Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.C(O)([C:23](F)([F:25])[F:24])=O.FC(F)C(O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH:7][C:6](=[O:5])[CH:23]([F:25])[F:24])[CH2:9]2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)C(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCN(c2ccc(Br)cn2)C1)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Dissolve [(R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (4.24 g, 12.43 mmol) in CH2Cl2 (10 mL) and add TFA (5 mL). Stir at RT for 1 h. Evaporate the excess reagent. Dissolve the resulting crude material in CH2Cl2 (50 mL) and cool to 0° C. Add difluoroacetic acid (1.78 g, 18.64 mmol), EDCI (3.57 g, 18.64 mmol), HOBt (2.52 g, 18.64 mmol) and Et3N (5.2 mL, 37.3 mmol). Stir the reaction at 0° C. for 30 min and at RT overnight. Dilute with CH2Cl2 (100 mL) and wash with 0.1 M NaOH (2×50 mL) and H2O (100 mL). Dry the solution with Na2SO4, filter, and concentrate. Purify the crude material, eluting with 100% EtOAc to give 1.98 g (50%) of the title compound. MS/ES m/z (79Br) 321.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][C@@H:22]3[CH2:26][O:25]C(C)(C)[O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][C@@H:22]([OH:23])[CH2:26][OH:25])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC[C@@H](CN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)O1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(C[C@@H](O)CO)CC1
Reaction time: 10 h
Yield: 89.5 %

Procedure:
A solution of 4.16 g (9.72 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-[1,4]diazepan-5-one in 35 ml of methanol and 3.8 ml of water was treated with 1.95 g of Dowex 50WX8 (activated with aqueous 25% HCl and washed neutral wit water). The reaction was stirred for 10 h at reflux temperature, cooled, evaporated, dissolved in CH2Cl2, dried over Na2SO4 and evaporated to yield 3.37 g (89%) of the title compound as light yellow foam. MS: 387.1 (MH+, Cl).
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:32])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1.CO>CC(CC)=O>[ClH:1].[CH3:32][N:8]([CH3:7])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccc(F)cc2)CC1
Solvent: CCC(C)=O
Solvent: CO
Solvent: O
Product: Cl

Procedure:
Chlorotrimethylsilane (0.118 ml) and water (8 μl) were added to a solution of the less polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-(4-fluoro-phenyl)-acetamide (300 mg, 0.8 mmol) in ethyl methyl ketone (2 ml) and a little methanol. After concentration it was possible to isolate the hydrochloride in a yield of 397 mg (quantitative) (Example 57).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:24][CH:23]=[CH:22][C:15]=2[CH:16]=[N:17][C:18]=1[N+:19]([O-])=O)[CH3:11].Cl>CCO.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:24][CH:23]=[CH:22][C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11]
Reactant: C[C@@H](Oc1c([N+](=O)[O-])ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: C[C@@H](Oc1c(N)ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
To a solution of 7-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-nitrofuro[3,2-c]pyridine (40 mg, 0.11 mmol) in EtOH (1 mL) was added Fe powder (24 mg, 0.43 mmol) and 1M HCl (aq.) (0.05 mL, 0.05 mmol). The reaction mixture was stirred at 95° C. for 20 min. After cooled down to room temperature, the reaction mixture was passed through a pad of Celite. The filtrate was concentrated in vacuo and residue was purified by preparative TLC (5% MeOH in DCM) to afford the title compound as a brown oil (25 mg, 68% yield). 1H NMR (CDCl3, 400 MHz): δ=1.86 (d, J=6.60 Hz, 3H), 4.75 (br, s, 2H), 6.55 (q, J=6.97 Hz, 1H), 6.65 (d, J=2.20 Hz, 1H), 7.04 (t, J=8.43 Hz, 1H), 7.27 (dd, J=8.80, 4.77 Hz, 1H), 7.39 (d, J=2.20 Hz, 1H), 8.05 (s, 1H). MS (ES+): m/z 341.03, 343.01 (100) [MH+]. HPLC: tR=2.77 min (ZQ3: polar—5 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](O)=[O:11].C1COCC1>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][OH:11]
Reactant: O=C(O)C1Cc2ccccc2N1
Solvent: O
Solvent: C1CCOC1
Product: OCC1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A slurry of racemic indoline-2-carboxylic acid (5.00 g) and anhydrous THF (60 mL) is cooled to 0° C. under an atmosphere of nitrogen. To this slurry is added 1.0 M borane-THF complex (100 mL) via syringe over 40 minutes. The resulting solution is allowed to warm to room temperature while stirring overnight. Water (ca. 400 mL) is slowly added to quench the reaction. The mixture is extracted with diethyl ether (400 mL). The combined organic layers are washed with saturated sodium bicarbonate solution followed by brine, dried (Na2SO4), filtered, and concentrated to afford 4.31 g (94%) of the title compound as a colorless foam. Physical characteristics: MS (ESI+) m/z 150 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].IC1C=C(C=CC=1C)C(O)=O.O=S(Cl)Cl.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][C:36]=2[C:42]([F:45])([F:44])[F:43])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:39][C:38]1[CH:40]=[CH:41][C:35]([CH2:34][N:31]2[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]2)=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)=[O:6]
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(C(=O)O)cc1I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Iodo-4-methylbenzoyl chloride (0.48 g, 1.7 mmol), prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCl2 (as previously described), was added to a solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (0.47 g, 1.7 mmol), N,N-diisopropylethylamine (0.26 g, 2.0 mmol), and a catalytic amount of DMAP in THF (10 mL). After stirring at rt for 2 h, the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to dryness and purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas), to provide 0.51 g of product as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[CH2:14]([C@H:18]1[CH2:22][O:21][CH:20]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[NH:19]1)[CH:15]([CH3:17])[CH3:16].[Cl-].[NH4+]>C1COCC1>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([C@H:20]([NH:19][C@@H:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:22][OH:21])[C:23]([F:28])([F:29])[C:24]([F:25])([F:27])[F:26])=[CH:7][CH:2]=1
Reactant: Brc1ccccc1Br
Reactant: CC(C)C[C@H]1COC(C(F)(F)C(F)(F)F)N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of dibromobenzene (9.85 g, 41.8 mmol) in 100 mL of THF was added nBuLi (16.5 mL of 2.5M hexanes solution, 41.2 mmol) giving a thick suspension. After stirring 10 min, a solution of (4S)-4-isobutyl-2-(pentafluoroethyl)-1,3-oxazolidine (3.3 g, 13 mmol) in 3 mL THF was added giving a dark brown solution. The solution was allowed to warm to room temperature, then was poured into saturated aqueous ammonium chloride and extracted with ether. Purification by silica gel chromatography (10% to 40% ethyl acetate/hexanes gradient) gave the title compound as a single diastereomer.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][CH:7]2[N:12]3[C:13](=[O:39])[CH:14]([NH:28]C(=O)OCC4C=CC=CC=4)[CH2:15][N:16]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])(=[O:19])=[O:18])[CH:11]3[CH2:10][N:9]([CH:40]([CH3:42])[CH3:41])[C:8]2=[O:43])=[CH:4][CH:3]=1.Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[NH2:28][CH:14]1[C:13](=[O:39])[N:12]2[CH:7]([CH2:6][C:5]3[CH:44]=[CH:45][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:8](=[O:43])[N:9]([CH:40]([CH3:41])[CH3:42])[CH2:10][CH:11]2[N:16]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])(=[O:19])=[O:18])[CH2:15]1
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)OCc3ccccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
A solution of 79 mg of benzyl [6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate in 2 ml of a 33% solution of HBr in glacial acetic acid is stirred for 2 h. The reaction solution is mixed with aqueous sodium carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium carbonate and concentrated under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=558.07 (calculated monoisotopic); measured value (M+H)+: 559.10.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:7]4[C:2](=[O:1])[NH:3][CH:4]=[CH:5][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:46]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(-c3ccc[nH]c3=O)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
A mixture of 2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxylic acid (102 mg, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol), 1-hydroxybenzotriazole (108 mg, 0.80 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (99 mg, 0.49 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.22 mL, 1.6 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and crystallizations from acetonitrile to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamide (69 mg, 54%) as yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.80 (d, J=7.5 Hz, 1H), 8.49 (dd, J=7.3, 2.1 Hz, 1H), 8.18 (dd, J=7.8, 0.9 Hz, 1H), 7.80 (dd, J=6.3, 2.1 Hz, 1H), 7.72 (dd, J=8.2, 0.9 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 6.51 (dd, J=7.2, 4.0 Hz, 1H), 4.42-4.36 (m, 1H), 3.57-3.50 (m, 1H), 3.33-3.24 (m, 2H), 3.08-3.01 (m, 1H), 2.99-2.94 (m, 3H), 2.25-2.20 (m, 2H), 1.84-1.80 (m, 2H), 1.65-1.58 (m, 1H); MS (ESI+) m/z 365 (M+H); HPLC>99% (AUC), tR=11.31 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:34][C:35]1[C:36]([F:43])=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O.CCOCC>O1CCCC1>[Br:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:37]([CH:38]=[CH:12][O:13][CH3:14])[C:36]=1[F:43]
Reactant: O=Cc1cccc(Br)c1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC=Cc1cccc(Br)c1F
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 31.5 mL) was added to an ice-bath cooled, stirred slurry of (methoxymethyl)triphenylphosphonium chloride (5.07 g) in tetrahydrofuran (50 mL) keeping the temperature of the reaction mixture below 10° C. The mixture was stirred for 30 min. A solution of 3-bromo-2-fluorobenzaldehyde (2 g) in THF (5+3 mL) was added dropwise and the cold bath was removed. The mixture was stirred at ambient temperature for 1.5 h. The mixture was quenched with saturated ammonium chloride solution and extracted into ethyl acetate (70 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to afford crude product. Ether (50 mL) was added and the mixture was left overnight in the fridge. The solid was filtered off and the filtrate was concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% ethyl acetate in isohexane to afford the subtitled compound (1.84 g) as a liquid. (5:3 mixture of isomers). 1H NMR (300 MHz, CDCl3) δ (a mixture of isomers) 7.98 (ddd, J=1.5, 7.1 and 8.4 Hz, 1H), 7.36-7.18 (m, 3H), 7.17 (d, J=13.1 Hz, 2H), 7.00-6.88 (m, 2H), 6.28 (d, J=7.1 Hz, 1H), 5.85 (d, J=13.1 Hz, 1H), 5.47 (d, J=7.1 Hz, 1H), 3.81 (d, J=6.5 Hz, 3H), 3.72 (d, J=6.5 Hz, 3H).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]([C@@H:9]([CH3:42])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([C:22]2[C:23]([NH:38][CH2:39][CH2:40][CH3:41])=[N:24][C:25]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:37])[NH2:36])=[CH:31][CH:30]=3)=[N:26][CH:27]=2)=[O:21])[CH:16]=[CH:17][CH:18]=1)=[O:11])[CH3:8])=[O:6].[NH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C)C=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:25]2[N:24]=[C:23]([NH:38][CH2:39][CH2:40][CH3:41])[C:22]([C:20]([NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:7]([CH3:8])[C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)[CH3:42])[CH:14]=3)=[O:21])=[CH:27][N:26]=2)=[CH:30][CH:31]=1)(=[O:37])[NH2:36]
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)/C=C/CBr)c1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)/C=C/CN2CCNCC2)c1
Reaction time: 0.67 h
Yield: 56.5 %

Procedure:
To a solution of (S,E)-N-(3-(2-(4-bromo-N-methyl-2-butenamido)propanamido)phenyl)-2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamide (3-7, 100 mg) in N,N-dimethylformamide (2 mL), piperazine (135 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour and 40 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (eluent, 85% ethyl acetate/15% methanol) to obtain (S,E)-2-((4-carbamoylphenyl)amino)-N-(3-(2-(N-methyl-4-(piperazin-1-yl)-2-butenamido)propanamido)phenyl)-4-(propylamino)pyrimidine-5-carboxamide (4-1, 57 mg) as white solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:14]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: CN1CCCC1Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
Dissolve 27.9 g of 2-benzyl-1-methylpyrrolidine in 130 ml of conc. sulfuric acid, and add 100 ml of conc. nitric acid dropwise at 0°, with stirring, to the resulting solution. Continue stirring for a further 30 minutes at room temperature. Pour the mixture into 1 liter of ice water and alkalize with sodium hydroxide solution, with cooling. Extract the thus-produced preparation 4 times with, in each case, 150 ml of diethyl ether. Dry the ether phase over sodium sulfate and concentrate it to a red oil to obtain the title compound at a yield of 33.8 g (96% of theory). The hydrogen fumarate (from isopropanol) melts at 145° to 146°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1([CH3:26])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:23]2[CH2:24][CH2:25][N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:26])[CH2:21][CH2:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
A mixture of 7.88 g (0.0356 m) of p-nitrobenzenesulfonylchloride, 6.27 g (0.0356 m) of 1-(o-tolyl)piperazine, 4.96 ml (0.0356 m) of triethylamine, and 100 ml of tetrahydrofuran is stirred at room temperature for 18 hours. The solvent is then removed in vacuo and the residue is extracted with methylene chloride/aqueous sodium bicarbonate and brine. The organic layer is filtered through sodium sulfate and taken to dryness. Crystallization from methylene chloride/Skellysolve® B hexanes gives 9.51 g of 1-[(p-nitrophenyl)sulfonyl]-4-(o-methylphenyl)piperazine of melting point 176°-177.5° C. and 1.33 g of a second crop (84%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.8 %

Procedure:
Into a suspension of methyl 6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-6-oxohexanoate (405 mg, 0.74 mmol) in THF/H2O (2/1) (15 mL) was added NaOH (1.0 N, 3.7 mL). The resulting solution was stirred at rt for 2.5 hr and quenched with HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration, washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrs gave the title compound as a yellow powder (363 mg, 91%) in 99.0% purity by HPLC (MaxPlot detection between 230 and 400 mn).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([O-:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[N:18]1([C:15]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)[O-])CCCCC1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N2CCCC2)CCCCC1

Procedure:
1-[(tert-Butoxycarbonyl)amino]cyclohexancarboxylate, pyrrolidine, 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide hydrochloride and 1-hydroxybenzotriazole were allowed to undergo the reaction at room temperature in methylene chloride. By post-treating the reaction liquid, tert-butyl [1-(pyrrolidin-1-ylcarbonyl)cyclohexyl]carbamate was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12](B(O)O)=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>O.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>[Br:8][C:4]1[CH:3]=[C:2]([C:21]2[C:15]3[S:14][C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:17]=4[C:16]=3[CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: OB(O)c1cccc2c1sc1ccccc12
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc3c2sc2ccccc23)c1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A nitrogen flushed mixture of 1,3-dibromobenzene (18.63 g, 78.92 mmol), dibenzo{b,d}thiophen-4-ylboronic acid (6.0 g, 26.3 mmol), Pd(PPh3)4 (304 mg, 0.414 mmol), toluene (200 mL) and a slurry of K2CO3 (10.9 g, 78.92 mmol) in water (20 mL) were refluxed for 23 h. After the mixture cooled to room temperature the organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by vacuum distillation (Kugelrohr) followed by flash chromatography on silica (hexane:dichloromethane) to give 4-(3-bromophenyl)dibenzo[b,d]thiophene (3.5 g 39.2%).
Reaction SMILES: [S:1]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=O)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[S:1]([NH:17][CH2:18][CH2:19][C:20]([Cl:26])=[O:22])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)O)cccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)Cl)cccc12
Temperature: 0 °C

Procedure:
970 mg(3 mmol) dansyl beta alanin were dissolved in 5 mL dried dichloromethane and stirred under argon flux at 0° C. Then 0.6 mL (6.6 mmol) oxalyl chloride was added drop wise at 0° C., and subsequently, a few drops of dried dimethylformamide were added which lead to gas development. The mixture was stirred at room temperature for 100 min. The solvents were removed by using a rotary evaporator and then the remainder was twice evaporated with dichloromethane. The crude product was used directly in the next step.
Reaction SMILES: [Cl-].[C:2]1([S+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:30])([S:26]([OH:29])(=[O:28])=[O:27])[C:23]([O-:25])=[O:24].[Na+]>>[OH:25][C:23]([C:22]([F:30])([F:21])[S:26]([O-:29])(=[O:28])=[O:27])=[O:24].[C:15]1([S+:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C([O-])C(F)(F)S(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: O=C(O)C(F)(F)S(=O)(=O)[O-]

Procedure:
Into 2036 parts of 11.2% aqueous triphenylsulfonium chloride solution, 859 parts of 17.6% aqueous sodium difluorosulfoacetate solution was added and the resultant mixture was stirred at 25° C. for about 20 hours. The mixture was filtered to obtain white solid and white solid obtained was washed with 150 parts of ion-exchanged water. 506 Parts of tert-butyl methyl ether was added to white solid obtained. The resultant mixture was stirred and filtered to obtain solid. The solid obtained was dried to obtain 246.9 parts of triphenylsulfonium hydroxycarbonyldifluoromethanesulfonate, which is called as TPS-1.