Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:22]=2)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(=O)CCC1=O.O>C(#N)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:22]=2)=[C:11]([Br:27])[C:10]([C:23]([F:26])([F:24])[F:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1cc(-c2ccc3c(c2)CCCO3)n(Cc2ccccc2)n1
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1nn(Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1Br
Yield: 63 %

Procedure:
A solution 1-benzyl-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49c) (260 mg, 0.73 mmol) and N-bromosuccinimide (157 mg, 0.88 mmol) in acetonitrile (5 mL) was refluxed for 45 minutes. Water (5 mL) was added, and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organics layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 100/0 to 90/10) to provide the 1-benzyl-4-bromo-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49d) (200 mg, 0.46 mmol, 63%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CCC(=O)CC>[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: Oc1ccc(-c2cc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: BrCCOc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
A mixture of 10.5 g. (0.05 mol.) of 2-p-hydroxyphenylbenzofuran and 47 g. (0.25 mol.) of 1,2-dibromoethane in 200 ml. of 3-pentanone containing 46 g. (0.3 mol.) of potassium carbonate was heated at 100° for 12 hours. The mixture was filtered while hot and the solid remaining was washed with hot acetone. The combined filtrate and washings were concentrated to give 2-[4'-(2-bromoethoxy)phenyl]benzofuran.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([N+:12]([O-])=O)[N:5]=1)[CH:2]=[CH2:3]>C(O)C.[Pd]>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([NH2:12])=[N:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1nc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc(N)ccc1OC
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To a solution of 2-allyl-3-methoxy-6-nitropyridine (2.0 g, 10.3 mmol) in ethanol (34 mL) was added 10% palladium on carbon (219 mg, 2.06 mmol). The reaction was evacuated and back filled with hydrogen. This was repeated two more times. The reaction mixture was stirred under hydrogen at 1 atm for 16 h, then filtered through a pad of celite and the filter cake washed thoroughly with ethyl acetate. The filtrates were concentrated in vacuo and purified by chromatography (silica, 25 to 90% ethyl acetate in hexanes) to give 5-methoxy-6-propylpyridin-2-amine (1.41 g, 8.48 mmol, 82%) as an off white solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 7.09 (d, J=8.8 Hz, 1H), 6.38 (d, J=8.8 Hz, 1H), 4.28 (br. s, 2H), 3.77 (s, 3H), 2.68 (t, J=7.9 Hz, 2H), 1.69 (m, 2H), 0.99 (t, J=7.4 Hz, 3H); MS (EI/CI) m/z: 166.8 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.C(N(CC)CC)C.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)C>[CH2:16]([N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:3]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: NC1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCOCC1
Temperature: 80 °C
Yield: 83.7 %

Procedure:
Intermediate 1 (0.20 g) and triethylamine (0.55 ml) were suspended in ethanol (8 ml) and 4-aminotetrahydropyran (Intermediate 21, 0.088 g) was added. The mixture was stirred under nitrogen, heated at 80° C. for 16 h, then concentrated in vacuo. The residue was partitioned between DCM and water. The layers were separated and the organic layer was loaded directly onto an SPE cartridge (silica, 5 g) which was eluted sequentially witI; (i) DCM, (ii) DCM:Et2O (2:1), (iii) DCM:Et2O (1:1), (iv) Et2O and (v) EtOAc. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 16 (0.21 g). LCMS showed MH+=319; TRET=2.93 min.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](Cl)=[O:23])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>O1CCCC1>[OH:3][NH:2][C:22](=[O:23])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:15][CH:16]=1
Reactant: O=C(Cl)C=Cc1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.27 g, 3.88 mmol) in tetrahydrofuran (5 ml) saturated NaHCO3 solution (3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(3-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (83a) (0.27 g, 0.68 mmol) in tetrahydrofuran (3.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from acetonitrile and washed with diethyl ether affording the title compound as a white solid (0.1 g, 37%). M.p. 190-191.5° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.29 (1H, d, J=16.0 Hz); 7.16 (2H, d, J=8.0 Hz); 7.24-7.78 (8H, m); 7.86 (4H, m); 8.94 (1H, br s); 10.57 (1H, s); 10.66 (1H, br s). HPLC analysis on Zorbax SB-C18 column: impurities 4% (column size 4.6×150 mm; mobile phase acetonitrile—0.1% H3PO4F gradient from 30 to 100%; sample concentration 0.2 mg/ml; flow rate 1.0 ml/min; detector UV 254 nm). Anal. Calcd for C21H18N2O4S, %: C 63.94, H 4.60, N 7.10. Found, %: C C 63.64, H 4.45, N 7.00.
Reaction SMILES: [CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(O)([C:16]#[N:17])C.CO.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([CH:7]1[CH:11]([C:16]#[N:17])[CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(O)C#N
Reactant: CCCCCCC1=CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCC1C(=O)CCC1C#N

Procedure:
A mixture of 16,6 g of 2-n-hexyl-2-cyclopentenone (see foot note (1) under Table II) 12 g of acetone cyanhydrine (Org. Synth. Coll. Vol.2, p.7), 32 ml of methanol and 0.8 g of sodium carbonate in 12 ml of water, is heated at reflux temperature for 11/2 hours.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].C(N(CC)CC)C.Cl.[F:24][C@H:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][CH2:28][NH:27][CH2:26]1.O>CN(C=O)C>[F:24][C@H:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][CH2:28][N:27]([CH:2]2[CH2:6][CH2:5][N:4]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[C:3]2=[O:15])[CH2:26]1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(CN2CCC(N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 120 °C
Yield: 92.4 %

Procedure:
A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (200 mg, 0.75 mmol), triethylamine (0.52 mL, 3.7 mmol) and 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride (173 mg, 0.75 mmol) in DMF (3 mL) was heated to 120° C. in a microwave reactor for 1.5 h. The mixture was allowed to cool and was then mixed with 60 mL water and extracted 5 times with 40 mL of DCM. The combined organic extracts were washed with 80 mL of brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give 265 mg of 3-((3S,4S)-3-fluoro-4-(4-hydroxy-phenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of 2 diastereoisomers. LCMS (method P) RT 0.92 min m/z 383.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]([F:9])[F:8])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([N+:18]([O-])=O)[CH:12]=1.O.C(OCC)(=O)C>CO.C(O)(=O)C.[Fe]>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[N:4]=[C:5]([CH3:10])[N:6]([CH:7]([F:9])[F:8])[C:2]=2[Cl:1])=[CH:12][C:13]=1[NH2:18]
Reactant: Cc1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)c(Cl)n1C(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(Cl)c(N)c2)c(Cl)n1C(F)F
Reaction time: 3 h

Procedure:
7 g (22 mmol) of 5-chloro-4-(4-chloro-3-nitrophenyl)-1-difluoromethyl-2-methyl-1H-imidazole were dissolved in 200 ml of methanol with heating. This solution was added dropwise to a suspension of 3.6 g (65 mmol) of iron powder in 150 ml of glacial acetic acid, stirred at reflux temperature. After 3 hours, the reaction mixture was poured into 500 ml of water. A further 500 ml of ethyl acetate were added to the mixture, whereupon the iron residues were filtered off. The aqueous phase was separated off and mixed with another 500 ml of ethyl acetate. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. To remove the remaining acetic acid, the crude product was treated with 100 ml of toluene, whereupon the mixture was again concentrated to dryness. Yield: 5.7 g.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].N1C=CC=CC=1.[C:11]([C:14]1[CH:39]=[CH:38][C:17]([CH2:18][NH:19][C:20]2[C:30]3[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][C:21]=2[Cl:37])=[CH:16][CH:15]=1)(=O)[CH3:12]>C(O)C>[Cl:37][C:21]1[CH:22]=[CH:23][C:24]2[CH2:25][CH2:26][N:27]([C:31](=[O:36])[C:32]([F:35])([F:33])[F:34])[CH2:28][CH2:29][C:30]=2[C:20]=1[NH:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:11](=[N:4][O:3][CH3:2])[CH3:12])=[CH:39][CH:38]=1
Reactant: CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 82.6 %

Procedure:
Add O-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol) and pyridine (0.02 mL, 0.24 mmol) to a solution of 6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (50 mg, 0.12 mmol) in ethanol (10 mL). Heat the mixture to reflux for 1.5 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in vacuo to obtain 7-chloro-6-[4-(1-methoxyimino-ethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (45 mg, 83%). MS (ES+) m/z: 454 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:9])[CH2:7][NH:8][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC(=O)OC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
To a solution of glycine t-butyl ester (5.0 grams, 29.82 mmol) In methylene chloride (50 ml) is added triethylamine (6.65 ml, 62.63 mmol) followed by 4-methoxybenzenesulfonyl chloride (29.82 mmol, 6.2 grams). The solution is stirred for 24 hours, diluted with water and extracted with ethyl acetate. The combined extracts are dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 6:1 hexaneyl acetate) to provide (4-methoxybenzenesulfonylamino) acetic acid t-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](F)=[O:6].[NH3:12]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH2:12])=[O:6]
Reactant: N
Reactant: O=C(F)c1ccc(F)c(Br)c1
Solvent: O
Product: NC(=O)c1ccc(F)c(Br)c1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
800 g (3.6 moles) of 3-bromo-4-fluoro-benzoyl fluoride were metered into 760 g of 25% strength aqueous ammonia solution (11 moles of NH3), which had been diluted with a further 760 ml of water, at a rate such that an internal temperature of 40° to 50° C. was maintained by the weakly exothermic reaction. After stirring for a further 30 minutes, the crystalline product was isolated by filtration, washed with water and dried. 765 g (97% of theory) of 3-bromo-4-fluoro-benzoic acid amide with a melting point of 131°-133° C. were obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].O(C1C=CC(C2CCNCC2)=CC=1)C1C=CC=CC=1.ClCC(Cl)=O.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][C@H:58]2[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:65]([F:68])([F:67])[F:66])([O-:50])=[O:49]>>[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][C@H:58]2[CH2:63][CH2:62][C@H:61]([O:64][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:65]([F:66])([F:67])[F:68])([O-:50])=[O:49]
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: O=C(CCl)N1CCC(c2ccc(Oc3ccccc3)cc2)CC1
Agent: O=C(Cl)CCl
Agent: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-phenoxy-phenyl)-piperidine (also known as 2-chloro-1-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-ethanone) was prepared with a 74% yield from 4-(4-phenoxy-phenyl)-piperidine (prepared in accordance with Example 8) and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-ethanone was prepared from the 1-chloracetyl-4-(4-phenoxy-phenyl)-piperidine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (14% yield). The structure was confirmed using Protocol I-A. Calculated mass=598; observed mass=598; HPLC retention time=4.81 min.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Reactant: COC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=O)N(Cc1ccccc1)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of N-benzyl-2-nitroaniline (1.62 g, 7.1 mmol) and methyl 3-chloro-3-oxopropanoate (1.17 mg, 8.5 mmol), Et3N (1.8 g, 17.8 mmol) in 50 mL of CH2Cl2 was stirred at 80° C. for 2 days. The solvent was evaporated, and the residue was purified by combi-flash to give methyl 3-(benzyl(2-nitrophenyl)amino)-3-oxopropanoate as a yellow solid. LRMS (M+H)+: 328 m/z.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([CH2:16][S:17][CH3:18])[CH:3]=1.[CH2:19]([O:21][CH:22](OCC)OCC)[CH3:20].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9](=[CH:22][O:21][CH2:19][CH3:20])[C:10]([CH:12]2[CH2:13][CH2:14]2)=[O:11])=[C:4]([CH2:16][S:17][CH3:18])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CSCc1cc(Br)ccc1C(=O)CC(=O)C1CC1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Br)cc1CSC)C(=O)C1CC1

Procedure:
A mixture of 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropylpropan-1,3-dione [4.4 g, containing approximately 1.0 g methyl 4-bromo-2-(methylsulphenylmethyl)benzoate], triethylorthoformate (3.5 ml) and acetic anhydride (2.9 ml) was heated at reflux for three hours. The mixture was then evaporated giving an impure sample of 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione as a red oil (4.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.[F-].[K+].Cl[C:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([CH3:29])[C:20](=[O:30])[CH2:19][N:18]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>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]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]2[N:21]([CH3:29])[C:20](=[O:30])[CH2:19][N:18]=[C:17]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:23]=2[CH:24]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ncc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Yield: 75.1 %

Procedure:
As illustrated in the scheme above and following General Procedure 5, (2,4-dimethoxy-5-pyrimidinyl)boronic acid (0.939 g, 5.10 mmol), Pd2(dba)3 (0.064 g, 0.07 mmol), dry KF (0.890 g, 15.3 mmol), 5,7-dichloro-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.12 g, 4.61 mmol) and P(t-Bu)3 (0.42 mL of a 10% solution in hexanes, 0.21 mmol) were combined and heated for 20 h. After workup, purification of the crude product by silica gel column chromatography (1:3 hexanes:EtOAc) provided the title compound as a pale orange solid (1.20 g, 75%). 1H-NMR (CDCl3): δ 8.50 (s, 1H), 7.49 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 4.84 (d, J=10.8 Hz, 1H), 4.06 (s, 3H), 3.79 (s, 3H), 3.76 (d, J=10.8 Hz, 1H), 3.42 (s, 3H). MS (ESI) (M+H)+=347.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([OH:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2].[C:19](#[N:23])[CH2:20][C:21]#[N:22].C(NCC)C.O>CN(C=O)C>[NH2:23][C:19]1[O:17][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:20]=1[C:21]#[N:22]
Reactant: N#CCC#N
Reactant: CCc1ccc(C(=O)C(O)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3)oc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cool a mixture of 145 g (603 mmol) 1-(4-ethylphenyl)-2-hydroxy-2-phenylethanone and 51.8 g (784.4 mmol) malononitrile in 2.23 liters DMF to 0° C. and add 53.7 ml (518 mmol) diethylamine, with cooling. After 1 h, heat the reaction mixture to RT and stir for a further 4 h, before adding 1.5 liter water. After 30 min, pour off a large proportion of the water and replace with 750 ml of fresh water. Stir the mixture vigorously, before decanting from the sticky organic residue. Dissolve the residue in ethyl acetate, dry, and concentrate under vacuum, until the product begins to crystallize. Add 450 ml diisopropyl ether, stir and then leave to stand overnight. Filter off the crystalline precipitate with suction, wash twice with 50 ml diisopropyl ether and dry under vacuum. 98.5 g (56.6% of theor.) of the target product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=O)=O)=CC=1>>[CH3:31][CH:25]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:24][CH2:23][O:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)CC(C)(C)C)cc1
Product: COC(=O)c1cc(OCCC(C)CC(C)(C)C)ccc1O
Yield: 76 %

Procedure:
Synthesis was carried out in the same manner as in Example 1, except for replacing methyl 2,4-dihydroxybenzoate with methyl 2,5-dihydroxybenzoate and replacing 2-ethylhexyl bromide with 3,5,5-trimethylhexyl p-toluenesulfonate, to obtain methyl 5-(3,5,5-trimethylhexyloxy)-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 10) as a colorless, clear and oily substance in a yield of 76%. The analytical results are shown below. ##STR31##
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:38]=[CH:37][C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:36])[C:32]([O:34]C)=[O:33])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:36])[C:32]([OH:34])=[O:33])[CH2:29][CH2:30]3)=[CH:37][CH:38]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)N1CCC(COc2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCC3CCN(C(=O)C(=O)O)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl {4-[(4-{[4-(2-tert-butylphenyl)piperazin-1-yl}carbonyl]phenoxy)methyl]piperidin-1-yl}(oxo)acetate (0.5 g, 0.96 mmol) and 1 M sodium hydroxide solution (15 mL) in tetrahydrofuran (100 mL) and methanol (100 mL) was stirred at room temperature for 3 h. Solvent was removed and 1 M hydrochloric acid solution added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a solid (0.5 g, quant.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][C:3]=1[CH3:35].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][C:3]=1[CH3:35]
Reactant: Cc1cc(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)ccc1F
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)c(C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 55.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-3-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 0.13 mmol) obtained in step 2 and ethanesulfonamide (56 mg, 0.51 mmol), the title compound (0.041 g, 57%) was obtained.