Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:24])[N:19]([OH:23])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.O[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:24])[N:19]([O:23][CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1O
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1OCCN1CCCC1

Procedure:
To a solution of (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-hydroxy-1,3-thiazolidine-2,4-dione (Example 288; 0.044 mmol), 1-(2-hydroxyethyl)pyrrolidine (1.5 equiv.) and triphenylphosphine (1.5 equiv.) in THF (5 mL) was added DIAD (1.5 equiv.) and the resultant solution was stirred overnight at rt. The mixture was then concentrated in vacuo, and the residue was purified by reverse phase HPLC (MeCN/water/formic acid) to provide (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethoxy)-1,3-thiazolidine-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[NH:6][CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])([O-])=O.[H][H]>[Pd]>[CH2:8]([CH:7]([NH:6][C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[NH2:1])[CH2:10][CH3:11])[CH3:9]
Reactant: CCC(CC)Nc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: CCC(CC)Nc1ccccc1N

Procedure:
In a 2 liter hydrogenator is placed 2.5 g. of 10% palladium on carbon catalyst, 800 ml. of absolute alcohol and 250 g. of o-nitro-N-(1-ethylpropyl) aniline. Hydrogen is introduced and the reduction is complete in about 21/2 hours. The reaction is exothermic and the temperature subsides as the reaction goes to completion. The catalyst is removed by filtration and the ethanol is evaporated to yield a nearly quantitative yield (214 g.) of product as a dark oil. A pure sample is obtained by vacuum distillation, b.p. 2.0 mm Hg=125°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([O:21][CH3:22])=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].Cl.[H][H]>CCO.[Pd]>[NH2:18][C:16]1[C:15]([O:21][CH3:22])=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[O:5])=[C:2]([F:1])[CH:17]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Yield: 100.4 %

Procedure:
To a solution of 2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)-4-nitrobenzamide (55 g, 177 mmol) in EtOH (450 mL) was added 10% Pd/C (11 g), followed by 4.4 mL of concentrated HCl. The reaction mixture was hydrogenated using a hydrogen balloon for 22 h. The solution was filtered through celite and concentrated to a minimum volume, after which solid was filtered, washed with ether. The filtrate concentrated again and trituated with EtOH and repeated several times to get out more products. The solid was combined and further dried to give total 50 g of product as light yellow powder (>98%). 1H NMR (400 MHz, DMSO-d6) δ 1.64-2.02 (m, 4 H) 2.61 (s, 3 H) 2.90 (t, J=11.0 Hz, 2 H) 3.24 (m, 2 H) 3.72-3.81 (m, 3 H) 3.84-4.03 (m, 1 H) 5.60 (s, 2 H) 6.29-6.50 (m, 1 H) 7.01 (d, J=6.8 Hz, 1 H) 7.69 (dd, J=7.3, 4.8 Hz, 1 H). [M+H] calc'd for C14H20FN3O2, 282; found 282.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.OO>O.CN(C)C=O>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]([NH2:31])=[O:2])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of potassium carbonate (96 mg, 0.69 mmol) in water (0.5 mL) was added to 2-{[6-(2,4-difluorophenyl)-2-naphthyl]sulfonyl}benzonitrile (Example 2, 138 mg, 0.34 mmol) in N,N-dimethylformamide (6 mL). Hydrogen peroxide (35 wt %, 120 μL, 1.37 mmol) was added dropwise. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with water (60 mL). The resulting precipitate was collected by filtration and recrystallised from ethyl acetate/isohexane to give the title compound (118 mg, 82%). 1H NMR (500 MHz, d6-DMSO) δ 8.68 (1H, s), 8.22 (1H, d, J=8.6 Hz), 8.16 (3H, dd, J=6.9, 15.7 Hz), 8.02 (1H, d, J=8.8 Hz), 7.98 (1H, s), 7.81 (1H, d, J=8.5 Hz), 7.75-7.69 (2H, m), 7.66 (1H, t, J=7.2 Hz), 7.60 (1H, s), 7.47 (1H, d, J=7.2 Hz), 7.45-7.39 (1H, m), 7.27-7.23 (1H, m); m/z (ES+) 407 [(M-NH2)+]
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][F:10])[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH2:9][F:10])[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: FCC(c1cccc(Br)n1)N1CCOCC1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(CF)N4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-[1-(6-bromopyridin-2-yl)-2-fluoroethyl]morpholine (36.3 mg, 0.13 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (37 mg, 0.13 mmol) as the starting materials.
Reaction SMILES: [OH:1][CH2:2]CN1C(C)(C)CCCC1(C)C.[O:14]1[CH2:30][CH:15]1[CH2:16][O:17][CH2:18][CH2:19]N1C(C)(C)CCCC1(C)C>>[CH2:18]([O:17][CH2:16][CH:15]1[O:14][CH2:30]1)[CH:19]1[O:1][CH2:2]1
Reactant: CC1(C)CCCC(C)(C)N1CCOCC1CO1
Reactant: CC1(C)CCCC(C)(C)N1CCO
Product: C(OCC1CO1)C1CO1

Procedure:
From 1-(2-hydroxyethyl)-2,2,6,6-tetramethylpiperidine: 1-(5,6-epoxy-3-oxahexyl)-2,2,6,6-tetramethylpiperidine, boiling point 88°-90° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([OH:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:3]=1.[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[OH:18][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=1)[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:4]=[CH:8]/[CH:9]([OH:18])[CH2:10][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:19][CH3:25])[N:3]=1
Reactant: Cc1ccccc1
Reactant: OCc1cccc(C(O)Cc2cccc(Br)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCCCCCCCC(O)/C=C/c1cccc(CC(O)c2cccc(CO)c2)n1

Procedure:
Under the conditions of example 24D, 96 mg of 2-bromo-6[(2RS)-2-hydroxy-2-(3-hydroxymethylphenyl)-ethyl]-pyridine and 160 mg of (1E)-1-(tri-n-butylstannyl)-1-undecen-(3RS)-3-ol in 1 ml of toluene is reacted in the presence of 1,1'-bis-(diphenylphosphino)-ferrocene-palladium(II) chloride as catalyst and worked up. The crude product is chromatographed on silica gel with hexane/0-25% ethyl acetate. 20 mg of the title compound is obtained as wine-red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1>C(OCC)(=O)C.CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:31])([F:32])[F:30])=[CH:12][N:11]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-(3-methoxy-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I5) (0.358 g, 0.572 mmol) in ethyl acetate (25 mL) and dimethylformamide (5 mL) was added 10% Pd/C (0.200 g). The mixture was evacuated and backfilled three times with hydrogen gas then stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a plug of Celite, washing with ethyl acetate then the filtrate was evaporated in vacuo and dried under high vacuum to give the title compound (I6) (0.360 g, 100%) as a viscous yellow oil; 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9 H), 3.00-3.20 (m, 8 H), 3.59 (t, 4 H, J=4.8 Hz), 3.67 (s, 3 H), 3.75 (s, 2 H), 3.90 (s, 3 H), 6.55-6.57 (m, 2 H), 7.19-7.26 (m, 4 H), 7.75 (s, 1 H), 8.26 (d, 1 H, J=9.4 Hz) and 8.50 (s, 1 H). LCMS Method B: rt 6.55 min; m/z 630.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[SH-:14].[Na+]>C(O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[S:14])[CH:3]=[CH:4][NH:5]2)=[CH:10][CH:9]=1
Reactant: [SH-]
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(=S)cc[nH]c2c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 61.7 %

Procedure:
4-Chloro-7-methoxyquinoline(965 mg, 5 mmol) and 70% sodium hydrosulfide (800 mg, 10 mmol) were added to ethanol (100 ml) and stirred at room temperature for 6 days. Ethanol was removed under reduced pressure from the reaction mixture. The residue was chromatographed by silica gel column chromatography, eluted with mixed solution of methylene chloride with methanol (16 : 1) for collection of yellow bands. The solvent was removed and the residue was added with a small amount of methylene chloride. The resulting precipitates were collected by filtration to obtain 590 mg (62%) of the titled compound. This compound was completely the same as the compound 1 obtained in the Example 1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C1(C)C=CC=CC=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>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.C(N(CC)CC)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:8][N:9]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: C#Cc1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cc2n[nH]c3ccccc23)cc1
Yield: 19.3 %

Procedure:
Into a dry reaction vessel, 10.3 g (44 mmol) (2-iodophenyl)hydrazine, 100 mL toluene, 50 mL triethylamine, 8.41 g (57.2 mmol) p-nitro phenylacetylene, 500 mg (Ph3P)2PdCl2, 250 mg cuprous iodide were respectively added, and reacted at 110° C. under protection of nitrogen for 4.5 h. It was cooled, rotate evaporated to dryness to remove the solvent, chromatographed on a column to obtain a red liquid 2.15 g (8.50 mmol), at a yield of 19.3%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30][CH3:31])=[N:16]2)=[O:11].[CH3:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([N:32]([CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:49](=[O:50])[C:48]1[CH:52]=[CH:53][C:45]([CH3:44])=[CH:46][CH:47]=1)[CH2:30][CH3:31])=[N:16]2)=[O:11]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
Triethylamine (0.011 mL, 0.079 mmol) was added to a solution of 3-benzyl-2-[1-(3-tert-butoxycarbonylamino-propylamino)-propyl]-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.013 g, 0.026 mmol) and 4-methyl-benzoyl chloride (0.01 mL, 0.079 mmol) in CH2Cl2 (0.50 mL) at 0 C. The reaction mixture was stirred at 0° C. for 4 h, quenched with saturated NaHCO3 (3 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 8/1 to 1/1 hexane/EtOAc to afford the title compound (0.015 g, 94%) as a solid: 1H NMR (CDCl3) δ 7.02–7.32 (m, 11H), 5.95 (m, 3H), 4.85 (m, 1H), 3.86 (s, 3H), 3.25 (m, 2H), 2.65 (m, 2H), 2.32 (s, 3H), 2.00 (m, 1H), 1.80 (m, 1H), 1.60 (m, 1H), 1.32 (s, 9H), 0.85 (m, 1H), 0.65 (m, 3H); MS (ESI+) 616 (M++H); HRMS (ESI+) calculated: 616.3135 (M++H). found: 616.3110 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.C([NH2:25])=O>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[N:25]=[C:11]([OH:12])[C:10]3[C:9](=[C:17]([CH3:18])[C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)c(NC(=O)c2ccc(F)cc2)c1C
Reactant: NC=O
Product: COc1ccc2c(O)nc(-c3ccc(F)cc3)nc2c1C
Yield: 83 %

Procedure:
2-(4-Fluoro-benzoylamino)-4-methoxy-3-methyl-benzoic acid (91) (830 mg, 2.7 mmol) was heated to 150° C. in formamide (20 ml) for 4 h. The excess formamide was removed by distillation. Water was added and the precipitated product was filtered of to give pure title compound (642 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.C(OCC)(=[O:30])C>>[CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:30])[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccc(I)cc3)ccc2O1
Reactant: CCOC(C)=O
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccc(I)cc3)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 21, from 3,4-dihydro-2,2-dimethyl-6(4-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-[3,4-dihydro-2,2-dimethyl-6-(4-iodobenzoyl)-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 171°-173° C. (from ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH2:10](Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: CCBr
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc(Br)cc1F
Yield: 99.3 %

Procedure:
100 g (0.524 mol) of 4-bromo-2-fluorophenol and 66.7 g (0.612 mol) of ethyl bromide were dissolved in 2 1 of ethyl methyl ketone and refluxed for 24 hours in the presence of 185 g (1.34 mol) of potassium carbonate. The solution was subsequently filtered, the filtrate was evaporated, and the crude product was filtered through silica gel with n-hexane, giving 114 g (99% of theory) of 4-bromo-1-ethoxy-2-fluorobenzene as a colourless liquid.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:32][CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: Brc1ccc(Br)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Yield: 18.2 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (3 g; 7.3 mmol) in 7 ml of dioxane was treated under nitrogen with 2,5-dibromopyridine (1.9 g; 8.1 mmol) and DIEA (1.4 ml; 8.1 mmol) and heated in a pressure tube for 2 days at 210C. Upon cooling, additional DIEA (1.4 ml) was added and heated 2 more days. Upon cooling, the reaction mixture was partitioned between ethyl acetate and 0.5N HCl. The organic phase was washed with 0.5N HCl and saturated brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography using an ethyl acetate-hexane gradient (5–60%) afforded the title compound (0.75 g; 18% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]1[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[CH2:7]2.CI.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]1[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]1)[CH:7]2[CH3:27]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1c2c(Br)cc(F)cc2CN1C1CCN(C2CCCCC2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2cc(F)cc(Br)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 7-bromo-2-(1-cyclohexylpiperidin-4-yl)-5-fluoro-2,3-dihydro-1H-isoindol-1-one (70 mg, 0.177 mmol) and methyliodide (1.1 equiv., 0.195 mmol, 0.012 mL) in anhydrous tetrahydrofuran (3.5 mL) under nitrogen at −78° C., 1M sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.2 equiv., 0.212 mL) was slowly added. The reaction mixture was stirred for 90 min and quenched by adding dropwise a 10% ammonium hydroxide solution. Dichloromethane was added, the layers were separated, and the aqueous layer was extracted twice dichloromethane. Organic layers were collected, dried and evaporated. Crude (58 mg) was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH2:21][O:22][CH3:23])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH2:21][O:22][CH3:23])=[CH:14][C:10]=1[C:11]([NH2:26])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCOCCc1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCOCCc1ccc(OCc2ccccc2)c(C(N)=O)c1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 2-benzyloxy-5-(2-methoxymethoxyethyl)benzoic acid (900 mg) in tetrahydrofuran (25 ml) was added 1,1′-carbonyldiimidazole (507 mg) at room temperature, and the mixture was stirred for 1 hour. To the reaction mixture was added 28% ammonium hydroxide (3 ml), and the resulting mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, crystallization of the residue from hexane and diethyl ether (1/1) gave 2-benzyloxy-5-(2-methoxymethoxyethyl)benzamide (700 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CI.[NH4+].[Cl-]>C1COCC1>[F:13][C:14]1[C:22]([CH3:1])=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)ccc(C(=O)O)c1F

Procedure:
To a stirred solution of diisopropylamine (1.7 g, 16.4 mmol) in THF 2.6 M solution of n-BuLi (1.1 g, 16.4 mmol) was added at −30° C. and the mixture was stirred for an hour at the same temperature. To this mixture a solution of 2,4-difluorobenzoic acid (1.0 g, 6.3 mmol) in THF was added slowly at −78° C., followed by methyl iodide (2.2 g, 15.7 mmol) and it was stirred for another 2 h at the same temperature and allowed to attain the room temperature. The reaction mixture was treated with saturated aqueous NH4Cl solution and the aqueous layer extracted with ethylacetate (3×25 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After removal of solvent, the residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give product as a white solid. Yield: 0.77 g (70%)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[NH:23][C:22]2=[O:31]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[NH:23][C:22]2=[O:31]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: O=C1NC2(CCNCC2)c2c(Cl)cccc21
Product: O=C1NC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 7-chlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1 tR=1.73, min, m/z=437
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:9])=[O:21])[N:19]=2)[CH:16]=1
Reactant: Cc1ccccc1CN
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: Cc1ccccc1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using o-tolylmethanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:16][C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Br)cc(OCc2ccccc2)c1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of 3-benzyloxy-5-bromo-phenylamine (23.50 g, 84.40 mmol) in acetone (550.0 mL) was added benzoyl isothiocyanate (18.50 mL, 93.13 mmol) and the reaction mixture was stirred at room temperature for 30 min. After the completion of the reaction (TLC monitoring), the solvent was evaporated and the residue thus obtained was washed with hexane to get the desired product (33.0 g, 89%).