Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[N:6]1([CH2:5][C:4]2[CH:3]=[C:2]([CH:14]=[CH:13][CH:12]=2)[O:1][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-3-hydroxybenzylpiperidine (9.55 g) and anhydrous potassium carbonate (13.8 g) in dimethylformamide (100 ml) was stirred at ambient temperature for 17 hours. 4-Bromobutyronitrile (5 ml) was added and the mixture stirred at ambient temperature for 24 hours. Water (10 volumes) was added and the resulting mixture extracted with ethyl acetate. The extracts were washed with water, dried and the solvent removed to leave an oil which was purified by distillation (190°-200° C./0.1 mm) or by chromatography on a column packed with an activated magnesium silicate (sold under the trade name FLORISIL) to give 4-(3-piperidinomethylphenoxy)butyronitrile as an oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[C:16]=3[CH:15]=[CH:14]2)=[CH:10][CH:9]=1.[OH-].[Na+].CN([CH:33]=[O:34])C>>[CH:33]([C:15]1[C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:27][CH:26]=2)[CH:14]=1)=[O:34]
Reactant: COC(=O)c1cccc2c1ccn2Cc1ccc(OC)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c1c(C=O)cn2Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Phosphorus oxychloride (7.74 ml, 84.6 mmol) was added slowly to ice-cold DMF (200 mL) and the resulting mixture was stirred at 0° C. for 1 h. To this mixture was added a solution of methyl 1-(4-methoxybenzyl)-1H-indole-4-carboxylate (16.6 g, 56.4 mmol) from Step A above in DMF (100 mL) and the mixture was stirred for 2 h. The reaction mixture was poured into an ice/water mixture and the pH was adjusted to 7 by adding 1 N NaOH. The compound was extracted with ethyl acetate (3×500 mL) and the combined organic layers were washed with water (4×250 mL) and brine (4×250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (ethyl acetate/hexanes: 20-40%) to afford methyl 3-formyl-1-(4-methoxybenzyl)-1H-indole-4-carboxylate (16.7 g, 93%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.48, (s, 1H), 7.99 (s, 1H), 7.85 (dd, J=10.0, 5.0 Hz, 1H), 7.55 (dd, J=10.0, 5.0 Hz, 1H), 7.30 (t, J=10.0 Hz, 1H), 7.12 (d, J=10.0 Hz, 2H), 6.86 (d, J=10.0 Hz, 2H), 5.31 (s, 2H), 3.99 (s, 3H), 3.71 (s, 3H); MS (ESI+) m/z 324 (M+H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=O)=[CH:16][CH:15]=1.[C:23]1([C@@H:29]([NH2:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:23]1([C:29](=[N:31][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH3:22])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=N[C@@H](C)c1ccc(C)cc1)c1ccccc1
Yield: 89 %

Procedure:
At first, 0.24 g (1.25 mmol) of p-toluenesulfonic acid monohydrate were added to a toluene solution (25 ml) containing 3.35 g (25 mmol) of 4-methylacetophenone (3c) as a ketone and 3.03 g (25 mmol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine, followed by heating under reflux for 24 hr and by removing water (formed as a by-product) with a Dean-Stark tube during the reaction, in order to conduct the reaction. Then, the reaction liquid after the reaction was washed with a saturated sodium hydrogencarbonate aqueous solution, followed by drying with sodium sulfate anhydride, then filtration, then concentration, and then vacuum drying, thereby obtaining as a crude product 5.66 g of (S)-N-(1-phenylethylidene)-1-(4-methylphenyl)-ethylamine ((S)-3ca, yield: 89%).
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].II.Cl>O1CCOCC1.[Zn]>[OH:8][C:2]([CH3:1])([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: CCCCCC(C)=O
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCC(C)(O)CC(=O)OCC

Procedure:
To a solution of 2-heptanone (10.1 mL) in 1,4-dioxane (150 mL) were added ethyl bromoacetate (9.6 mL), zinc (8.5 g) and iodine (3.7 g) at room temperature and the solution was sonicated. After 2 hours 1N hydrochloric acid was added dropwise to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue purified by flush column chromatography (n-hexane:ethyl acetate=15:1), to give the title compound (13.9 g) having the following physical data.
Reaction SMILES: [Si]([O:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CCO.C1COCC1>[OH:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(-c3noc(=O)[nH]3)ccc1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13.4 g of tert-butyl 4-{[tert-butyl(dimethyl)silyl]oxy}-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate in 200 mL of EtOH-THF (5.5:1) at 0° C. was added 67 ml of 1M HClaq dropwise, and the reaction mixture was stirred at r.t. for 18 h. The reaction mixture was cooled to 0° C., and the mixture was basified with NaHCO3. The mixture was concentrated in reduced pressure, and the residue was acidified with 1M HClaq. The aqueous mixture was extracted with a mixture of CHCl3-MeOH (9:1) three times, and the combined organic layers was washed with brine, dried over Na2SO4, and concentrated in reduces pressure to give the product as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[N+]=[N-])[CH3:11]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:10]([O:12][C:13]([C@@H:14]1[CH2:6][C@H:5]1[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:17])[CH3:11]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cccc(F)c1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Around-bottomed flask was charged with 3-fluorostyrene (13.0 g, 0.107 mol) in anhydrous methylene chloride (130 mL). To this mixture was added rhodium acetate dimer (1.30 g, cat amount). A solution of ethyldiazoacetate (33.28 g, 0.291 mol) in anhydrous methylene chloride (130 mL) was added to the reaction via a syringe pump over 5 h and stirred at room temperature for 1 h in darkness. The reaction mixture was filtered through a plug of celite, which was washed with water followed by brine. The organic layer was dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica, EtOAc/petroleum ether 1:9) gave rac-trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (13.0 g, 59%) as a colorless liquid sufficiently pure for the next step.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][O:11][CH3:12])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][CH:21]([F:31])[C:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][N:24]([CH3:30])[N:23]=1>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]([O:11][CH3:12])[C:27]([C:26]2[C:22]([CH:21]([F:31])[F:20])=[N:23][N:24]([CH3:30])[CH:25]=2)=[O:28])[CH3:9])=[CH:6][CH:7]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a stirred solution of N-[1-(4-Iodo-phenyl)-ethyl]-O-methyl-hydroxylamine (2.1 g, 7.57 mmol), prepared as described in example P12, in dichloromethane (25 ml) was added triethyl amine (3.15 ml, 22.68 mmol) followed by a solution of 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (1.5 g, 7.94 mmol) in dichloromethane (5 ml) slowly in ice cold condition. The reaction mixture was stirred at ambient temperature for 16 h. Reaction mixture was poured into 40 ml ice-water. Aqueous layer was extracted with dichloromethane (2×40 ml). The combined organic layer was washed with 2(N) HCl(2×20 ml) followed by saturated sodium bicarbonate (2×20 ml) and dried over sodium sulfate. Organic layer was concentrated under vacuum to give light yellow liquid. Crude was purified by chromatography to afford 2.05 g (62% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(4-iodo-phenyl)ethyl]-methoxy-amide as white solid. Mp. 72-74° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1.C(OCC)(=O)C>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:19])=[O:18]
Reactant: OCC[C@H]1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCC[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 1.00 g (0.861 mmol) of 2-[(3S)-oxolan-3-yl]ethan-1-ol in anhydrous THF (1.5 mL) are added triethyl amine (0.13 mL, 0.947 mmol) and methanesulfonyl chloride (0.07 mL, 0.947 mmol) slowly at 0° C. The reaction is stirred at room temperature for 2 h. The mixture is diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 solution (2×5 mL) and 1M aqueous HCl solution (2×5 mL). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to afford 167 mg of 2-[(3R)-oxolan-3-yl]ethyl methanesulfonate. Yield: 100%, 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.40-1.60 (1H, m), 1.70-1.87 (1H, m), 1.95-2.12 (1H, m), 2.16-2.37 (1H, m), 2.96 (3H, s), 3.32 (1H, dd, J=8.22, 7.16 Hz), 3.62-3.91 (3H, m), 4.13-4.24 (2H, m).
Reaction SMILES: [C:1]1([C:7]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[C:15]4=[C:16]([C:21]5[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:41]=[CH:40][C:39]([N:42]([C:58]2[CH:63]=[CH:62][C:61](Br)=[CH:60][CH:59]=2)[C:43]2[CH:55]=[CH:54][C:53]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:46]([CH3:57])([CH3:56])[C:45]=3[CH:44]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:36]1([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:37]=[CH:38][C:39]([N:42]([C:43]2[CH:55]=[CH:54][C:53]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:46]([CH3:57])([CH3:56])[C:45]=3[CH:44]=2)[C:58]2[CH:63]=[CH:62][C:61]([C:23]3[CH:24]=[CH:25][C:26]4[N:14]5[C:13]6[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=6[C:7]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[C:20]6[C:15]5=[C:16]([CH:17]=[CH:18][CH:19]=6)[C:21]=4[CH:22]=3)=[CH:60][CH:59]=2)=[CH:40][CH:41]=1
Reactant: CC1(C)c2ccccc2-c2ccc(N(c3ccc(Br)cc3)c3ccc(-c4ccccc4)cc3)cc21
Reactant: OB(O)c1ccc2c(c1)c1cccc3c1n2-c1ccccc1C3(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccc5c(c4)c4cccc6c4n5-c4ccccc4C6(c4ccccc4)c4ccccc4)cc3)cc21

Procedure:
85 g (190 mmol) of 8,8-diphenyl-8H-indolo[3,2,1-de]acridine-3-boronic acid, 98 g (190 mmol) of biphenyl-4-yl-(4-bromophenyl)-(9,9-dimethyl-9H-fluoren-2-yl)amine and 13 g (123 mmol) of sodium carbonate are suspended in 180 ml of toluene, 180 ml of dioxane and 60 ml of water. 3.0 mg mmol) of Pd(PPh3)4 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/isopropanol and finally sublimed in a high vacuum. The purity is 99.9%. The yield is 124 g (147 mmol), corresponding to 78% of theory.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C.C(Cl)Cl.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([N:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:29][CH2:28]4)=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(CBr)N1CCc2ccccc21
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Solvent: ClCCl
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1CCc2ccccc21

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (10 g, 45.4 mmol), K2CO3 (7.2 g, 52.5 mmol) and N-(2-bromoacetyl)indoline (12 g, 50 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The mixture was cooled and filtered. The solution was concentrated down until solid appeared. The crystals were collected: weight 12.68 g. The mother liquor was concentrated to dryness. The residues were purified further by flash chromatography to yield an additional 1.35 g. Total yield was 14.03 g. A 2 g sample was dissolved in ethanol/methylene chloride and was treated with a solution of fumaric acid (612 mg) in ethanol to yield 2.58 g, m.p. 226°-227° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.O>CN(C)C=O>[C:18]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: Cc1nc2c([N+](=O)[O-])cnn2c(Cl)c1CCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cnn2c2c1CCN2C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
In 18 ml of anhydrous dimethylformamide were dissolved 1.75 g (6.36 mmol) of 7-chloro-6-(2-chloroethyl)-5-methyl-3-nitropyrazolo[1,5-a]pyrimidine, and 0.93 g (12.72 mmol) of tert-butylamine and 1.61 g (15.94 mmol) of triethylamine were successively added to the solution, and the mixture was stirred at room temperature for 6 hours. Thereafter, the reaction mixture was poured into water and extracted with ethyl acetate (150 ml×2). The ethyl acetate layers were put together, washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=2:1) and recrystallized from ethanol to obtain 0.78 g (yield: 44.6%) of the intended product.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32](O)=[O:33])[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([CH3:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]2)[CH2:70][CH2:69]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[C:23]([NH2:30])=[C:22]([CH3:31])[CH:21]=3)[C:32](=[O:33])[N:77]3[CH2:76][CH2:75][N:74]([CH:71]4[CH2:72][CH2:73][O:68][CH2:69][CH2:70]4)[CH2:79][CH2:78]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C(F)(F)F)c1N
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 100 mg (0.19 mmol) (R)-2-(4-amino-3-methyl-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 67 mg (0.21 mmol) TBTU and 50 μL (0.36 mmol) triethylamine in 1 mL DMF was stirred for 10 min at RT. Then 40 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added and the reaction mixture was stirred for a further 20 h at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: C([O-])(=O)C.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([I+:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:26]1([CH3:37])[CH:31]=[CH:30][C:29]([S:32]([O:35]C)(=[O:34])=[O:33])=[CH:28][CH:27]=1>COC(C)(C)C>[C:26]1([CH3:37])[CH:27]=[CH:28][C:29]([S:32]([O-:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1.[C:22]([C:19]1[CH:20]=[CH:21][C:16]([I+:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Bis(p-tert-butylphenyl)iodonium acetate (467 mg; 1.0 mmol) and methyl p-toluenesulfonate (204 mg; 1.1 mmol) were suspended in t-butyl methyl ether (5 ml). The suspension was heated at 55° C.-58° C. and refluxed for 5 hours while being stirred. The reaction mixture was cooled, and formed white solid was removed through filtration. The white solid was washed with t-butyl methyl ether, and dried under vacuum, to thereby yield 521 mg of bis(p-tert-butylphenyl)iodonium p-toluenesulfonate (yield: 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[N:31]=1>N1C=CC=CC=1>[CH3:28][O:29][C:30]1[N:31]=[C:32]([N:38]2[CH2:43][CH2:42][N:41]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[C:3]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:40][CH2:39]2)[CH:33]=[C:34]([O:36][CH3:37])[N:35]=1
Reactant: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)c1
Reactant: COc1cc(N2CCNCC2)nc(OC)n1
Solvent: c1ccncc1
Product: COc1cc(N2CCN(c3nc(C(F)(F)F)nc(-c4cccc(S(N)(=O)=O)c4)c3-c3ccccc3)CC2)nc(OC)n1
Reaction time: 8 h

Procedure:
A solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide (0.1 g, 0.242 mmol) in pyridine (1.5 ml) was treated with 2,4-dimethoxy-6-piperazin-1-ylpyrimidine (0.081 g, 0.363 mmol) and the reaction mixture was stirred for 8 hours. Subsequently the reaction mixture was poured onto ice-cold water and extracted with ethyl acetate (25 ml). The organic layer was washed with brine and evaporated to furnish the title compound. 1H-NMR (CDCl3) δ: 3.39-3.41 (m, 4H), 3.51-3.52 (m, 4H), 3.87-3.88 (s, 6H), 7.07-7.09 (d, 2H), 7.20-7.26 (m, 3H), 7.30-7.32 (m, 1H), 7.47-7.61 (t, 1H), 7.64 (s, 1H), 7.82-7.87 (m, 2H). MS m/z: 601.8 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH2:47][CH2:48][O:49]S(C)(=O)=O)[CH:44]=[CH:45][CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.C1C[O:64]CC1>>[CH:48]([OH:49])=[O:64].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][N:58]3[CH2:59][CH2:60][N:55]([CH3:54])[CH2:56][CH2:57]3)[CH:42]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: CN1CCNCC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCN5CCN(C)CC5)c4)c4ccccc43)cn12
Product: O=CO

Procedure:
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and N-methylpiperazine (33 μL, 0.30 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (16 mg, 33%). LCMS (Method 5): Rt 3.54 min, m/z 745.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H, m), 1.75-1.97 (4H, m), 2.00-2.08 (1H, m), 2.11 (3H, s), 2.12-2.17 (1H, m), 2.29 (4H, br s), 2.42 (4H, br s), 2.51-2.55 (2H, m), 2.76-2.80 (2H, m), 2.90 (1H, ddd, J=12.1, 9.1, 4.1 Hz), 3.16 (1H, dt, J=11.9, 4.2 Hz), 3.28-3.34 (1H, m), 4.82 (1H, td, J=8.6, 5.6 Hz), 5.52 (1H, t, J=4.3 Hz), 6.32 (1H, s), 7.08 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.8, 2.2 Hz), 7.24-7.42 (8H, m), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.69 (1H, d, J=2.1 Hz), 8.10 (1H, s), 8.19 (1.4H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.FC(F)(F)C(O)=O>CC(O)CC.ClCCl>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:2]3[N:3]=[C:4]([O:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=4)[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=[N+]([O-])c1cccc(Oc2nc(Cl)nc3ccsc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCC(C)O
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)c4sccc4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
The compound (12.9 mmol) obtained in Step 3 was dissolved in 2-butanol (70 mL), and 4-(4-methylpiperazin-1-yl)benzeneamine (12.9 mmol) and trifluoroacetic acid (12.9 mmol) were added thereto. The mixture was stirred at 100° C. for 16 hours to complete the reaction, diluted with dichloromethane, and then washed with sat. NaHCO3 aqueous solution. The organic layer was dried with anhydrous sodium sulfate and then filtered and distilled under a reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol=20:1 (volume ratio)) to obtain the title compound (yield: 42%).