Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)(=O)C1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:18]([C:17]3[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[O:8][CH2:7][C:6]=2[CH:9]=1
Reactant: OCc1cc(Br)ccc1O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C2OCc3cc(Br)ccc3O2)cc1
Temperature: 5 °C
Yield: 69.8 %

Procedure:
An intimately ground mixture of 5-bromo-2-hydroxybenzyl alcohol (4.06 g), 4-nitrobenzaldehyde (3.93 g) and benzoic acid (0.2 g) was stirred and heated to 85° C. (±5° C.) under nitrogen for 88 hours. The clear melt which formed initially gradually solidified throughout the reaction period. The resulting solidified mass was cooled and dissolved in ethyl acetate (250 ml). The solution was then washed with 20% aqueous sodium carbonate, 20% aqueous sodium bisulphite and finally with brine. After drying over sodium sulphate, the organic phase was evaporated to yield a solid residue which was purified by briefly suspending in hot ethanol (approx. 75 ml) and cooling to 0°-5° C. The pure product was obtained as pale buff-coloured crystals (4.69 g, 70%), mp 163°-164° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([CH2:24][CH3:25])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=O)[CH3:2].Cl.[NH2:27][OH:28].Cl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([CH2:24][CH3:25])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[N:27][OH:28])[CH3:2]
Reactant: NO
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=O
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a mixture of 0.75 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde and 10 ml of pyridine was added 0.15 g of hydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.67 g (yield, 75%) of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde oxime, nD24.5 1.5278.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:31]([CH3:32])[C:27]1[CH:26]=[C:25]([O:24][C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][CH2:23][CH:14]([C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)=[O:13])[CH2:15]3)=[CH:20][CH:19]=2)[CH:30]=[CH:29][N:28]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CNc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of N-(3-tert-butylphenyl)-7-{[2-(methylamino)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (337 mg, 0.78 mmol) in THF (8 mL) was added TEA (0.219 mL, 1.57 mmol). The reaction mixture was cooled to 0° C. and acetyl chloride (0.062 mL, 0.86 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 hr. during which time further portions of TEA (0.219 mL, 1.57 mmol) and acetyl chloride (0.62 mL, 0.86 mmol) were added. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography. The product was further purified by HPLC (250 mm C18 column) eluting with 40% A/60% B to 100%/0% B (25 min gradient) (A=99/1 H2O in AcCN, 0.1% FA, B=95/5 AcCN/H2O, 0.1% FA). The product was dissolved in DCM and MeOH and 2M HCl-Et2O solution was added. The solvents were evaporated to provide 7-({2-[acetyl(methyl)amino]pyridin-4-yl}oxy)-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-395 as the HCl salt (22 mg, 5.4%). 1H NMR (300 MHz, d6-DMSO, HCOOH Salt) δ: 9.94 (s, 1H), 8.31 (d, 1H), 7.63 (t, 1H), 7.50 (d, 1H), 7.24-7.18 (m, 2H), 7.10-7.05 (m, 2H), 6.76 (dd, 3H), 3.24 (s, 3H), 2.95-2.71 (m, 5H), 2.13-1.99 (m, 4H), 1.85-1.72 (m, 1H), and 1.26 (s, 9H). LCMS: (FA) ES+470.2, ES−472.9
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=O)[NH:30][CH:31]=2)=[O:26])[CH2:19]1>C(O)C.N1CCCCC1>[CH3:24][C@H:22]1[NH:23][C@@H:18]([CH3:17])[CH2:19][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:11][C:10]3=[O:16])[NH:30][CH:31]=2)=[O:26])[CH2:21]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.5 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (21.5 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 6 h
Yield: 63.3 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (50 g, 289.74 mmol) in AcOH (200 ml) was added NIS (63 g, 280.02 mmol) with stirring overnight at room temperature. Then the solids were collected by filtration and washed with water (50 ml). The solid was dried in an oven under reduced pressure to afford 5-chloro-4-iodo-2-nitroaniline as a yellow solid (70 g, 81%). Next, to a solution of 5-chloro-4-iodo-2-nitroaniline (15 g, 50.26 mmol) in dioxane (200 ml) and water (20 ml) was added (4-chlorophenyl)boronic acid (15.7 g, 100.40 mmol), K3PO4 (21.2 g, 99.87 mmol) and Pd(PPh3)4 (3 g, 2.60 mmol) with stirring for 6 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to afford 5-chloro-4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (9 g, 63%). To a solution of 5-chloro-4-(4-chlorophenyl)-2-nitroaniline (12 g, 42.39 mmol) in ethanol (150 ml) was added hydrogen chloride (conc, 10 ml) to this was followed by the addition of Zn powder (16.6 g, 253.34 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. Then the resulting mixture was concentrated under vacuum, dissolved in water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (8.7 g, 81%). Finally, a solution of 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine (7 g, 27.65 mmol) in heptafluorobutanoic acid (70 ml) was stirred for 1.5 h at 120° C. Then the mixture was poured into water (200 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford 5-chloro-6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as an off-white solid (7.3977 g, 62%).
Reaction SMILES: [C:1]1([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[N+]([C:24]([CH2:51][CH2:52][CH2:53][CH3:54])=[CH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[C:39]([N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])([O-])=O.C(O)(C(F)(F)F)=O>C1COCC1>[C:33]([O:32][C:30]([C:29]1[CH:37]=[CH:38][C:26]([C:25]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:24]=2[CH2:51][CH2:52][CH2:53][CH3:54])=[C:27]([C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[CH:28]=1)=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a solution of (E)-ethyl 2-(2-phenylhydrazono)acetate (31 mg, 0.16 mmol) in THF (1 mL) at −78° C. was added potassium tert-butoxide (0.161 mL, 0.161 mmol). After stirring at −78° C. for 15 min, a solution of tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (75 mg, 0.161 mmol) in THF (1.0 mL) was added. After stirring at −78° C. for 15 min, TFA (0.024 mL, 0.323 mmol) was added and the reaction mixture became colorless. The reaction mixture was stirred at −78° C. for 2 h and was then allowed to warm to room temperature and stirred at room temperature for 30 min. The reaction mixture was quenched with sat. aq. sodium bicarbonate solution and then extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-40% EtOAc/hexanes) to give the title compound (33 mg, 34%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.09 (dd, J=8, 2 Hz, 1H), 8.05-8.03 (m, 1H), 7.49-7.37 (m, 6H), 7.26-6.81 (m, 4H), 5.02-4.98 (m, 1H), 4.47-4.38 (m, 1H), 4.32-4.27 (m, 2H), 4.16-3.98 (m, 1H), 3.58-3.40 (m, 1H), 2.82-2.51 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.20 (t, J=8 Hz, 1.5H), 1.47-0.91 (m, 4H), 0.60-0.56 (m, 3H); MS(ESI+) m/z 608.3 (M+H)+.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].Cl.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:13][N:14]=[N:15]2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([NH:5][CH2:4][CH2:3][Cl:2])(=[O:26])=[O:27])=[CH:23][CH:24]=3)=[CH:13][N:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: NCCCl
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Agent: Cl
Product: O=S(=O)(NCCCl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1

Procedure:
This compound is prepared in a similar manner to the procedure of Example 10 using equimolar quantities of 2-chloroethylamine hydrochloride instead of 3-chloropropylamine hydrochloride and 4-(7-chloro-4-cinnolinylamino)benzenesulphonyl chloride hydrochloride instead of 4-(7-chloro-4-quinolinylamino) benzenesulphonyl chloride.
Reaction SMILES: Cl.[F:2][C@H:3]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=2)[C:20]1=[O:33].CCN(C(C)C)C(C)C>CN(C=O)C>[F:2][C@H:3]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][N:5]([CH:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=3)[C:20]2=[O:33])[CH2:4]1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Reactant: COc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@H]2F)cc1F
Temperature: 120 °C
Yield: 126.1 %

Procedure:
A mixture of (3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride (30 mg, 0.11 mmol, from step G), 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.19 mmol, intermediate 6,) and DIPEA (0.02 mL, 0.11 mmol) in DMF (3 mL) was heated to 120° C. for 90 min in a microwave reactor. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure to obtain 60 mg of 3-((3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one (diastereomeric pair), which was used in the next step without purification. LCMS (Method P) RT=1.12 min, m/z 433 (M+H+).
Reaction SMILES: N(N=[N+]=[N-])[C@H:2](C(N[C@H](C(N=[N+]=[N-])=O)CCCNC(N)=O)=O)C(C)C.N(N=[N+]=[N-])[C@H](C(N[C@H](C(N=[N+]=[N-])=O)CCCCN)=O)CC1C=CC=CC=1.[O:51]=[C:52]1[O:58][C@H:57]([C@H:59]([CH2:61]O)[OH:60])[C:55](O)=[C:53]1O>CN(C=O)C>[CH3:61][CH:59]([OH:60])[CH2:57][O:58][C:52]([C:53]([CH3:55])=[CH2:2])=[O:51]
Reactant: CC(C)[C@H](NN=[N+]=[N-])C(=O)N[C@@H](CCCNC(N)=O)C(=O)N=[N+]=[N-]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [N-]=[N+]=NN[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)N=[N+]=[N-]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC(C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The copolymer alkyne-P(HPMA-DTX-Gem)-alkyne and N3-Val-Cit-N3 or N3-Phe-Lys-N3 will be dissolved in degassed solution of L-ascorbic acid (0.5×) in DMF. Under nitrogen atmosphere, CuBr (0.5×) solution in DMF will be added. The reaction mixture will be kept stirring for 48 h at room temperature. The polymer will be precipitated into acetone and purified by dialysis against 10 mM EDTA solution, then in water to remove copper salts, and then freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:11]([CH3:12])=[CH:10][C:8]([NH2:9])=[C:7]([CH3:13])[C:6]=1[Cl:14].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1.CCCCCC>[Cl:14][C:6]1[C:7]([CH3:13])=[C:8]([NH:9][C:26]([NH:25][C:23](=[O:24])[C:22]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:21]=2[F:20])=[O:27])[CH:10]=[C:11]([CH3:12])[C:5]=1[O:4][C:3]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:2]=1[CH3:1]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Cc1ccc(Oc2c(C)cc(N)c(C)c2Cl)c(C)c1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(Oc2c(C)cc(NC(=O)NC(=O)c3c(F)cccc3F)c(C)c2Cl)c(C)c1
Temperature: 50 °C

Procedure:
Into a solution of 4-(2,4-dimethylphenoxy)-2,5-dimethyl-3-chloroaniline (1.75 grams, 6.3 mmol) prepared in Part B in 7 milliliters of toluene, which solution was warmed to a temperature of 50° C., was added 1.14 grams (6.2 mmol) of 2,6-difluorobenzoyl isocyanate in 1.5 milliliters of toluene. The reaction mixture was heated to a temperature of 90° C. and maintained at this temperature for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with 20 milliliters of hexane and then cooled in an ice bath. A precipitate formed which was collected by filtration and washed with a cold solution of 50% hexane in toluene. After vacuum drying, a white solid (1.26 grams) which was identified as 1-[3-chloro-4-(2,4-dimethylphenoxy)-2,5-dimethylphenyl]-3-(2,6-difluorobenzoyl)urea was obtained having a melting point of 183° C.-185° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:33](=[O:35])[C:32]3[CH:36]=[CH:37][C:29]([F:28])=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=3)[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(F)c(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 4-fluoro-3-trifluoromethylbenzoic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1>CO>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:2]3[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[CH:21]=2)[CH:17]=[N:18]1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(C(=O)O)c(Nc2ccc3cn[nH]c3c2)n1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To the solution of 2-chloro-6-methylnicotinic acid 10 g and 6-aminoindazole 8.6 g in methanol 100 ml was added pyridine 9.5 ml, and then the solution was refluxed for 3 days. The reaction mixture was cooled, added H20 30 ml slowly at 20° C., and then stirred for 2 hr. The reaction mixture was filtered and the obtained solid was washed with methaol 20 ml. The desired compound (13.3 g, yield 85%) was obtained by drying of the solid product at 40˜50° C. in vacuo.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]4[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[N:29]4)[CH2:22][CH2:21]3)[S:18][CH:19]=2)[CH2:11]1)(=O)[CH3:2].[NH2:39][OH:40].O>C(O)C>[OH:40][N:39]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:38])[CH2:27][N:28]4[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:36])([F:37])[F:35])=[N:29]4)[CH2:24][CH2:25]3)[S:18][CH:19]=2)[CH2:11]1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)=NO1
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (150 mg) in ethanol (5 ml) was added dropwise hydroxylamine (50% in water, 4 eq.) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave 1-[4-(4-{5-[2-(N-hydroxyethanimidoyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (33 mg).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][CH2:49][CH2:50][NH:51][CH2:52][CH2:53][O:54][CH3:55]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:51]([CH2:52][CH2:53][O:54][CH3:55])[CH2:50][CH2:49][O:48][CH3:47])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCNCCOC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CCOC)CCOC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with bis-(2-methoxy-ethyl)-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C42H56Cl2N5O5 [(M+H)+] 780.3653, observed 780.3657.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[C:18]([C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C)ccc1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1C(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a N,N-dimethylformamide (8.5 mL) solution of methyl 2-bromo-5-methylbenzoate (752 mg), tributyl(1-ethoxyethenyl)stannane (1.22 mL) and bis(triphenylphosphine)palladium(II) dichloride (115.1 mg) were added, and the resultant was stirred at 100° C. for 1 hour. The reaction solution was allowed to cool to room temperature and then filtered through Celite, and the filtrate was concentrated under reduced pressure. Acetone (10 mL) and a 1 mol/L aqueous hydrochloric acid solution (3.0 mL) were added to the obtained residue, and the resultant was stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction operation twice using chloroform. Organic layers were separated from aqueous layers using a phase separator. The organic layers were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=86/14→65/35) to obtain the title compound (0.49 g) as a pale yellow oil.