Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1.C(N(CC)CC)C>CO>[F:1][C:2]([F:7])([F:6])[C:3](=[N:5][NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)[NH2:4]
Reactant: COc1ccc(NN)cc1
Reactant: N=C(N)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(NN=C(N)C(F)(F)F)cc1
Reaction time: 6 h
Yield: 108.3 %

Procedure:
To a solution of trifluoroacetoamidine (4.24 g, 37.8 mmol) in methanol (20 mL), were added 4-methoxyphenylhydrazine hydrochloride (4.72 g, 27 mmol) and then triethylamine (3.77 mL, 27 mmol) at room temperature. The mixture was stirred for 6 hours. The solvent was removed under reduced pressure. 20 mL of water and 50 mL of ethyl acetate-tetrahydrofuran (9:1) were added to the residue and the organic layer was separated and the aqueous layer was extracted with 50 mL of ethyl acetate-tetrahydrofuran (9:1). A combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (6.82 g, 108.2% yield). The residue was used for the next reaction without purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:16]Br>C(O)(=O)C>[BrH:16].[Br:16][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH2:1]2)=[CH:5][C:6]=1[NH:10][C:11]1[NH:15][CH2:14][CH2:13][N:12]=1
Reactant: c1cc2c(cc1NC1=NCCN1)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Brc1cc2c(cc1NC1=NCCN1)CCC2
Reaction time: 0.08 h
Yield: 14.5 %

Procedure:
To a solution of 2-(5-Indanylamino)-2-imidazoline (100 mg, 0.497 mmol) in acetic acid (7 mL) was added a solution of bromine (153 mg, 0.957 mmol) in acetic acid (1 mL). The resulting mixture was stirred for 5 min, and the solvent was removed. The residue was flash chromatographed over silica gel (EtOAc:MeOH:Et3N=6:2:1) to afford a solid, which was recrystallized from dichloromethane/hexane to give a beige solid (25 mg, 14% yield): mp 220-221° C.; HRMS (EI) calcd. for C12H14N3Br 279.0371, obsd. 279.0383. Anal. Calcd. for C12H14N3BrH·Br2/3H2O: C, 38.63; H, 4.41; N, 11.26; Br, 42.83. Found: C, 39.10; H, 4.21; N, 10.87; Br, 42.37.
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([CH:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[C:8]([OH:10])=[O:9])[O:4][N:3]=1.O.NN.C(O)(=O)C>O>[NH2:11][C@@H:7]([C@H:5]1[O:4][N:3]=[C:2]([Br:1])[CH2:6]1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C(C1CC(Br)=NO1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CC(=O)O
Product: N[C@H](C(=O)O)[C@@H]1CC(Br)=NO1
Reaction time: 7 h
Yield: 46.8 %

Procedure:
To 710 mg (2.3 mmole) of 3-bromo-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid in 15 ml of water is added 260 μl of hydrazine hydrate and the solution stirred at 50° for 7 hours. After cooling, the solution is adjusted to pH 5.5 with acetic acid (80 μl), filtered, and the precipitate washed with 13 ml water. The filtrate is diluted with 200 ml of 2-butanol and allowed to crystallized in the refrigerator for 18 hours. Filtration yielded 240 mg of (αS,5S)-α-amino-3-bromo-4,5-dihydro-5-isoxazole acetic acid; concentrating the mother liquors approximately 15% afforded 50 mg of a second crop of (αS,5S)-α-amino-3-bromo-4,5-dihydro-5-isoxazole acetic acid (71α).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][OH:12].[CH3:13]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.O>C(Cl)Cl>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: OCCCc1ccccc1CO
Solvent: ClCCl
Solvent: O
Product: COCCCc1ccccc1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of the title A compound, 3-(2-hydroxymethyl-phenyl)-propan-1-ol (14.9 g, 90 mmol) and proton-sponge (25 g, 1.3 eq.) in methylene chloride (500 mL) is added at 0° C. under nitrogen trimethyloxonium-tetrafluoroborate (17.3 g, 117 mmol). The reaction mixture is further stirred for 5 h at room temperature before filtration. The filtrate is poured into water and the aqueous layer extracted twice with methylene chloride. The combined organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 7/3 to 1/1 and to AcOEt/MeOH 9/1) to afford the title compound: TLC, Rf (hexane/AcOEt 4/1)=0.57. MS 198.0 [M+18].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1F

Procedure:
Example 48 was prepared from bis(4-fluorophenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([O:25][CH2:26][C:27]([O:29]CC)=O)[C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:8]=[CH:9][CH:10]=1>>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([O:25][CH2:26][C:27]([NH:3][CH2:1][CH3:2])=[O:29])[C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCN
Product: CCNC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of EtNH2 in alcohol (30% by weight, 10 mL) was added (3R)-tert-butyl 3-((3-chlorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (100 mg, 0.243 mmol). The mixture was stirred at rt overnight. The mixture was concentrated under vacuum to give crude product, which was purified by preparative tlc (elution solvent: 5:1 petroleum ether/EtOAc) to give (3R)-tert-butyl 3-((3-chlorophenyl)(2-(ethylamino)-2-oxoethoxy)methyl)piperidine-1-carboxylate (57.9 mg. 58%) as a colorless oil. MS (E/Z): 411 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][N:9]=[C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11]1.[N:19](OC(C)(C)C)=[O:20].Cl>C(O)(C)(C)C>[CH3:7][O:8][N:9]=[C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]1=[N:19][OH:20]
Reactant: CON=C1COc2ccccc21
Reactant: CC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CON=C1C(=NO)Oc2ccccc21
Yield: 47.4 %

Procedure:
3.92 g (0.035 mol) of potassium tert-butoxide are dissolved in 40 ml of tert-butanol. A solution of 5.7 g (0.035 mol) of benzofuran-3-one O-methyl-oxime and 7.2 g (0.07 mol) of tert-butyl nitrite in 10 ml of tert-butanol is added to this solution. The mixture is stirred without cooling for two hours and then admixed with 20 ml of 2N aqueous hydrochloric acid. The crystalline product is filtered off, washed repeatedly with water and dried in a desiccator. 3.19 g (47.1% of theory) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime are obtained as a mixture of two stereoisomers comprising 86.33% of isomer A and 12.98% of isomer B (HPLC).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][O:17][C:18]2[C:19]([C:24](O)=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:10])[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[N:42]1[N:43]=[C:44]([NH2:47])[NH:45][CH:46]=1>ClCCl.CN(C)C=O>[N:42]1[N:43]=[C:44]([NH:47][C:24](=[O:25])[C:19]2[C:18]([O:17][CH2:16][C@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:9]([C@H:6]3[CH2:5][CH2:4][C@H:3]([C:2]([F:27])([F:1])[F:28])[CH2:8][CH2:7]3)=[O:10])=[CH:23][CH:22]=[CH:21][N:20]=2)[NH:45][CH:46]=1
Reactant: Nc1nnc[nH]1
Reactant: O=C(O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nnc[nH]1)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (30 mg, 0.08 mmol, EXAMPLE 34 Step 3) in dichloromethane (1 mL) were added oxalyl chloride (33 microL, 0.38 mmol) and a catalytic amount of N,N-dimethylformamide at room temperature. After being stirred at room temperature for 30 min, the volatile was removed under reduced pressure. The resulting residue was dissolved in toluene (1 mL). Triethyl amine (10 microL, 0.08 mmol) and 4H-1,2,4-triazol-3-amine (8 mg, 0.09 mmol) were added to the mixture. After being refluxed for 15 h, the volatile was removed by evaporation. The residual material was dissolved in dichloromethane. The organic layer was washed with aq. sodium bicarbonate and concentrated in vacuo to afford the title compound as a brown oil. The crude product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][OH:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>O>[C:20]([O:19][CH2:18][C:4]1([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC1=CCc2ccccc2C1(CO)CCC(C)C
Solvent: c1ccncc1
Solvent: O
Product: COC1=CCc2ccccc2C1(CCC(C)C)COC(C)=O
Yield: 81 %

Procedure:
A mixture of Example 179A (0.18 g, 0.7 mmol), acetic anhydride (0.2 mL), and pyridin (1 mL) was stirred at room temperature for 18 h. The solution was diluted with water (3 mL) and extracted with ethyl acetate (2×1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (hexane to 5% ethyl acetate/hexane) afforded product as a colorless oil (0.17 g, 81%). 1H NMR (300 MHz, CDCl3) δ ppm 0.66 (m, 1 H), 0.76 (dd, J=9.56, 6.62 Hz, 6 H), 0.89 (m, 1 H), 1.38 (m, 1 H), 1.61 (m, 1 H), 1.81 (s, 3 H), 1.95 (m, 1 H), 3.50 (s, 2 H), 3.58 (s, 3 H), 4.24 (d, J=10.66 Hz, 1 H), 4.42 (d, J=10.66 Hz, 1 H), 5.01 (t, J=3.49 Hz, 1 H), 7.20 (m, 4 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(Cl)Cl>[F:17][C:5]1[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[N:7][C:2]([NH:18][CH:19]2[CH2:24][CH2:23][CH:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:21][CH2:20]2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1-n1ccc2ccccc21
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCC(Nc2ncc(F)c(-n3ccc4ccccc43)n2)CC1

Procedure:
1-(2-Chloro-5-fluoro-pyrimidin-4-yl)-1H-indole (0.095 g, 0.38 mmol), N-(4-amino-cyclohexyl)-methanesulfonamide (0.17 g, 0.76 mmol), and DIEA (0.13 mL, 0.76 mmol) were stirred in NMP (2 mL) at 170° C. for 4.5 hours. The solvent was removed at 100° C. in vacuo to yield an oil which was then dissolved in DCM, washed with cold water and brine, and fried with sodium sulfate. The solvent was removed in vacuo to yield an oil. The product was purified using flash chromatography (SiO2) eluting with 1% MeOH/DCM to obtain N-[4-(5-fluoro-4-indol-1-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide as a white solid (Compound 115, 0.025 g, 16%, mp 270.0-270.5° C.).
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[N:21]([C@@H:24]1[CH2:28][NH:27][CH2:26][C@H:25]1[OH:29])=[N+:22]=[N-:23]>>[N:21]([C@@H:24]1[CH2:28][N:27]([C@H:7]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:26][C@H:25]1[OH:29])=[N+:22]=[N-:23]
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Reactant: [N-]=[N+]=N[C@@H]1CNC[C@H]1O
Product: [N-]=[N+]=N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@H]1O

Procedure:
Prepared as described in Example 9B using (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (5.06 g, 14.7 mmol) and (3R,4R)-4-azidopyrrolidin-3-ol (2.08 g, 16.2 mmol) in place of (S)-tert-butyl pyrrolidin-3-ylcarbamate in Step D (2.44 g, 52%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.O1CCOCC1.[ClH:24]>C(OCC)(=O)C>[ClH:24].[F:1][C:2]([F:17])([F:16])[CH2:3][O:4][CH:5]1[CH2:8][NH:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)(F)COC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate (350 mg, 1.37 mmol) in ethyl acetate (1.0 mL) was mixed with 4 M hydrogen chloride-1,4-dioxane solution (3.0 mL) under cooling with ice and then stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a mixture containing the title compound as a colorless oil (224 mg). The mixture was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][CH2:13][OH:14])[N:9]=[C:10](I)[C:3]=12.[CH3:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][CH2:13][OH:14])[N:9]=[C:10]([C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:25]([C:23](=[O:24])[CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[CH:17]=3)[CH2:26][CH2:27]4)[C:3]=12
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Reactant: Nc1ncnc2c1c(I)nn2CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4nn(CCO)c5ncnc(N)c45)ccc32)c1
Temperature: 120 °C

Procedure:
To a 25 mL pressure tube was charged 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol (63.8 mg, 0.209 mmol), 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (79 mg, 0.209 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8.54 mg, 0.011 mmol), and sodium bicarbonate (35.1 mg, 0.418 mmol) followed by dioxane (8 mL), and water (2 mL). The reaction was heated at 120° C. for 40 min in microwave. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 100 mL of EtOAc was added to the mixture). The EtOAc solution was concentrated to dryness, and re-dissolved with CH2Cl2/MeOH (8 mL/2 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc, Si SF15-24g, to afford a brown solid. The brown solid was further purified by recrystallization in CH3CN to give a brown solid as the title compound. LC/MS (ES) m/z=429.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.24 (s, 2H), 3.80-3.88 (m, 4H), 4.19-4.27 (m, 2H), 4.37 (t, J=5.81 Hz, 2H), 4.89 (t, J=5.68 Hz, 1H), 7.07-7.14 (m, 3H), 7.20-7.28 (m, 1H), 7.45 (d, J=8.08 Hz, 1H), 7.51 (s, 1H), 8.21 (d, J=8.34 Hz, 1H), 8.23 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][Br:11])(=[O:4])=[O:3].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:11].[CH3:1][S:2]([NH:5][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NC(=O)CCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)NC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 62.8 %

Procedure:
A solution of 2.20 g. (8.57 mmoles) of the N-methanesulfonyl-5-bromovaleramide, prepared as above, 2.24 g. (8.57 mmoles) of triphenylphosphine, and 20 ml. of acetonitrile was heated to reflux under nitrogen overnight. The solution was then concentrated by rotary evaporation and the resultant solid was triturated with hot benzene (4X). The triturated solid was recrystallized from absolute ethanol:ether to afford the white, crystalline [4-(methanesulfonylaminocarbonyl)butyl]triphenylphosphonium bromide weighing 2.80 g. (63.7% yield) melting at 190° -191°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH2:25]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][NH:22][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)[CH2:25][CH2:26]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a mixture of 4-hydroxybenzoic acid (2.5 g, 0.0182 mol), 1-hydroxybenzotriazole hydrate (3.33 g, 0.0218 mol), benzyl 4-(aminomethyl)piperidine-1-carboxylate (4.5 g, 0.0182 mol) and triethylamine (3.03 mL, 0.0218 mol) in DMF (30mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.2 g, 0.0218 mol) and the mixture allowed to stir at rt for 18 h. The mixture was quenched into water (200 mL) and extracted with ethyl acetate (200 nL). The ethyl acetate extract was washed with 10% aqueous sodium bicarbonate (100 mL), brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue chromatographed on silica using 10–20% acetone/dichloromethane to give 6.3 g of 4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester as a foam. The foam was dissolved in hot isopropyl acetate (125 mL), filtered, and allowed to cool and crystallize. The reaction volume was reduced in vacuo to 50 mL, allowed to stir overnight at rt and filtered. The resulting solid was dried in vacuo (50° C.) yielding the 4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1>>[CH3:12][C@H:13]1[NH:14][C@@H:15]([CH3:19])[CH2:16][N:17]([C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=O)[nH]1
Yield: 73.7 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (1.00 g, 6.53 mmol) reacted with cis-2,6-dimethylpiperazine (900 mg, 7.84 mmol) to give 3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (1.20 g, 74%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:30])[C:24]([NH2:29])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:30])[C:24]([NH:29][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH3:21]
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: CCOC(=O)C(N)(CC)CC
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and 2-amino-2-ethyl-butanoic acid ethyl ester (CAN 189631-96-7) as starting materials. MS (EI): m/e=425.4 [M+H]+.
Reaction SMILES: O[C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[OH:8].[C:9]1(C)C=C[CH:12]=[CH:11][CH:10]=1.[OH-].[NH4+:17]>CO.C(O)CCC.O>[NH2:17][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[O:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=c1c(O)c(O)c1=O
Reactant: Cc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Solvent: O
Product: CCCCOc1c(N)c(=O)c1=O
Reaction time: 2 h
Yield: 88 %

Procedure:
Preparation C: In a 5-Liter flask equipped with stirrer and nitrogen inlet/outlet tubes was placed 1,2-dihydroxy-1-cyclobutene-3,4-dione (400.0 g, 3.506 moles), 1-butanol (1.2 L) and toluene (800 mL). The mixture was stirred and heated under reflux with a Dean-Stark water trap until water stopped passing over (136 mL water collected, about 5.5 hours). The clear reaction mixture was heated under reflux for a further one hour, then cooled under nitrogen to 0°-5° C. The cooled stirred solution was treated dropwise at such a rate that the reaction remains at or below 10° C. (2.5 hours required) with a solution containing 14M ammonium hydroxide (240 mL, 3.37 moles), 1-butanol (960 mL) and methanol (40 mL). Stirring was continued at ambient temperature for 2 hours, then the mixture was cooled to 0°-5° C. for 1.5 hours and filtered. The product was washed with toluene (800 mL) and dried to give 492.4 g (88.0%) of the title compound; mp=165°-168° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+](C1C=C([N+]([O-])=O)C=CC=1C(NCC(OCC1C=CC=CC=1)=O)=O)([O-])=O.[Cl:46][C:47]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][C:48]=1[C:49](Cl)=[O:50]>>[Cl:46][C:47]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][C:48]=1[C:49]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:50]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])ccc1Cl)OCc1ccccc1
Yield: 82 %

Procedure:
The reaction of 2-chloro-5-nitrobenzoyl chloride (prepared from 2-chloro-5-nitrobenzoic acid, 1.0 g and SOCl2, 10 mL) with benzyl glycinate.PTS salt (1.9 g, 5.9 mmol) in the presence of triethylamine (2.0 mL, 14.88 mmol) as described in intermediate 1 gave the title compound as a colorless solid (1.42 g, 82%), mp 116-118° C. 1H NMR (400 MHz, CDCl3): δ 8.54 (1H, d, J=2.8 Hz), 8.23 (1H, dd, J=8.6, 2.6 Hz), 7.61 (1H, d, J=8.8 Hz), 7.38 (5H, br s), 6.88 (1H, br s), 5.24 (2H, s), 4.32 (2H, d, J=4.8 Hz); LC-MS (positive ion mode): m/z 349, 351 (M+H)+.