Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][NH:13][CH2:12]2)[CH3:10])=[N:6][CH:7]=1.CCN(CC)CC.[Br:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl>[Br:31][CH2:32][C:33]([N:13]1[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH:11]([CH:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH3:10])[CH2:12]1)=[O:34]
Reactant: O=C(Cl)CBr
Reactant: CC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 95.2 %

Procedure:
To a stirred solution of 5-chloro-2-{(RS)-1-[(3SR,4RS)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-pyridine (XV-B-2) 0.12 g (0.32 mmol) in CH2Cl2 (10 mL) at RT, 0.055 ml (0.38 mmol) of Et3N and 0.032 mL (0.33 mmol) of bromo-acetyl chloride were added. Stirring was continued over night and then concentrated under vacuo. The crude residue was dissolved in EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product was purified by flash chromatography (SiO2, EtOAc) to yield the title product 0.15 g (92%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: Brc1ccc(I)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Br)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
2-Bromo-5-iodopyridine (2.5 g, 8.8 mmol) was dissolved under nitrogen in 50 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (618 mg, 880 μmol, 0.1 equiv.), ethynyltrimethylsilane (950 mg, 1.34 ml, 9.6 mmol, 1.1 equiv.), triethylamine (1.78 g, 2.44 ml, 17.6 mmol, 3 equiv.) and copper(I)iodide (84 mg, 440 μmol, 0.05 equiv.) were added and the mixture was stirred for 3 hours at 50° C. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate:heptane gradient 0:100 to 15:85. The desired 2-bromo-5-trimethylsilanylethynyl-pyridine (1.95 g, 7.7 mmol, 87% yield) was obtained as a white solid, MS: m/e=254.1/256.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:45]([O:49][C:50]([NH:52][NH2:53])=[O:51])([CH3:48])([CH3:47])[CH3:46]>CN(C)C=O.O>[C:45]([O:49][C:50]([NH:52][NH:53][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([C:12]2[O:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][N:11]=2)[CH:15]=1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc(-c2cnc(-c3cccc(C(=O)O)c3)o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cnc(-c3cccc(C(=O)NNC(=O)OC(C)(C)C)c3)o2)cc1
Reaction time: 48 h
Yield: 78.2 %

Procedure:
1.5 g (5.0 mmol) of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoic acid from Preparation 4, 1.3 g (6.6 mmol) EDAC.HCl, 0.89 g (6.6 mmol) HOBT, and 0.87 g (6.6 mmol) hydrazinecarboxylic acid tert-butyl ester was dissolved in 20 mL of dimethylformamide. Stirring was continued 48 hours at room temperature. Water (60 mL) was added, and the product was extracted with 1:1 THF/EtOAc (2×). Combined the organic extracts and washed with saturated aqueous NaCl solution (3×), dried (MgSO4). Dried in a vacuum oven overnight at 70° C. to provide 1.6 g (82%) of desired product. MS: m/z (APCI, AP+) 410 [M−]+
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:7]([C:5]2[S:6][C:2]([Br:1])=[C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]=2)=[O:9])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)c(Br)s1
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2nc(-c3ccccc3)c(Br)s2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 8, step 8.5, intermediate 48.3 replacing 5-bromo-4-phenyl-thiazole-2-carboxylic acid and (S)-4-(2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester replacing intermediate 8.4.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:13][N:14]([CH3:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.[Cl-:25].[NH2:26][N+:27]1[CH:31]=[CH:30][N:29]([NH2:32])[C:28]=1[CH2:33][CH3:34].CO>C(Cl)Cl>[Cl-:25].[NH2:26][N:27]1[CH:31]=[CH:30][N+:29]([N:32]=[C:21]([CH3:22])[C:18]2[CH:19]=[CH:20][C:15]([N:14]([CH3:24])[CH3:13])=[CH:16][CH:17]=2)=[C:28]1[CH2:33][CH3:34]
Reactant: CC(=O)c1ccc(N(C)C)cc1
Reactant: CCc1n(N)cc[n+]1N
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CCc1n(N)cc[n+]1N=C(C)c1ccc(N(C)C)cc1

Procedure:
380 mg (2 mmol) of triethyloxonium tetrafluoroborate are dissolved in 15 ml of methylene chloride. 326 mg (2 mmol) of p-dimethylaminoacetophenone are added thereto at -15°. After 5 minutes there are added thereto at the same temperature 162 mg (1 mmol) of 1,3-diamino-2-ethyl-imidazolium chloride and the mixture is stirred at -10° for 1 hour and at 0° for 2 hours. After the addition of a small amount of methanol the mixture is evaporated and the residue is placed on a column loaded with 10 g of silica gel. The product is eluted with chloroform/methanol (87:13 parts by weight) and crystallized using ether. The crystallizate is dissolved in 80 ml of water, placed on a column loaded with ion exchanger Amberlite IRA 400 (chloride) and elution is carried out with water. The eluate is evaporated and the residue is crystallized from ethanol/water. There is obtained 3-amino-1-[[p-(dimethylamino)-α-methylbenzylidene]amino]-2 -ethylimidazolium chloride of melting point 223°-225°.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:12][CH:10]2[CH2:11][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:24][CH:23]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of 1-diphenylmethyl-3-azetidinol (25 mmol) in DMF (100 mL) was added at 0° C. to a suspension of NaH (60% disp.in oil, 30 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 1 h, then 4-chlorobenzylchloride (25 mmol) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate (3×50 mL), the extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography [SiO2; hexane-ethyl acetate (9:1)] to yield the product as a yellow oil (7.3 g, 80%). The material was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:16]([O:21]C)([O:19][CH3:20])(=[O:18])=[O:17]>C(OCC)C>[CH3:20][O:19][S:16]([O-:21])(=[O:18])=[O:17].[CH3:20][N+:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Reactant: COS(=O)(=O)OC
Solvent: CCOCC
Product: COS(=O)(=O)[O-]
Product: C[n+]1cccc(-c2cccc([N+](=O)[O-])c2)c1
Reaction time: 2 h
Yield: 82 %

Procedure:
3-(3-nitrophenyl)pyridine (50 g, 0.25 mol) was added portion-wise with stirring to dimethyl sulfate (125 ml). The mixture was stirred at ambient temperature for 24 hours, during which time additional dimethyl sulfate was added (2×50 ml). At the end of the reaction diethyl ether (400 ml) was added, and the mixture was stirred in the cold for 2 hours. The precipitate was filtered off and washed several times with diethyl ether. Finally, the precipitate was stirred in pyridine (100 ml) at 45° C. for 30 min. THF (250 ml) was added. Stirring was continued for additionally 30 min whereafter the product was filtered off, washed with diethyl ether and dried to yield 1-methyl-3-(3-nitrophenyl)pyridinium methyl sulfate (66.6 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1.[C:27]([OH:30])(=O)[CH3:28].[CH2:31](O)C>O.[Zn]>[CH:27]([O:30][CH:22]([CH3:21])[CH3:10])([CH3:28])[CH3:31].[Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1
Reactant: CC(=O)O
Reactant: CCO
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(F)c(Cl)cc2[nH]1
Agent: [Zn]
Solvent: O
Product: CC(C)OC(C)C
Product: NC1c2ccccc2-c2c(-c3nc4cc(F)c(Cl)cc4[nH]3)cccc21

Procedure:
The procedure used in Example 216 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, dissolve 1.1 g of 4-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 6.7 ml of ethanol and 6.7 ml of water and 6.7 ml of acetic acid, at room temperature, add 782 mg of zinc in three stages, and, between each addition, stir for approximately one to two hours. Add Celite and filter. The filtrate is concentrated under pressure. The crude product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (9/1 by volume). After formation of a paste with diisopropyl ether, in this way we obtain 860 mg of 4-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of an off-white powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: CN(OC)C(=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[CH:5]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([Mg]Br)C=CC=CC=1.CCOCC>C1COCC1>[CH3:12][C:6]1[CH:5]=[CH:4][C:9]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COc1ccc(C(=O)N(C)OC)cc1C
Reactant: O=C(O)c1ccccc1
Agent: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccccc2)ccc1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N,3-dimethyl-N,4-bis(methyloxy)benzamide (Prepared from the corresponding benzoic acid following the standard literature procedure for the formation of Weinreb amide, 6.2 g, 29.6 mmol) was dissolved in anhydrous THF (110 mL) under nitrogen and the solution was cooled to 0° C. A solution of 3 M phenyl magnesium bromide in ether (15.0 mL, 44.4 mmol) was then added drop-wise while maintaining an internal temperature of 0° C. to 5° C. The resulting mixture was stirred for 3 h at 0° C. to 5° C. then quenched with 5% aqueous HCl (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuuo to give 9.2 g of the crude 39 that was used without additional purification. 1H NMR (400 MHz, CDCl3): δ 2.13 (s, 3H), 3.92 (s, 3H), 6.91 (d, J=8.8 Hz, 1H), 7.40-7.62 (m, 5H), 7.64-7.70 (m, 1H), 7.73-7.79 (m, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:38]4[C:43]([CH:44]=O)=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=[CH:28][C:29]=3[O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:46]1[CH2:50][C:49](=[O:51])[NH:48][C:47]1=[O:52]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:38]4[C:43]([CH:44]=[C:50]5[S:46][C:47](=[O:52])[NH:48][C:49]5=[O:51])=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=[CH:28][C:29]=3[O:30][Si:31]([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccccc2C=O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccccc2C=C2SC(=O)NC2=O)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.1 %

Procedure:
A solution of toluene (10 mL), piperidine (0.04 mL), acetic acid (0.04 mL), 6-[3-(1-adamantyl)-4-(t-butyldimethylsilyloxy)phenyl]-benzaldehyde (0.473 g, 1.06 mmol) and 2,4-thiazolidinedione (0.125 mg, 1.06 mmol) was heated at reflux for 23 hours under an argon atmosphere. The resulting suspension was filtered and the solid was stirred at room temperature in 30 mL of EtOH. After 20 minutes, the solid was filtered and dried under high vacuum to afford 0.400 g (70%) of 6-[3-(1-adamantyl)-4-(t-butyldimethylsilyloxy)phenyl]-benzylidene-2,4-thiazolidinedione, mp 277–278° C. 1H NMR (300 MHz, DMSO-d6): δ 0.33 (s, 6H), 1.00 (s, 9H), 1.72 (brs, 6H), 2.01–2.09 (m, 9H), 6.89 (d, J=7.8 Hz, 1H), 7.42–7.44 (m, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.79 (s, 1H), 12.60 (brs, 1H); 13C NMR (75 MHz, DMSO-d6): ppm −3.6, 18.6, 26.1, 28.4, 36.5, 119.2, 122.5, 125.0, 125.4, 126.6, 130.5, 130.9, 131.0, 131.3, 139.0, 142.0, 154.4, 167.2, 167.6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][O:55][CH3:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][O:55][CH3:56])[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: COCCN1CCN(c2cc(OC)c(N)cc2C)CC1
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(C)c(N4CCN(CCOC)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 100 °C
Yield: 55.6 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (200 mg, 0.4 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (99 mg, 0.36 mmol) and p-toluenesulfonicacid (180 mg, 0.95 mmol) were weighed into a 20 mL vial. 2 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (150 mg, 0.2 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 8.23 (d, J=5.13 Hz, 1H), 8.04 (d, J=1.83 Hz, 1H), 7.74 (dd, J=8.43, 2.20 Hz, 1H), 7.69 (d, J=9.17 Hz, 1H), 7.49 (s, 1H), 7.41-7.47 (m, 1H), 7.34-7.41 (m, 1H), 7.26 (d, J=8.43 Hz, 1H), 7.19 (t, J=8.07 Hz, 2H), 6.95 (t, J=6.97 Hz, 1H), 6.77 (s, 1H), 6.55 (d, J=5.13 Hz, 1H), 4.26 (q, J=6.84 Hz, 2H), 3.80 (s, 3H), 3.42-3.48 (m, 2H), 3.24 (s, 3H), 2.86 (t, J=4.40 Hz, 4H), 2.50-2.61 (m, 6H), 2.14 (s, 3H), 1.43 (t, J=6.97 Hz, 3H); MS (ESI): 749 [M+H]+.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.ClC[C:18]1[CH:23]=[CH:22][C:21]([O:24]C2C=CC=CC=2)=[CH:20][CH:19]=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[O:24]([C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][CH:2]=1)[CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1cccc(Oc2ccccc2)c1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 1-chloromethyl-4-phenoxybenzene (21.5 g), a 2M ethanolic solution of sodium ethylate (50 cc) and ethyl 2-mercaptoacetate (12.2 g) in ethanol (200 cc). Ethyl (3-phenoxybenzylthio)acetate (28.8 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br.CCCCCC>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc2cc(O)ccc12
Temperature: 10 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a cooled (0° C.) solution of 6-methoxy-benzofuran-3-carboxylic acid ethyl ester (90.0 g, 408.67 mmol) in DCM (700 mL) was slowly added BBr3 (159.0 g, 634.67 mmol) in DCM (200 mL) maintaining a controlled temperature (<5° C.). The resulting mixture was stirred (10° C., 6 h). The reaction mixture was slowly poured into ice/water with vigorous stirring followed by stirring in a temperature gradient (0° C.−rt, 18 h). The solids were filtered off and the filtrate was extracted with EtOAc (2×250 mL). The solids were dissolved (required heat) with the combined organic phase. The organic phase was washed with saturated NaHCO3 (700 mL), H2O (700 mL), dried, filtered and concentrated in vacuo to provide a yellow solid. The crude solid was suspended in EtOAc:hexane (20%), stirred (24 h) and filtered to provide the title compound as a solid (75.6 g). The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography using EtOAc:hexanes (20%) to provide the title compound (2.4 g) as a white solid (93% combined yield). MS (ESI): mass calcd. for C11H10O4, 206.2; m/z found, 207.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.15 (s, 1H), 7.88 (d, J=8.5, 1H), 7.01 (s, 1H), 6.90 (dd, J=8.5, 2.3, 1H), 5.05 (s, 1H), 4.4 (q, J=7.1, 2H) 1.42 (t, J=7.2, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]2[N:12](COC)[CH:13]=[C:14]([CH3:15])[C:5]=12)[CH3:2].[Cl:19][C:20]1[C:30]([CH2:31][C:32]#N)=[CH:29][C:28]([O:34][CH3:35])=[CH:27][C:21]=1[C:22]([NH:24][CH2:25][CH3:26])=[O:23].[O-:36]CC.[Na+]>CCO>[Cl:19][C:20]1[C:30]([C:31]2[C:32](=[O:36])[N:3]([CH2:1][CH3:2])[C:4]3[C:9](=[CH:8][N:7]=[C:6]4[NH:12][CH:13]=[C:14]([CH3:15])[C:5]4=3)[CH:10]=2)=[CH:29][C:28]([O:34][CH3:35])=[CH:27][C:21]=1[C:22]([NH:24][CH2:25][CH3:26])=[O:23]
Reactant: CCNC(=O)c1cc(OC)cc(CC#N)c1Cl
Reactant: CC[O-]
Reactant: CCNc1c(C=O)cnc2c1c(C)cn2COC
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1cc(OC)cc(-c2cc3cnc4[nH]cc(C)c4c3n(CC)c2=O)c1Cl
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-ethylamino-1-methoxymethyl-3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (10.9 mg, 0.044 mmole), 2-chloro-3-cyanomethyl-N-ethyl-5-methoxy-benzamide, anhydrous EtOH (0.2 ml) and sodium ethoxide (21% in EtOH, 0.4 mL) is heated at 120° C. on a oil bath for 4 h. The reaction solution is cooled to room temperature and quenched with sat. K2CO3. The mixture is extracted with chloroform/methanol (20:1) twice (2×15 mL). The extracts is washed with brine and dried over MgSO4. After removal of solvent, the residue is treated with acetic anhydride at 120° C. for 1 h. The solvent is removed and the residue is treated with HCl (6N, 1 mL) and heated at 100° C. for 2 h. The reaction mixture is cooled to room temperature and neutralized with solid K2CO3 to PH 11 and stirred at room temperature for 30 minutes. It is extracted with chloroform and methanol (20:1) and the extracts is combined and dried over MgSO4. After removal of the solvent, the residue is purified on silica gel column (Ethyl acetate:hexane=4:1) to give desired product. MS m/z 439.1 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:23]=4[CH:41]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:42]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:23]=4[CH:41]=3)=[O:42])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]ncn1-c1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(-c2cccc(Br)c2)cnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (250 mg, 1.04 mmol) and NaH (50 mg of a 60% dispersion in mineral oil, 1.25 mmol) in DMF (3 mL) was stirred at room temperature for 30 min. To the solution was added 1,1′,1″-(chloromethanetriyl)tribenzene (305 mg, 1.09 mmol) and the mixture stirred at room temperature for 4 hr. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 then concentrated in vacu. The residue was purified by silica gel chromatography (EtOAc/Hexanes) to give 4-(3-bromophenyl)-2-(triphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) δ 7.22-7.31 (m, 15 H), 7.40-7.42 (m, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.90 (s, 1H), 8.60 (s, 1H).