Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[C:4]2[CH2:3]1.[N:21]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([N:19]=[N+:20]=[N-:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)NN)ncn2-c2ccccc2C1=O
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1Cc2c(C(=O)N=[N+]=[N-])ncn2-c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A solution of 19 g (70 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide in 60 ml of water and 150 ml of glacial acetic acid is treated dropwise at 0° to 5° with a solution of 16.5 g of sodium nitrite in 30 ml of water. The white suspension is subsequently stirred in an ice-bath for 1 hour and cautiously poured into 150 g of sodium carbonate in 400 ml of water. The precipitated material is filtered off under suction, washed with water and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid azide which decomposes at 160°.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:11]=2[CH2:12][N:13]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[N:15]=[N:16][N:17]([CH3:19])[N:18]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.BrC[CH2:56][O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]>CC1CCCO1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([C:10]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][C:11]=2[CH2:12][N:13]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[N:15]=[N:16][N:17]([CH2:19][CH2:56][O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[N:18]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO[Si](C)(C)C(C)(C)C)n2)CCCCCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (51 mg; 0.086 mmol) in 2-methyltetrahydrofuran (1.0 mL) was added sodium carbonate (38 mg; 0.358 mmol), N,N-dimethylformamide (0.4 mL) and (2-bromoethoxy)-tert-butyldimethylsilane (100 mg; 0.418 mmol). Reaction was stirred for 16 hours at 60° C. The reaction was diluted with ethyl acetate, washed twice with water and then brine. The organic was dried over sodium sulfate and concentrated in vacuo. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-35% ethyl acetate in heptane) to give 45 mg (70% yield) of a colorless gum. 1H NMR (400 MHz CDCl3) δ ppm 7.77 (s, 1H), 7.73 (s, 2H), 7.47 (d, J=9.96 Hz, 2H), 7.41 (d, J=8.30 Hz, 1H), 5.11 (s, 2H), 4.80 (s, 2H), 4.55 (t, J=5.39 Hz 2H), 4.08 (t, J=5.39 Hz, 2H), 2.94 (s, 3H), 2.12 (m, 2H), 1.98 (m, 2H), 1.8-1.45 (m, 8H), 0.82 (s, 9H), −0.07 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21]([OH:23])=O)=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([NH:47][C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:11][CH2:12][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:14][CH2:15]3)=[O:9])[N:6]=2)=[O:23])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 644.3 (MH+).
Reaction SMILES: ClCCl.[O:4]=[C:5]1[N:9]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[NH:6]1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O>[O:4]=[C:5]1[N:9]([CH2:10][CH2:11][CH2:12][C:13]([O:15][Cl:23])=[O:14])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[NH:6]1
Reactant: O=C(O)CCCn1c(=O)[nH]c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCCn1c(=O)[nH]c2ccccc21)OCl
Temperature: 10 °C

Procedure:
Dichloromethane (3772 L) and then 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (525 kg; 2.4 kmol) were charged to a stirred-tank reactor, followed by N,N-dimethylformamide (21 L). The resulting mixture was cooled to 10° C. Afterward, oxalyl chloride (326.8 kg)) was dosed at 10-15° C. over 2-3 hours while stirring. The resulting mixture was then stirred at 15-20° C. for an additional 1-3 hours. All the above steps were conducted under a N2 atmosphere. Conversion was checked by in-process control (“IPC”).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.Cl[Si:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][Si:21](Cl)([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]1[Si:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][Si:18]1([CH3:26])[CH3:25]
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: NCc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si]1(C)CC[Si](C)(C)N1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The conversion of Polymer 1 into Polymer 2 was preceded by the preparation of 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine. 3-Bromobenzylamine hydrochloride (25.0 g, 112.3 mmol) was converted to the free base by neutralization with sodium hydroxide and extraction into methylene chloride. Drying and solvent removal resulted in 20.3 g of a brown liquid which was used as such. To the above 3-bromobenzylamine (20.3 g, 109 mmol), in a round bottom flask equipped with a condenser and under argon atmosphere, was added 150 mL of methylene chloride and 30.3 mL (217 mmol) of triethylamine. To this stirred mixture cooled with an ice bath was added slowly 109 mL (109 mmol) of 1 M 1,2-bis(chlorodimethylsilyl)ethane dissolved in methylene chloride. During the addition, considerable precipitate formed. The ice-bath was removed and the mixture was stirred for another 6.5 h at room temperature. The white solid was removed by filtration and washed with methylene chloride (2×30 mL). The filtrate was evaporated using a rotary evaporator resulting in further precipitate formation. Hexanes (100 mL) were added to this mixture. The solid was removed by filtration and washed with hexanes (2×20 mL). After hexane removal from the filtrate, a yellowish liquid was obtained which was distilled to yield 29.0 g (82% yield) of light yellowish liquid (bp. 93-5° C./0.05 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:5]=[CH:4][C:3]=2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:35])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CCl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a suspension of amine 4 (0.45 g, 1.55 mmol) in DCM (6.84 mL), cooled to −20° C., was added triethylamine (0.65 mL, 4.65 mmol) followed by a solution of 4-(chloromethyl)benzoyl chloride 73 (0.322 g, 1.71 mmol) in DCM (2.28 mL) via canula. The cold bath was then removed and the reaction mixture was stirred at room temperature for 1 h, washed with saturated NH4Cl, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude material was recrystallized from 30% AcOEt in hexane to give title compound 74 (0.431 g, 63% yield).
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[C:14]=2[C:18](=[O:32])[NH:19][CH2:20][C:21]2([OH:31])[CH2:26][CH2:25][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[Cl:33][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:34])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:19][CH2:20][C:21]1([OH:31])[CH2:26][CH2:25][CH:24]([C:27]([F:28])([F:30])[F:29])[CH2:23][CH2:22]1)=[O:32]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(C(=O)NCC3(O)CCC(C(F)(F)F)CC3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](CO)n1ccc2c(C(=O)NCC3(O)CCC(C(F)(F)F)CC3)c(Cl)ccc2c1=O

Procedure:
A mixture of (R)-2-(6-chloro-5-((1-hydroxy-4-(trifluoromethyl)cyclohexyl)methylcarbamoyl)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (76 mg, 0.00014 mol) and potassium carbonate (20 mg, 0.0001 mol) was stirred in methanol (6 mL, 0.1 mol) at room temperature ) at room temperature for 1 hour and concentrated. The residue was purified by reverse phase preparative HPLC to afford a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12](=[O:14])[CH3:13])[C:5]=2[O:4][CH2:3][CH2:2]1.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:7]1[C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CC(=O)Nc1cccc2c1OCCO2
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(Br)c2c1OCCO2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
To a solution of compound 8C (0.80 g, 4.15 mmol) in chloroform (2.4 mL) cooled to −20° C. was slowly added a solution of bromine (0.22 mL, 4.35 mmol) in chloroform (1 mL) so that the reaction temperature was maintained below −10° C. The reaction was stirred at 0° C. for 5 min, and then quenched immediately with water. The mixture was extracted with CH2Cl2 (3×), the combined extracts washed with saturated NaHCO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with CH2Cl2 to afford the title compound (0.98 g).
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[C:30]([O:38][CH2:39]Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:39][O:38][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCCl)c1ccccc1
Reactant: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1)c1ccccc1

Procedure:
Following the procedure similar to that of Example 45 but using 12.8 g. of 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 20 g. of potassium bicarbonate, 10 ml. of chloromethyl benzoate in 50 ml. of dry dimethylformamide there was obtained, after filtration of the ether extract through silica gel followed by combination of those fractions showing only one identical spot on thin layer chromotography and evaporation to dryness under reduced pressure, 14 g. of the title compound; m.p. 84°-86°C. (methyl alcohol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccccc1-c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3cccnc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-Amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 3.4 mmol) and 2-pyrid-3-yl benzoic acid (0.70 g, 3.7 mmol) in DMF (10 mL) was added HATU (1.42 g, 3.7 mmol) and diisopropylamine (0.65 mL, 3.7 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (4×50 mL). The organic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure. Chromatography of the resulting residue (SiO2: EtOAc:Hex) yielded 4-[2-fluoro-4-(2-pyridin-3-yl-benzoylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester which was further dissolved in MeOH (20 mL) and 4N HCl in dioxanes. After stirring for 5 h, the reaction mixture was concentrated down, neutralized with 1N NaOH, and extracted with EtOAc (3×75mL). The organic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH:17]1[C:22](=[C:23]=[O:24])[CH:21]=[CH:20][C:19]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:18]1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:17]1[CH:18]=[C:19]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:20]=[CH:21][C:22]=1[CH:23]([OH:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCNC1=CC(c2ccc(Cl)cc2Cl)C(=C=O)C=C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1ccc(C(O)c2ccccc2)c(-c2ccc(Cl)cc2Cl)c1
Yield: 75 %

Procedure:
Phenylmagnesiumbromide (1M in THF) (2eq) is added to a solution of 8 (50 mg) in THF (10 ml) at 78° C. under argon with stirring. The reaction is allowed to stir for 15 min. at 78° C. after the addition of Grignard at which time sat; aq. NH4Cl (4 ml) is added to quench the reaction. The mixture is diluted with EtOAc (60 ml) and water (2 ml), and the layers are separated. The organic layer is washed with sat. aq. NH4Cl (10 ml), water (10 ml), brine (10 ml), dried (Na2SO4), filtered and concentrated. The residue is purified by silica column chromatography eluting with EtOAc/hexane to give 13.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Cl.[N:16]([O-])=[O:17].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[N:16]=[O:17]
Reactant: C=C(C)Cn1c(N)cc(=O)n(C)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=C(C)Cn1c(N)c(N=O)c(=O)n(C)c1=O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.9 l), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (2445 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride, (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.2 l) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine2,4-dione, mp 152-153° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][CH2:46][C:47]([NH:49][C@@H:50]([C:52]([NH:54][C@H:55]([C:58]([NH:60][C@H:61]([C:66]([O:68]C(C)(C)C)=[O:67])[CH2:62][C:63](=[O:65])[NH2:64])=[O:59])[CH2:56][OH:57])=[O:53])[CH3:51])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8]>FC(F)(F)C(O)=O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][CH2:46][C:47]([NH:49][C@@H:50]([C:52]([NH:54][C@H:55]([C:58]([NH:60][C@H:61]([C:66]([OH:68])=[O:67])[CH2:62][C:63](=[O:65])[NH2:64])=[O:59])[CH2:56][OH:57])=[O:53])[CH3:51])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](C)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reaction time: 1 h

Procedure:
In 2 ml of trifluoroacetic acid is dissolved 250 mg of pGlu-(D)-Ala-Lys(Boc)-Ser-Gln-Gly-(D)-Ala-Ser-Asn-OBut and the solution is allowed to stand at room temperature for 60 minutes. The solvent is distilled off and the residue is precipitated with ether and recovered by filtration. The resulting powders are dissolved in 50 ml of water and passed through a column of Amberlite IRA-410 (acetate-form) (2×5 cm). The effluent is combined with washings and lyophilized. The powdery lyophilizate is dissolved in a small amount of water and put onto a column of Sephadex LH-20 (2.5×125 cm), elution being carried out with 0.1 N-acetic acid. The fractions from 182 ml through 218 ml are pooled and lyophilized. Yield 86 mg (34%); [α]D23 -6.0°(c=0.25, water); Rf4 =0.23; amino acid analysis (as hydrolyzed with HCl): Lys, 0.97(1); Asp, 0.97(1); Ser, 1.80(2); Glu, 2.07(2); Gly, 1.00(1); Ala, 1.93(2); average recovery 82%.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5])#[N:2].[CH3:15][N:16]([CH3:27])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O.N1CCCCC1>N1C=CC=CC=1>[C:1]([C:3](=[CH:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([N:16]([CH3:27])[CH3:15])[CH:18]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5])#[N:2]
Reactant: COc1ccc(C=O)cc1N(C)C
Reactant: N#CCC(=O)NCCCCCC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=C(C#N)C(=O)NCCCCCC(=O)O)cc1N(C)C
Reaction time: 20 h

Procedure:
3.96 g (20 mMol 6-(2-cyan-acetylamino)hexanoic acid was dissolved in 27 ml pyridine. 3.64 g (20 mMol) 3-dimethylamino-4-methoxybenzaldehyde and 0.6 mL piperidine were added to the solution and the reaction mixture was stirred for 20 hours. After evaporation of the reaction mixture the residue was solved in 150 ml ethyl acetate and 150 ml water and the pH was adjusted with pure acetic acid to 4.2. The aqueous phase was extracted with ethyl acetate. The collected ethyl acetate phases were washed with NaCl-Solution, dried and evaporated. The residue was chromatographed on SiO2 with ethyl acetate under low pressure. The product was crystallized from little ethyl acetate.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:28].CCOC(C)=O>>[ClH:28].[N:15]1([C:13](=[O:14])[CH2:12][C:9]2[CH:10]=[N:11][C:6]([N:1]3[CH:5]=[N:4][N:3]=[N:2]3)=[CH:7][CH:8]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)nc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(-n2cnnn2)nc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazine-1-carboxylate (60 mg, 0.16 mmol) in HCl/EtOAc (3 mL) was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduce pressure to give 1-(piperazin-1-yl)-2-[6-(1H-tetrazol-1-yl)pyridin-3yl]ethanone hydrochloride. MS m/z 274 (M+1)+. 1H-NMR (400 MHz, MeOD) δ 9.89 (s, 1H), 8.46 (s, 1H), 8.05˜8.07 (m, 1H), 7.99˜8.00 (m, 1H), 3.99 (s, 2H), 3.85˜3.92 (m, 4H), 3.24˜3.30 (m, 4H).