Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[Li]CCCC.CON(C)[C:22](=[O:26])[CH:23]([CH3:25])[CH3:24]>>[C:22]([C:3]1[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CON(C)C(=O)C(C)C
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Agent: [Li]CCCC
Product: CC(C)C(=O)c1cccnc1NC(=O)C(C)(C)C
Yield: 69.4 %

Procedure:
A solution of N-(pyridin-2-yl)pivalamide (3.20 g, 18.0 mmol), n-BuLi (15.00 mL, 2.1 eq.) and N-methoxy-N-methylisobutyramide (2.60 g, 1.1 eq) were reacted as outlined in Scheme 1 to give 3.10 g (69%) of N-(3-isobutyrylpyridin-2-yl)pivalamide. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J=7.03 Hz, 6 H) 1.35 (s, 9 H) 3.55 (dt, J=13.70, 6.78 Hz, 1 H) 7.08 (dd, J=7.91, 4.69 Hz, 1 H) 8.19 (dd, J=8.20, 2.05 Hz, 1 H) 8.63 (dd, J=4.83, 1.90 Hz, 1 H) 11.51 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].OS(C(F)(F)F)(=O)=O.[Br:21]N1C(=O)CCC1=O>CC#N>[Br:21][C:9]1[C:10]([OH:12])=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(O)cc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
A solution of methyl 2-chloro-4-hydroxybenzoate (5.0 g, 26.8 mmol) in MeCN (100 mL) was cooled to −30° C. Triflic acid (2.60 mL, 29.48 mmol) was added followed by N-bromosuccinimide (5.25 g, 29.48 mmol) and the reaction was warmed to room temperature and stirred for 1.5 hours. The reaction was quenched by the addition of saturated aqueous Na2CO3 solution (50 mL). The solution was extracted with EtOAc (2×100 mL), the combined organic layers were combined, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptanes to afford the title compound as a white solid (2.60 g, 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: COc1ccc(/C(C#N)=C/c2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 84.1 %

Procedure:
4-Nitrobenzaldehyde (760 mg) and 3,4-dimethoxybenzyl cyanide (890 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (1.31 g, yield: 85%).
Reaction SMILES: COC[O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][O:10][NH2:11])=[CH:7][CH:6]=1.O=[C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C([O-])(=O)C.[Na+].Cl>C(OCC)(=O)C.CCCCCC.CO.C(O)(=O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10]/[N:11]=[C:15](/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)\[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:13]=1
Reactant: COCOc1ccc(CON)cc1
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A mixture of 4-methoxymethoxybenzyloxyamine (4.99 g), methyl 4-oxo-4-phenylbutyrate (5.71 g), acetic acid (5.10 ml), sodium acetate (4.87 g) and methanol (200 ml) was heated under reflux for 15 hours. The reaction mixture was cooled to room temperature, dilute hydrochloric acid was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (50 ml) and methanol (5 ml). To this solution was added 1N hydrochloric acid (10 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (4.24 g, yield 50%) as a colorless oil from an ethyl acetate-hexane (2:5, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]#N)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[OH2:24]>>[CH3:1][N:2]1[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[C:4]2[CH:5]=[C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:8][C:3]1=2
Reactant: O
Reactant: CCOC(=O)Cc1ccc(N(C)Cc2ccccc2C#N)cc1
Product: CCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Reaction time: 2 h

Procedure:
A mixture of N-methyl-N-(2-cyanobenzyl)-4-ethoxycarbonylmethylaniline (6 g) and polyphosphoric acid (60 g) was stirred for 2 hours with heating at 130°-140° C. After the reaction, the reaction mixture was poured into iced water (500 ml) to precipitate crystals. The crystals were collected, washed in water, and then vacuum-dried over diphosphorus pentoxide to obtain the desired compound (2.5 g) as yellow prismatic crystals.
Reaction SMILES: [ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:28]1C2C=CC3C(=CC(C=O)=C4C=3C=CC=C4)C=2C=CC=1.NC(CC)(CO)CO>CCO.CCOCC>[ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH2:27][CH3:28])([CH2:23][OH:24])[CH2:25][OH:26])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Agent: CCC(N)(CO)CO
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reductive amination procedure described in 1B, 6-chrysenecarbaldehyde (1A) and 2-amino-2-ethyl-1,3-propanediol (Aldrich) gave 2-((6-chrysenylmethyl)amino)-2-ethyl-1,3-propanediol hydrochloride, mp 241°-243° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[C@@H:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]1[CH3:24].C=O.[BH3-][C:28]#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[C@@H:18]1[CH2:23][CH2:22][N:21]([CH3:28])[CH2:20][C@@H:19]1[CH3:24]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@@H]4CCNC[C@@H]4C)cc3N21
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@@H]4CCN(C)C[C@@H]4C)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of (R)-7-bromo-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.2 g, 5.59 mmol) in AcOH (10 mL) and MeOH (100 mL) was added paraformaldehyde (0.839 g, 28.0 mmol). The reaction mixture was stirred at ambient temperature for 1 h. NaBH3CN (0.557 g, 14.0 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Aqueous saturated NaHCO3 solution (30 mL) was added and the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a reverse-phase preparatory HPLC (Table 3, Method 35) to give (R)-7-bromo-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.8 g, 79%). 1H NMR (400 MHz, CD3OD) δ 7.22 (s, 1H), 6.86 (s, 1H), 4.87-4.91 (m, 1H), 4.58 (d, J=13.2 Hz, 2H), 3.15 (m, 1H), 3.04 (m, 1H), 2.84 (m, 1H), 2.23-2.39 (m, 6H), 2.07-2.18 (m, 1H), 1.55 (m, 1H), 1.43 (d, J=6.5 Hz, 3H), 0.83 (d, J=7.0 Hz, 3H). LC/MS (Table 1, Method 25) Rt=0.681 min.; MS m/z: 407 [M+H]+& 409 [M+H+2]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]5)[CH:27]=4)[CH2:23][C:22](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)cn1

Procedure:
Prepared from (4′-fluoro-3-{3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K47) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (196 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7]2)[CH2:3][CH2:2]1.I[C:16]1[CH:31]=[CH:30][C:19]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:24]1([CH2:23][CH2:22][CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:16]([N:1]3[CH2:6][CH2:5][C:4]4([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[CH2:8][O:7]4)[CH2:3][CH2:2]3)=[CH:31][CH:30]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: Ic1ccc(OCCCN2CCCCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: c1ccc2c(c1)COC21CCN(c2ccc(OCCCN3CCCCC3)cc2)CC1
Yield: 25.7 %

Procedure:
3H-spiro[2-benzofuran-1,4′-piperidine] (131 mg, 0.695 mmol), 1-[3-(4-iodophenoxy)propyl]piperidine (200 mg, 0.58 mmol) prepared in Reference Example (2), sodium tert-butoxide (78 mg, 0.812 mmol), Pd2(dba)3 (5 mg, 0.0058 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (7 mg, 0.0116 mmol) were mixed, and stirred overnight in 1,4-dioxane in a nitrogen atmosphere at 60° C. The reaction solution was filtered under suction through Celite, diluted with ethyl acetate, washed with water and saturated saline in that order, and the organic layer was dried with sodium sulfate. The solvent was evaporated off under reduced pressure, and the resulting residue was purified through preparative thin-layer chromatography (eluate: chloroform/methanol=10/1) to obtain the entitled compound as a colorless solid (60.5 mg, 26%).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:36]([CH2:38][NH2:39])[OH:37]>O1CCCC1.O>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:39][CH2:38][CH2:36][OH:37])=[O:6]
Reactant: NCCO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCO
Yield: 94 %

Procedure:
6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid was dissolved in 50 ml of tetrahydrofuran and 3.1 ml of triethylamine was added thereto. While cooling the mixture in ice with stirring, 2.1 ml of ethyl chlorocarbonate was added dropwise. Then the mixture was stirred for 15 minutes and 1.8 ml of ethanolamine was added thereto. After the mixture was stirred for 30 minutes at room temperature, water was added thereto and the resulting aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was separated from the aqueous layer, washed with 5% aqueous hydrochloric acid solution and then water, and dried over magnesium sulfate. The solvent was distilled off. The resulting reaction mixture was subjected to chromatography on a silica gel column to afford 6.5 g (yield 94%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:13])[CH3:12])=[CH:6][C:4]=1[NH2:5].[CH3:14][O:15][CH:16]([O:21][CH3:22])[CH2:17][C:18](O)=[O:19].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:14][O:15][CH:16]([O:21][CH3:22])[CH2:17][C:18]([NH:5][C:4]1[CH:6]=[C:7]([O:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:19]
Reactant: COC(CC(=O)O)OC
Reactant: COc1ccc(OC(C)=O)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(OC(C)=O)cc1NC(=O)CC(OC)OC
Temperature: 5 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
To a cooled solution (0° C.) of 2-methoxy-5-acetyloxy-aniline (5 g, 0.0276 mole), 3,3-dimethoxy-propanoic acid (5 g, 0.0373 mole) in 75 ml of methylene chloride was added DCC (5.7 g, 0.0276 mole) in 20 ml of methylene chloride. After completion of the addition, the solution was stirred for a further 4 hours. The reaction medium was concentrated to 25 ml, diluted with 200 ml of isopropyl ether, cooled to 5° C. and the resulting precipitate was isolated by filtration, giving N-(3,3-dimethoxypropanoyl)-2-methoxy-5-acetoxy-aniline 7.7 g (Yield=95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[C:4]([CH3:20])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH:46]1[CH2:53][CH:52]2[N:54]([CH3:55])[CH:48]([CH2:49][CH2:50][CH2:51]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:55][N:54]1[CH:48]2[CH2:49][CH2:50][CH2:51][CH:52]1[CH2:53][CH:46]([NH:45][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:20])=[N:12][C:11]=13)=[O:19])[CH2:47]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: Cc1cc(Cl)ccc1-c1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
A mixture of 2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxylic acid (59 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (79 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (72 mg, 0.26 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.11 mL, 0.82 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine (2×20 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative TLC (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamide (19 mg, 22%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.01 (br s, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.71 (dd, J=8.1, 0.9 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.43-7.36 (m, 2H), 4.67-4.60 (m, 1H), 3.25-3.15 (m, 2H), 2.88 (s, 3H), 2.70-2.55 (m, 2H), 2.48 (s, 3H), 2.10-2.00 (m, 3H), 1.65-1.40 (m, 3H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 424 (M+H); HPLC 98.4% (AUC), tR=13.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH2:22][O:23]CC3C=CC(OC)=CC=3)=[N:18][O:19][C:20]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH2:22][OH:23])=[N:18][O:19][C:20]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(COCc2noc(C)c2-c2ccccc2C(=O)c2ccc(Cl)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1onc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
To a round bottomed flask was added (4-chlorophenyl)(2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanone (69 mg, 0.154 mmol), DCM, and water. This solution was cooled to 0° C. before addition of DDQ (69.9 mg, 0.308 mmol) and the reaction stirred at 0° C. for 4 h before addition of NaHCO3 solution. The layers were separated and the aqueous extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone. LC/MS m/z 328 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1.[CH3:20][NH:21][CH3:22]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:21]([CH3:22])[CH3:20])[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1
Reactant: CNC
Reactant: Nc1nc(Cl)c2nnn(Cc3ccccc3F)c2n1
Solvent: CCO
Product: CN(C)c1nc(N)nc2c1nnn2Cc1ccccc1F
Reaction time: 2 h

Procedure:
2.8 g (10 mmol) of 5-amino-7-chloro-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine are dissolved in 150 ml of ethanol while heating at 40°-50°, and 10 ml of an aqueous solution of dimethylamine (40%) is added to the resulting solution. The reaction mixture is left to stand at room temperature for 2 hours. The precipitated product is then filtered off with suction and washed with water. Recrystallisation from ethanol yields 5-amino-7-(N,N-dimethylamino)-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine having a melting point of 165°-167°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[S:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])=[N:32][N:33]=1>C(#N)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[S:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])=[N:32][N:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-c1nnc(CBr)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: O=c1n(Cc2nnc(-c3ccccc3Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
30 mg (0.10 mmol) of the compound from Example 5A were dissolved in 3 ml of acetonitrile, and 48 mg (0.15 mmol) of cesium carbonate and 28 mg (0.10 mmol) of the compound from Example 86A were added. The mixture was stirred at 70° C. for 8 h. For work-up, the mixture was cooled to RT, diluted with 5 ml of methanol and filtered. The filtrate was concentrated under reduced pressure and the crude product was then purified chromatographically [Method 19]. This gave 11 mg (22% of theory) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:14]=[N:13][C:12](=[O:15])[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:14]=[N:13][C:12](=[O:15])[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1N=NC(c2cccc([N+](=O)[O-])c2)=N1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C2=NC(=O)N=N2)c1
Reaction time: 0.08 h
Yield: 75 %

Procedure:
3-Nitrophenyl-1,3,4-triazole-5-one (250 mg) was dissolved in 10 ml of ethanol, treated with 0.100 g of 10% palladium/carbon catalyst, and hydrogenated on a Parr apparatus at 25 psi for 5 minutes. The reaction mixture was filtered through Celite and concentrated to give 0.160 g of the title compound.
Reaction SMILES: [Cl:1][C:2](=[C:14]([Cl:16])Cl)[C:3]([OH:13])=[C:4]([C:10](=[NH:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:14]([Cl:16])=[N:12][C:10]([CH3:11])=[C:4]([C:3]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=N)=C(O)C(Cl)=C(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1c(C)nc(Cl)c(Cl)c1O

Procedure:
102.7 g (0.35 mol) of ethyl 4,5,5-trichloro-3-hydroxy-2-(1-imino-ethyl)penta-2,4-dienoate are heated at 180° C. in 1,2-dichlorobenzene for three hours. The volatile components are removed under a high vacuum up to 100° C. The residue is purified with dichloromethane on silica gel.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CS(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
8.40 g (40.7 mmol) 2,6-di-tert-butylphenol was dissolved in 100 ml dried DMSO. 2.32 g (58 mmol) sodium-hydroxide and 8.5 g (54 mmol) p-chloronitrobenzene were added into the DMSO solution. The DMSO solution was heated to 100˜120° C. for 12 hrs with stirring. Then the reaction mixture was allowed to cool to room temperature and poured into distilled water. The aqueous solution was acidified to pH 2˜4 and yellow precipitate was collected by filtration. The yellow precipitate was washed with water and dried. The crude yield was 85%. The yellow precipitate was purified by recrystallizing in cyanomethane, mp 157˜160° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH:8]([F:10])[F:9])=[C:5]([Cl:11])[C:4]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([Cl:21])=[CH:14][C:13]=2[F:22])=[N:3]1.O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[CH3:1][N:2]1[C:6]([O:7][CH:8]([F:10])[F:9])=[C:5]([Cl:11])[C:4]([C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([Cl:21])=[CH:14][C:13]=2[F:22])=[N:3]1
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A stirred solution of 14.9 grams (0.042 mole) of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chloro-5-nitrophenyl)pyrazole and 20 mL of water in 200 mL of acetic acid was warmed to 50° C., and 10.0 grams (0.179 mole) of iron powder was added portionwise. Upon completion of addition the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was then poured into about 400 mL of a mixture of 1:1 ethyl acetate and water. The mixture was filtered through diatomaceous earth, and the organic layer in the filtrate was separated. The aqueous layer was washed with about 200 mL of ethyl acetate, and the wash was combined with the organic layer separated from the filtrate above. The combination was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 5% methanol in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 12.2 grams of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chloro-5-aminophenyl)pyrazole. The NMR spectrum was consistent with the proposed structure.