NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)/C=C\C(=O)O
Reactant: NCCCNC1CCCCC1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C[C@H](NCCCNC1CCCCC1)C(=O)O
Yield: 81.9 %

Procedure:
In a manner analogous to that of Example 1, 400 ml of triethylamine are added to 350.2 g (2.0 mols+10% excess) of maleic acid-monoisopropyl ester, and the mixture is subsequently reacted with 311.3 g (2.0 mols) of 3-cyclohexylamino-1-propylamine at 59°-85° C. for 35 minutes. The reaction mixture is further processed in the manner described in Example 1 to yield 515 g (82.2% of theory) of the desired aspartic acid derivative, which decomposes at 151°-152° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1B(O)O>COCCOC>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cccc(C)c1B(O)O
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
2-Chloro-5-nitropyridine (1.0 g, 6.31 mmol), 2,6-dimethylphenylboronic acid (1.42 g, 9.47 mmol) and bis(di-tert-butyl(4-dimethylaminophenylphosphine)dichloropalladium(II) (0.044 g, 0.062 mmol) were added to 1,2-dimethoxyethan (32 ml), degassed and purged with nitrogen three times under reduced pressure. Under nitrogen atmosphere the mixture was stirred at room temperature for 30 minutes, 1M aqueous sodium carbonate (12 ml) was poured in, and the temperature was raised to 80° C. After the reaction at 80° C. for 3 hours, the mixture was cooled to room temperature and extracted with addition of ethyl acetate and water. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave the title compound (1.41 g, 98.1%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[CH3:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCC2CCOCC2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 42 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, Part D) (0.200 g, 0.777 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.100 g, 0.777 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL) cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the pre-loaded column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol), ethyl acetate and hexanes. After concentrating, take the product up in CH2Cl2 (25 mL) and wash with 1.0 N NaOH solution (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.121 g, 42.0%): MS ES+ 371.1 (M+H)+, base peak 242.0 (M-C7H14NO)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/in, 5-95% over 19 min], tR=7.9 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([Cl:26])=[C:6]([CH:25]=1)[O:7][C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[S:14][C:10]=2[C:9]=1[C:23]#[N:24].[N:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)=[C:29]=[O:30]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:5]1[CH:4]=[C:3]([F:27])[C:2]([NH:1][C:29](=[O:30])[NH:28][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:33][CH:32]=2)=[CH:25][C:6]=1[O:7][C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[S:14][C:10]=2[C:9]=1[C:23]#[N:24]
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2cc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.4 %

Procedure:
N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (150 mg, 0.372 mmol) produced in Example 23(vi) was dissolved in N,N-dimethylformamide (1.5 mL), 1-isocyanato-4-(trifluoromethyl)benzene (69 μL, 0.484 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (115 mg, 52%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: O=c1ncc(F)c[nH]1
Reactant: O=C(CBr)c1cccs1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(F)cnc1=O)c1cccs1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
A mixture of 5-fluoropyrimidin-2-one (456 mg) and 2-bromoacetylthiophene (820 mg) in triethylamine (1.33 ml) and ethanol (25 ml) was stirred at room temperature. After 2.5 h. the reaction mixture was concentrated to ca. 5 ml, diluted with ethyl acetate (300 ml) washed with water (3×50 ml), dried (MgSO4) and evaporated to a foam. This was crystallised from acetone to give the title pyrimidinone (225 mg), m.p. 183°-190° C. (dec) λmax (EtOH) 260 nm (ε10,308), 285.5 nm (ε 8,430).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][O:20][CH3:21]>CC(C)=O>[CH3:19][O:20][CH2:21][O:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCBr
Reactant: Cc1cc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1cccc2oc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-hydroxy-2-methylbenzofuran (7.1 g, 0.048 M), anhydrous powdered potassium carbonate (19.87 g) and acetone (82 ml), was added dropwise bromomethoxymethane (11.99 g, 7.88 ml, 0.0959 M) with ice cooling. After the addition was complete the reaction mixture was stirred at room temperature overnight, filtered and evaporated. The residual oil was distilled to give 4-methoxymethoxy-2-methylbenzofuran, b.p. 94°-97° C./0.8 mmHg.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[C:30]([NH2:38])(B(O)O)[NH:31][CH:32]=[CH:33][CH:34]=1>>[CH3:28][C:29]1[C:30]([NH2:38])=[N:31][CH:32]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)[CH:34]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1=CC=CNC1(N)B(O)O
Product: Cc1cc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cnc1N
Yield: 80 %

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine and 3-methyl-2-aminopyridine boronic acid were reacted in General Procedure A Suzuki Coupling to produce 378 in 80% yield after RP-HPLC purification. MS (Q1) 504.2 (M)+, purity 100% by UV 254 nm, 1H NMR (DMSO).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[CH:10]([C:12]([CH3:14])=O)=[CH2:11]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[CH:11][CH:10]=[C:12]2[CH3:14])[CH3:2]
Reactant: C=CC(C)=O
Reactant: CCc1ccccc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCc1cccc2c(C)ccnc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirred solution of 2-ethylaniline (1 g. 8.2 mmol.) in acetic acid (10 ml), activated silferc (1.32 g. ferric chloride 8.2 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.63 g, 9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.12 g. 8.2 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([N:56]=[C:57]=[O:58])=[CH:52][CH:51]=1)([O-:49])=[O:48].N1C=CC=CC=1.CCCCCC>C1(C)C=CC=CC=1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([O:16][C:57]([NH:56][C:53]2[CH:52]=[CH:51][C:50]([N+:47]([O-:49])=[O:48])=[CH:55][CH:54]=2)=[O:58])=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3O)c2)c(C(C)(C)CC)c1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3OC(=O)Nc3ccc([N+](=O)[O-])cc3)c2)c(C(C)(C)CC)c1

Procedure:
0.01 moles of 1-(2,4,6-trichlorophenyl)-3-[3-{α-(2,4-di-t-amylphenoxy)acetamido}benzamido]-hydroxy-5-pyrazolone and 0.01 moles of p-nitrophenyl isocyanate are dissolved in 100 ml of dehydrated toluene, then added with 0.02 moles of pyridine and heated for 1 to 1.5 hours under reflux. After the reaction the solvent is eliminated under reduced pressure and n-hexane is added. The obtained solid is collected by filtration, then washed with n-hexane and dried to obtain the coupler (3) in a state of colorless powder with a melting point of 96°-100° C.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Br:13])=[C:7]([O:14][CH3:15])[CH:6]=1)=O.CCOC(C)=O.C([O-])(O)=O.[Na+].[CH:28]([NH2:30])=[O:29]>>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([C:3]2[N:30]=[CH:28][O:29][C:2]=2[CH3:16])=[CH:6][C:7]=1[O:14][CH3:15]
Reactant: NC=O
Reactant: COc1cc(C(=O)C(C)Br)cc(OC)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncoc2C)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one (1.07 g, 3.04 mmol) in formamide (10 mL) in an oven-dried flask under argon was heated at 110° C. for 16 hrs. After cooling to room temp, EtOAc and saturated aqueous NaHCO3 were carefully added and the mixture was stirred for 15 minutes. It was then extracted with EtOAc twice and the combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated. Purification by chromatography (30% EtOAc-hexanes) gave 4-(4-bromo-3,5-dimethoxyphenyl)-5-methyloxazole as a yellow solid (0.496 g, 55% yield).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C.CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][CH2:20][N+:17]([O-:19])=[O:18])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])CCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 14.2 %

Procedure:
To an acetic acid (30.0 mL) solution of 4-(4-fluoro-phenoxy)-benzaldehyde (3.00 g, 48.4 mmol) described in Manufacturing Example 141-1-1 were added nitromethane (4.03 g, 66.0 mmol) and ammonium acetate (2.03 g, 26.4 mmol) under nitrogen atmosphere at room temperature, which was stirred for 4 hours at 110° C. Water and ethyl acetate were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, which gave a crude product (3.4 g). To a dimethyl sulfoxide (30.0 mL) solution of this crude product (3.4 g) and acetic acid (3.00 mL) was added sodium borohydride (793 mg, 21.0 mmol) at room temperature while cooling appropriately, which was stirred for 30 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:1) to obtain the title compound (1.80 g, 52.6%).
Reaction SMILES: C([Li])CCC.CO[C:8]([C:10]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:9]>C1COCC1.C(NC(C)C)(C)C>[O:28]1[CH2:27][CH2:26][N:25]([C:23]2[CH:22]=[CH:21][C:11]3[O:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:9])[C:10]=3[CH:24]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)CCCOc1ccc(N2CCOCC2)cc1C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1CCOc2ccc(N3CCOCC3)cc2C1=O
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
In THF (15 ml) was dissolved diisopropylamine (1.018 ml), and to the mixture was added dropwise at 0° C. n-butyl lithium (4.2 ml). The mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of ethyl 4-(2-methoxycarbonyl-4-morpholinophenoxy)butyrate (1829 mg, 5.18 mmol) in THF (5 ml) at −78° C., ice bath was removed, and the mixture was stirred for 7 hours. To the mixture was added at 0° C. 10% ammonium chloride solution (30 ml), and the mixture was extracted with ethyl acetate (30 ml×3). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 50 g, ethyl acetate/hexane=1/5), and the desired fraction was concentrated under reduced pressure to give ethyl 7-morpholino-5-oxo-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate (924 mg, 2.89 mmol, 56%).