Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[CH3:12][C:4]1[CH:3]=[C:2]([O:1][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Clc1ncccn1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(C)cc(Oc2ncccn2)cc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 2.15 g, 13.1 mmol), 2-chloropyrimidine (1.00 g, 8.73 mmol), copper (55.0 mg, 0.87 mmol), and potassium carbonate (3.62 g, 26.2 mmol) in 17.5 mL of DMF was stirred at 100° C. for 3.0 h. The reaction mixture was cooled to room temperature, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% EtOAc in hexanes as eluant) to give 1-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)ethanone (6-1, 1.16 g) as white solids in 55% yield: 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=4.5 Hz, 2 H), 7.05 (t, 1 H), 6.87 (s, 2 H), 2.49 (s, 3 H), 2.27 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][OH:29].Cl.[OH-].[Na+]>CO>[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20](/[C:23](=[N:28]/[OH:29])/[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=N\O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (53.5, 491 mg, 1.390 mmol) in methanol (30 mL) was added hydroxylamine hydrochloride (140 mg, 2.015 mmol), followed by hydrochloride dropwise to give a pale yellow clear solution. The reaction mixture was stirred at it overnight. LCMS showed the reaction was complete. Aqueous NaOH (1N) solution was added at 0° C. until pH 8-9. Solvent was evaporated, and the residue was purified by column chromatography to afford 410 mg (88% yield) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.21 (s, 1H), 8.97 (dd, 1H), 8.45 (d, 1H), 8.22 (d, 1H), 7.57-7.71 (m, 3H), 5.25 (q, 1H), 2.01 (d, 3H), 1.84 (s, 3H). LCMS (method A): [MH]+=369, tR=5.45 min.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([O:39][C:40](=[O:49])[C@H:41]([CH3:48])[NH:42][C:43](=[O:47])[N:44]([CH3:46])[NH2:45])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:49])[C@H:41]([CH3:48])[NH:42][C:43](=[O:47])[N:44]([CH3:46])[NH:45][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[CH3:38]
Reactant: CCOC(=O)[C@H](C)NC(=O)N(C)N
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](C)NC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of acetylalanylalanylproline (3 mmole) and N-methylmorpholine (3 mmole) in dry tetrahydrofuran (110 ml) at -20° to -25° C. is added isobutyl chloroformate (3 mmole) and stirred at -20° C. for 10 minutes. A solution of 2-azaalanylalanine ethyl ester (3 mmole) in tetrahydrofuran (15 ml) is added dropwise. The resulting mixture is allowed to warm to room temperature over a period of 1 hour and stirred overnight. The precipitate is filtered off and the filtrate is concentrated to dryness. Chromatography on silica gel (70 gm) and elution with 8% methanol in chloroform gives acetylalanylalanylprolyl-2-azaalanylalanine ethyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:24][C:25]1[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:24][C:25]1[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:27][N:26]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(C)(=O)=O)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 223.1.1) to give the title compound as a white solid. (HPLC: tR 2.31 min (Method A); M+H=498 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.87 (s, 1H), 9.01 (s, 1H), 8.41-8.38 (m, 1H), 8.18-8.11 (m, 2H), 7.98-7.93 (m, 1H), 7.91-7.88 (m, 1H), 7.62-7.59 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.18 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 44 %

Procedure:
Sulphuric acid (83%, 20 ml) was cooled in an ice-bath, and 3-chloro-4-hydroxybenzoic acid (4 g, 22 mM) stirred in. After 10 minutes, nitric acid (70%, 1.43 ml, 22 mM) was run in, and the mixture stirred at 0° for 2 hours. After pouring onto ice, the solid was filtered, and recrystallised from aqueous ethanol to give title compound as yellow crystals (2.1 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[CH:19]1([CH:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]=4[F:44])[C:36]3=[O:45])=[CH:30][CH:29]=2)[C:25](O)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:19]1([CH:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]3[CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]=4[F:44])[C:36]3=[O:45])=[CH:30][CH:29]=2)[C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=2)[CH2:5][C:6]2([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH2:7]2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Reactant: O=C(O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(CN4Cc5c(F)cccc5C4=O)cc3)C3CCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
77.5 mg (0.31 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 96 mg (0.26 mmol) of cyclopentyl{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetic acid in 1 ml of DMF. At 0° C., 136 μl (0.78 mmol) of DIEA and then, a little at a time, 119.2 mg (0.31 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 1 h. The reaction mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. This gave 146 mg (93% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:18][C@H:19]2[CH2:23][O:22][C:21]([NH2:24])=[N:20]2)CC2C=CC(OC)=CC=2)[CH:5]=[CH:6][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:18][C@H:19]2[CH2:23][O:22][C:21]([NH2:24])=[N:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(C[C@H]2COC(N)=N2)c2cccc(Cl)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: NC1=N[C@@H](CNc2cccc(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.8 %

Procedure:
To a stirred solution of (S)-4-{[(3-chloro-phenyl)-(4-methoxy-benzyl)-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine (97 mg) at r.t. in dichloromethane (10 ml) were added anisole (0.31 ml) and trifluoroacetic acid (2.74 ml). The mixture was stirred at r.t. for 48 h and was then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aq. sodium bicarbonate solution, the phases were separated, and the organic phase was dried and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient:dichloromethane->dichloromethane/methanol 85:15) to give (S)-4-[(3-chloro-phenylamino)-methyl]-4,5-dihydro-oxazol-2-ylamine (22 mg, 35%) as a white gum. MS (ISP): 228.1 ([{37Cl}M+H]+), 226.2 ([{35Cl}M+H]+)
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br-:19].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:19][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: O=c1cc(-c2ccccc2)c2ccc(O)cc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1cc(-c2ccccc2)c2ccc(Br)cc2o1

Procedure:
7-hydroxy-4-phenyl-2H-chromen-2-one, (5.07 g, 21.3 mmol) and triphenylphosphine dibromide (9.88 g, 23.4 mmol) were heated in a sand bath at 320-350° C. for 3 h. The cooled mixture was dissolved in dichloromethane, silica gel (150 g) was added and the mixture was evaporated. Column chromatography with hexane/EtOAc: 70:30, gave the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:17]=[CH:16]C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[C:3]([O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16])=[CH:4][C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: Oc1cc(F)cc(F)c1Br
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1Br
Yield: 75 %

Procedure:
Prepared in 75% yield from 2-bromo-3,5-difluorophenol following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 6.59-6.43 (m, 2H), 5.94-5.80 (m, 1H), 5.22-5.09 (m, 2H), 4.47-4.36 (m, 1H), 2.59-2.37 (m, 2H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][N:22]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1.Cl.C(OCC)(=O)C>C(OCC)C>[ClH:20].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:21]2[N:22]=[CH:23][C:24]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=3)=[CH:25][CH:26]=2)=[CH:31][CH:30]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Oc1ccc(Cl)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(Cl)cc3)nc2)cs1)C(=O)O

Procedure:
A compound obtained by an operation similar to that of Example 67-1 and using 2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 2-chloro-5-hydroxypyridine synthesized in reference to patent reference [WO9825920] as starting materials, followed by an operation similar to that of Example 68 and using 4-chlorophenylboric acid was dissolved in diethyl ether and the solution was reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [CH2:1]([N:19]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:56]([Br:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C1COCC1>[Br-:63].[CH2:56]([N+:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC[N+](CCCCCCCCCCCCCCCCCC)(CCCCCCCCCCCCCCCCCC)Cc1ccccc1
Product: [Br-]
Reaction time: 24 h

Procedure:
N-benzyl-N,N,N-trioctadecylammonium bromide is prepared according to the following process. 0.10 g (0.13 mmol) trioctadecylamine, 0.30 ml (2.5 mmol) benzyl bromide (98%, Aldrich), and 3 ml THF (certified grade, Fisher) are placed into a 10 ml round-bottomed flask. The mixture is refluxed under a dry nitrogen atmosphere with stirring for 1 day. 80 mg (65%) white solid, mp 82°-83° C., is recovered after the solvent is evaporated, and the residue is recrystallized twice in a mix of hexane and ether. IR(KBr) 2916, 2851 (C-H stretching, vvs), 1473, 1386(C-H bending, w) cm-1. 1HNMR(CDCl3) δ 7.74-7.36 (aromatic H, m, 4H), 5.19-4.76 (CH2,s, 2H), 3.69-3.12(CH2, m, 6H), 2.05-0.67 (heptadecyl groups, m, 104H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH:35][CH2:34][C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:38])[F:39])=[CH:37][CH:36]=1)=[O:7]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.2 %

Procedure:
Publicly known [e.g. De.Paulis et al, J. Med. Chem., 1022(1922)]2-methoxy-5-nitrobenzoic acid (9.00 g, 45.7 mmol) was dissolved in 450 ml of dichloromethane and, after triethylamine (8.11 ml, 58.4 mmol) and ethyl chlorocarbonate (4.70 ml, 49.3 mmol) were added, the mixture was stirred for 45 minutes at room temperature. Next, 4-trifluoromethylbenzylamine (9.59 g, 54.8 mmol) was added dropwise, which was stirred for 30 minutes at room temperature. The reaction mixture was poured into water. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to obtain 12.5 g of the aimed compound as yellow powder. Further, the filtrate was concentrated and recrystallized from ethyl acetate to obtain 2.13 g of the second crystals. Total 14.6 g (91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62]C1C=CC=CC=1C(O)=O)#[N:55].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62][C:29]1[CH:30]=[CH:31][CH:2]=[CH:3][C:4]=1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6])#[N:55]
Reactant: N#Cc1ccccc1Sc1ccccc1C(=O)O
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Sc3ccccc3C#N)nn2)cc(OC)c1OC
Yield: 80 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 2-[(2-cyanophenyl)thio]benzoic acid (217 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 2-[(2-cyanophenyl)thio]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (282 mg, 80%) as a yellow solid. MS m/z 542 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[N:9]=1)=[O:7])[CH3:4].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[C:22]([F:28])[CH:21]=1.Cl.[CH2:30]([OH:32])[CH3:31]>CN(C=O)C.O>[CH2:3]([O:5][C:6]([C:8]1([O:32][CH2:30][CH3:31])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:17])(=[O:18])[N:9]1[CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][C:22]=1[F:28])=[O:7])[CH3:4]
Reactant: CCOC(=O)C1=NS(=O)(=O)c2ccccc21
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(OCC)c2ccccc2S(=O)(=O)N1Cc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 68 %

Procedure:
Sodium hydride (0.21 g, 7.02 mmol, 80% dispersion in mineral oil) was added to a stirred, room temperature solution of (VII) (1.40 g, 5.85 mmol) and dry ethanol (0.38 mL), 6.44 mmol) in DMF (8 mL). An exotherm resulted and after 10 min, 4-bromo-2-fluorobenzyl bromide (1.72 g, 6.44 mmol) was added. After 2 h, the reaction mixture was added to an aqueous solution consisting of 10% aq. HCl (25 mL) and water (125 mL). This was extracted with ether (150 mL) and the ether extract was washed with brine (150 mL) and silica gel (25 mL) was added to it. The ether was removed and the silica adsorbate was flash chromatographed (7:3 petroleum ether: ethyl acetate) to provide the title compound as an oil (1.89 g, 68%): NMR (CDCl3, 300 MHz): d 7.89 (m, 1H, ArH), 7.70 (m, 2H, ArH), 7.55 (m, 2H, ArH), 7.26 (m, 2H, ArH), 4.60 (d, 1H, J=16.7 Hz, NCH2), 4.50 (d, 1H, J=16.7 Hz, NCH2), 4.05 (m, 2H, CO2CH2), 3.22 (m, 1H, OCH2), 2.94 (m, 1H, OCH2), 1.11 (t, 3H, CH3), 1.05 (t, 3H, CH3); IR (neat, cm-1): 1750: MS (+FAB): 472, 474 (MH+, 5%), 426, 428 (35%), 398, 400 (20%), 187, 189 (100%).
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43](CC3C=CC=CC=3)[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:6])([CH3:5])[CH3:4].I[C:54]1[C:55](C(C)C)=NN[CH:58]=1.IC1C=CC(CC2C=CNN=2)=CC=1>>[CH3:1][Si:2]([CH3:52])([O:7][C@@H:8]1[C@H:21]([O:22][Si:23]([CH3:28])([CH3:29])[C:24]([CH3:27])([CH3:25])[CH3:26])[C@@H:11]([CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:17])([CH3:18])[CH3:16])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43]([CH:54]([CH3:55])[CH3:58])[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(-c4cnn(Cc5ccccc5)c4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)c1n[nH]cc1I
Agent: Ic1ccc(Cc2cc[nH]n2)cc1
Product: CC(C)n1cc(-c2nc(N)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)cn1

Procedure:
Compound 16 was prepared in the manner of compound 11 substituting 4-iodo-(1-methylethyl)pyrazole for 4-iodo-benzylpyrazole to afford compound 16: 1H NMR(CDCl3) 0.00 (s, 3H, CH3), 0.01 (s, 3H, CH3), 0.04 (s, 3H, CH3), 0.07 (s, 3H, CH3), 0.11 (s, 3H, CH3), 0.14 (s, 3H, CH3), 0.78 (s, 9H, t-bu), 0.83 (s, 9H, t-bu), 0.91 (s, 9H, t-bu), 1.55(d, 6H, C(CH3)2), 3.8 (d, 1H), 4.05 (d, 1H), 4.08-4.15(m, 1H), 4.30-4.32 (m, 1H), 4.44-4.56 (m, 2H), 5.55(bs, 1H, D2O exchangeable), 6.05 (s, 1H), 8.05 (s, 1H), 8.10 (s, 1H), 8.2 (s, 1H)
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[C:7]([C:21]#[N:22])=[C:6]([C:23]#[N:24])[C:5]=1[S:25][C:26]([F:29])([F:28])[F:27].C(Cl)Cl.O>FC(F)(F)C(O)=O>[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:11][C:10]=2[Cl:20])[C:7]([C:21]#[N:22])=[C:6]([C:23]#[N:24])[C:5]=1[S:25]([C:26]([F:29])([F:28])[F:27])=[O:1]
Reactant: OO
Reactant: N#Cc1c(SC(F)(F)F)c(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1c(S(=O)C(F)(F)F)c(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C#N
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 33.7 %

Procedure:
Hydrogen peroxide (278 mg, 35%, 2.9 mmol) was added to solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-2,3-dicyano-4-trifluoromethylthiopyrrole (850 mg, 1.9 mmol) in trifluoroacetic acid (10 ml). The resulting solution was stirred at 20° C. for 0.75 hour. Another portion of hydrogen peroxide ( 0.97 mmol) was added and the mixture stirred at 20° C. for a further hour. The reaction mixture was poured into methylene chloride (60 ml) and water (60 ml) and the organic layer washed with water (2×), dried (sodium sulfate), concentrated and purified by chromatography on silica gel, eluting with heptane/ethyl acetate (4:1) to give the title compound as a yellow solid (293 mg, 0.64 mmol); 19F-NMR: −64.35, −75.59.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:24])=[CH:17][CH:18]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3oc4c(c3c2)CCCC4)cc1
Yield: 62.2 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), anisoyl chloride (0.91 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (25 mL) provided 4-methoxy-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.0 g). Mp 197.0-197.5° C.; Anal. Calcd. for C20H19NO3: C, 74.75; H, 5.96; N, 4.36; Found: C, 74.67; H, 5.87; N, 4.46.