Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH:18]1[CH:19]=[CH:20]C2N(O)N=[N:24][C:22]=2[CH:23]=1.CCN(C(C)C)C(C)C.N1CCCCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:24]1[CH2:20][CH2:19][CH2:18][CH2:23][CH2:22]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CCCCC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol), DIPEA (78 μL, 0.47 mmol), piperidine (23 μL, 0.23 mmol) and EDAC (45 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was diluted in dichloromethane and washed with water. The organic layer was concentrated to dryness and the residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 95/5) to give the title compound (39 mg, 69%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][CH:9]([F:13])[C:10](O)=[O:11].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C>[F:8][CH:9]([F:13])[C:10]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:11]
Reactant: O=C(O)C(F)F
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)F
Temperature: 25 °C
Reaction time: 61 h
Yield: 13.9 %

Procedure:
400 mg (4.26 mmol) of 2-aminopyridine was dissolved in 10 ml of anhydrous dichloromethane, 322 μl (490 mg, 5.11 mmol) of difluoroacetic acid, 982 mg (5.10 mmol) of EDC-HCl and 622 mg (5.11 mmol) of DMAP were added thereto, and the resulting mixture was stirred at room temperature for 61 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, washed once with water and twice with a 1% HCl aqueous solution, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 102 mg (yield 14%) of 2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:28][C:29]=2[CH3:30])[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2OCc2nc(-c3ccccc3)oc2C)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.09 g), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (834 mg, yield: 82%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 127–128° C.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH:6]1([C:9](=[NH:11])[NH2:10])[CH2:8][CH2:7]1.C([O:14][C:15]([C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:22]3[C:27]([C:28]=2[CH:29]=1)=[CH:26][CH:25]=[CH:24][CH:23]=3)=O)C>O.C(O)C.C1(C)C=CC=CC=1>[CH:6]1([C:9]2[N:10]=[C:15]([C:17]3[N:18]=[CH:19][C:20]4[NH:21][C:22]5[C:27]([C:28]=4[CH:29]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)[O:14][N:11]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: N=C(N)C1CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2c(c1)[nH]c1cnc(-c3nc(C4CC4)no3)cc12
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of sodium ethoxide, prepared from sodium metal (0.6 g, 26 mmol) and anhydrous ethanol (50 mL), cyclopropylmethanimidamide (1.67 g, 16 mmol) and 9H-β-carboline-3-carboxylic acid ethyl ester (2.0 g, 8.0 mmol) were added. Toluene (50 mL) was added and the resulting mixture was heated to 120°-130° C. The ethanol and water formed during the reaction were removed by azeotropic distillation. The reaction was complete after 30 min. The solid was filtered from the reaction mixture, washed with water and dried. This afforded the title compound (1.15 g, 52%) as an yellow solid. M.p. 256°-257° C.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[C:17]([Si:14]([O:8][CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[C:2]#[CH:1])([CH3:16])[CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(O)CCCC
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CC(CCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a solution of hept-1-yn-3-ol (5.0 g, 0.0446 mol) in dry DMF (50 mL) were added imidazole (3.64 g, 0.054 mol) and tert-butyldimethylsilyl chloride (6.06 g, 0.054 mol). The resulting mixture was stirred at RT for 18 h and then treated with saturated NH4Cl (25 mL) and ethyl acetate (250 mL). The organic layer was washed with saturated NH4Cl (50 mL), water (4×100 mL), brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to afford the crude product (9.57 g, 95%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H), 1.31-1.38 (m, 4H), 1.65-1.67 (m, 2H), 3.35 (s, 1H), 4.32-4.33 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH:44]([CH3:46])[CH3:45])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].Br[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CS(C)=O>[CH3:45][CH:44]([CH3:46])[C@H:2]([NH:1][C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[N:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4]
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Reactant: Brc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)[C@H](Nc1ncccn1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 90 °C
Yield: 110.8 %

Procedure:
A mixture of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-2) (0.45 g, 0.72 mmol), 2-bromopyrimidine (0.37 g, 2.34 mmol) and iPr2NEt (0.20 mL, 1.18 mmol) in toluene-DMSO (4:1, 5 mL) was heated at 90° C. overnight. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (YMC Pack C-18, 30×100 mm/MeCN—H2O-TFA). The title compound (0.56 g, 74%), as its TFA salt, was obtained as a yellow-orange glass.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17]C)=[O:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO.C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(-c2nc(CC(=O)OC)cs2)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1cc(-c2nc(CC(=O)O)cs2)ccn1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of methyl 2-[2-(2-ethyl-4-pyridyl)-1,3-thiazol-4-yl]acetate (Step a, 0.5 g, 1.9 mmol) and LiOH (2 N, 5.0 mL) in THF (5 mL) and MeOH (2 mL) was stirred at RT for 7 h. HCl (aq. 1 N) was added to adjust the reaction mixture to pH ˜2. The solution was evaporated and the resulting residue was partitioned between EtOAc (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer was extracted again with EtOAc (2×20 mL). The organic layers were combined, dried (Na2SO4), and concentrated to afford a solid, which was suspended in CH2Cl2 and filtered to give the compound as a white solid. MS m/z: 249 (M+1). Calc'd for C12H12N2O2S. 248.06.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11]C(=O)CC)[CH2:5]2.O.[ClH:17]>CCOCC.C1COCC1>[ClH:17].[NH2:11][CH:6]1[CH2:7][C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH2:5]1
Reactant: CCC(=O)NC1Cc2ccc(N)cc2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 90 %

Procedure:
Amide 25 (0.62 g, 3.0 mmol) was dissolved in 8 mL of dry ether, and BH3 (16 mL of a 1 M solution in THF) was added dropwise, over a 1 h period. After the addition was completed, the reaction mixture was heated to reflux for 1 h. The mixture was cooled to room temperature, and 1.6 mL of water was added cautiously. Subsequently, 3.2 mL of 10% HCl was added, and all volatile solvents were evaporated under reduced pressure. The remaining aqueous solution was basified with 10% NaOH and extracted with ethyl acetate (2 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure, which yielded 23 as a clear oil (0.52 g, 90%): 1H-NMR (CDCl3, 200 MHz) 0.92 (t, J=7.3, 3H), 1.43-1.61 (m, 2H), 2.58-2.71 (m, 4H), 3.00-3.11 (m, 2H), 3.52-3.65 (m, 3H), 6.49 (d, J=7.8, 1H), 6.55 (s, 1H), 6.96 (d, J=7.8, 1H); 13C NMR 11.6, 23.2, 38.9, 39.9, 50.0, 59.8, 111.5, 113.4, 125.0, 131.6, 142.9, 145.0; MS (EIPI) m/e 190 (M+). Part of the product was converted to the dihydrochloride and recrystallized from ethanol, yielding white crystals: mp 238-242° C. Anal Calcd (Obsd) for C12H18N2.2HCl: C: 54.96 (54.59), H: 7.63 (7.66), N: 10.69 (10.46).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[N+:32](=[CH2:34])=[N-:33]>C(OCC)(=O)C.C(OCC)C>[CH2:10]([C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14](=[O:16])[CH:34]=[N+:32]=[N-:33])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
A solution of Boc-Norleucine (6.9 g, 30 mmol) in ethyl acetate (EtOAc) (80 mL) was cooled to -25° C. and N-methylmorpholine (3.3 mL, 30 mmol) was added followed by isobutyl chloroformate (4.2 mL, 32 mmol). The mixture was stirred for 15 minutes at -25° C. and diethylether (Et2O) (50 mL) was then added. After cooling the mixture to -50° C., the white precipitate was filtered under N2 and the cold filtrate was treated with a solution of diazomethane in Et2O (130 mL, 0.4 M, 52 mmol). The mixture was allowed to proceed overnight, gradually warming up to room temperature. Excess of diazomethane was removed by bubbling a N2 stream through the solution and the solvent was then evaporated. The residual oil was dissolved in EtOAc (100 mL) and was washed with saturated NaHCO3 (1×100 mL) and brine (1×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield 7.5 g (98)% of crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C([O:13][C:14]([C:16]1[S:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]2)=[N:19][N:20]=1)=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:14]([C:16]2[S:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH2:25][CH2:26]3)=[N:19][N:20]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: NCCc1ccc(F)cc1
Product: O=C(NCCc1ccc(F)cc1)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-(4-fluorophenyl)ethylamine in place of isoamylamine to react with 5[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.098 g, yield 98%). 1H NMR (300 MHz, CDCl3) δ 7.74-7.71 (m, 1H), 7.64-7.52 (m, 2H), 7.34-7.32 (m, 1H), 7.17-7.05 (m, 3H), 6.99-6.94 (m, 2H), 4.09-4.02 (m, 1H), 3.9-3.82 (m, 1H), 3.76-3.61 (m, 4H), 3.54-3.51 (m, 2H), 3.35-3.31 (m, 2H), 2.86 (t, J=7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.6, 163.3, 160.0, 158.3, 155.6, 134.1, 133.9, 132.4, 130.2, 130.1, 129.7, 129.1, 126.9, 126.7, 126.8, 125.4, 121.8, 115.6, 115.3, 49.5, 48.9, 45.9, 40.9, 40.7, 34.9. MS (ES+) m/z 508 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(COc2cccc(Cl)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(COc2cccc(Cl)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of compound 35c (340 mg, 1.18 mmol) and LiOH (114 mg, 4.74 mmol) in THF/MeOH/H2O (3/3/3 mL) was stirred for 4 h. A 15% citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resultant residue, compound 35d (230 mg) was dried under reduced pressure for 18 h and used without further purification.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[CH2:24](OCC)C>>[C:1]1([C:8]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([CH3:24])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[O:10])[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: c1nc[nH]n1
Reactant: CCOCC
Product: CC(C(=O)c1ccc(Cl)c(Cl)c1)(c1ccccc1)n1cncn1
Temperature: 25 °C

Procedure:
Benzal-3', 4'-dichloroacetophenone (13.8 g; 0.05 mol) and 1,2,4-triazole (3.4 g; 0.05 mol) were fused together at 120°-140° for 30 minutes. After cooling to room temperature, diethyl ether (10.0 ml) was added to precipitate the unreacted benzal 3',4'-dichloroacetophenone which was filtered off. The filtrate was concentrated to give a solid residue which, on crystallisation from carbon disulphide/absolute ethanol gave 2-phenyl-2-(1,2,4-triazol-1-yl)-3',4'-dichloropropiophenone (compound 2), m.p. 68°-71° C.
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][CH2:22][CH2:23][N:24]3[CH2:35][CH2:34][C:27]4([NH:31][C:30](=[O:32])[NH:29][C:28]4=[O:33])[CH2:26][CH2:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[I:36][CH3:37]>CO>[I-:36].[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][CH2:22][CH2:23][N+:24]3([CH3:37])[CH2:35][CH2:34][C:27]4([NH:31][C:30](=[O:32])[NH:29][C:28]4=[O:33])[CH2:26][CH2:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=O)C2(CCN(CCCN3CCN(C(=O)/C=C/c4ccc(Cl)c(Cl)c4)CCC3=O)CC2)N1
Reactant: CI
Solvent: CO
Product: C[N+]1(CCCN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)CCC2(CC1)NC(=O)NC2=O
Product: [I-]
Reaction time: 48 h
Yield: 103 %

Procedure:
To a solution of 8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (example 48) (10 mg, 19 umol) in MeOH (0.5 ml) was added iodomethane (10 uL, 95 umol) and the reaction left for 2 days at room temperature. Concentration of the mixture affording the title product (13 mg, 98%) as a white solid. MS: 536.1 (M+, 2Cl).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH:5][C:6](=[O:31])[C@H:7]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:8][C:9](=[O:24])[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C(=O)C)=[CH:16][CH:15]=1)=[O:13].[OH-].[Na+].Cl.O>CO>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)c1ccc(OC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)c1ccc(O)cc1)C(=O)O

Procedure:
5.1 g of p-acetoxyhippuryl-L-histidyl-L-leucine methyl ester is dissolved in 20 ml of methanol, and to this solution is added 20 ml of a 1 N.aqueous solution of NaOH at a temperature of 4° C., and after stirring for one hour, the pH of the solution is lowered to 5 by adding HCl, and water and methanol are distilled off. The residue is dissolved in methanol and filtered, and to this solution is added ethyl ether. The crystals deposited after standing at -20° C. are filtered to obtain p-hydroxyhippuryl-L-histidyl-L-leucine.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:38][CH:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:38][CH:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: C1CN(C2CNC2)CCO1
Product: O=C1N=C(N2CC(N3CCOCC3)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Azetidin-3-yl-morpholine following General Procedure C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]1=[O:20].C(N(CC)CC)C.C(N(C(C)C)CC)(C)C.[Cl-].[O:53]=[C:54]1[N:63]([CH:64]2[CH2:69][CH2:68][NH2+:67][CH2:66][CH2:65]2)[CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:55]1>ClCCl>[CH2:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:6]([NH:5][C:1]([N:67]2[CH2:68][CH2:69][CH:64]([N:63]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][C:54]3=[O:53])[CH2:65][CH2:66]2)=[O:2])([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)[C:7]1=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccccc2CN1C1CC[NH2+]CC1
Reactant: O=C(Cl)Cl
Reactant: NC1(Cc2ccc(OCc3ccccc3)cc2)CCCCN(Cc2ccccc2)C1=O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(Cc2ccc(OCc3ccccc3)cc2)CCCCN(Cc2ccccc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Phosgene (20% wt. in toluene; 0.49 mL, 0.92 mmol) was added to a solution of 3-amino-1-benzyl-3-[4-(benzyloxy)benzyl]azepan-2-one (76 mg, 0.18 mmol) and triethylamine (0.80 mL, 0.55 mmol) in dichloromethane (2 mL) at 0° C. After 30 min, the mixture was concentrated and redissoved in acetonitrile (5 mL). Diisopropylethylamine (0.060 mL, 0.37 mmol), and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidinium chloride (49 mg, 0.18 mmol) were added and the mixture was heated to reflux. After 1 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane gave the title compound (114 mg). MS 672 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9](C(OC(C)(C)C)=O)[CH:10]([CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=1)[CH3:11]>C1(OC)C=CC=CC=1>[CH3:8][NH:9][CH:10]([CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][C:18]([NH2:22])=[C:19]([CH3:21])[CH:20]=1)[CH3:11]
Reactant: Cc1cc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cnc1N
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1cnc(N)c(C)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 12.2 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (17.76 g, 155.76 mmol) was added dropwise, via addition funnel, over 30 min to a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine (1.11 g, 3.47 mmol) in anisole (15 mL). The resulting solution was stirred for 45 min at 0-5° C. and was then concentrated by rotary evaporation. The viscous, brown oil was further dried under high vacuum for 18 h. The crude product was cooled (0-5° C.), basified with 10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL), and extracted with CHCl3 (5×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum yielding a dark-brown oil. The crude product was purified by column chromatography on silica gel (50 g), eluting with CHCl3—CH3OH-Et3N (4:1:1, v/v/v). Selected fractions containing the product (Rf 0.13) were combined and concentrated by rotary evaporation, and the residue was re-chromatographed on silica gel (50 g) eluting with CHCl3—CH3OH (7:3, v/v). Fractions containing the product (Rf 0.12) were combined and concentrated by rotary evaporation. The residue was dissolved in CHCl3, and the CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried affording a yellow oil (0.087 g) which tended to crystallize. The semi-crystalline material was dissolved in a warm solution of hexane containing a small amount of ethyl acetate. The warm solution was decanted from an insoluble gum. The solution was allowed to cool to ambient temperature and was further cooled at 5° C. for 18 h. The resulting crystalline solids were collected, washed with hexane, and vacuum dried at 40° C. for 16 h. The yield was 30.8 mg (4.3%) of a light-yellow powder, mp 78-81° C.