Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CC(C)=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccc(F)cc2)cc1
Yield: 81.4 %

Procedure:
A mixture of 4-cyanophenol (11.91 g, 100.0 mmol), K2CO3 (55.20 g, 400.0 mmol), and 4-fluorobenzylbromide (22.68 g, 120.0 mmol) were heated in acetone (400 mL) at reflux (5 h). The volatiles were evaporated and the residue was diluted in CH2Cl2 (300 mL), and then washed with H2O (500 mL), dried (MgSO4), and concentrated in vacuo. The solid was recrystallized with MeOH to give white needles (18.50 g, 81%): Rf=0.89 (hexanes/EtOAc 911); mp 82-83° C.; 1H NMR (CDCl3) δ 5.07 (s, CH2O), 7.01 (d, J=9.0 Hz, 2 ArH), 7.09 (t, J=8.7 Hz, 2 ArH), 7.37-7.42 (m, 2 ArH), 7.59 (d, J=9.0 Hz, 2 ArH); 13C NMR (CDCl3) δ 69.5 (CH2O), 104.2 (CCN), 115.5 (ArC), 115.6 (d, J=22.5 Hz, C3′), 119.0 (CN), 129.4 (d, J=7.9 Hz, C2′), 131.4 (C1′), 133.9 (ArC), 161.7 (ArC), 162.6 (d, J=245.6 Hz, C4′); Anal. Calcd. for C14H10FNO2: C, 74.00; H, 4.44; F, 8.36; N, 6.16. Found: C, 74.06; H, 4.28; F, 8.26; N, 6.16.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.NC[C@@H]1CC[C@H](C(O)=O)CC1.[H][H]>[OH-].[Na+].[Ru]>[NH2:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:7]([OH:9])=[O:8])[CH2:10][CH2:11]1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Ru]
Agent: NC[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Na+]
Product: NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Trans-4-aminomethylcyclohexane-1-carboxylic acid was prepared using 30 g of p-aminomethylbenzoic acid, 3 g of 5% ruthenium supported on activated carbon and 300 ml of 14N hydrochloric acid or a 20% aqueous sodium hydroxide solution as a solvent under the conditions shown in Table 2 below. For the purposes of comparison, the results obtained by isomerizing 100% cis-4-aminomethylcyclohexane-1-carboxylic acid under the same conditions as above but without using hydrogen for reduction are also shown in Table 2.
Reaction SMILES: [CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:2][CH2:3][C:4]#[CH:5].Cl[C:38](=[N:45][OH:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>ClCCl>[C:39]1([C:38]2[CH:5]=[C:4]([CH2:3][CH2:2][CH2:1][C:6]3[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]4[C:18]=3[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]4[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[O:46][N:45]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCCCc1c2c3c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2nn1CCC)CCCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2c1CCCc1cc(-c2ccccc2)no1)CCCC3
Temperature: 40 °C
Yield: 59.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of di(tert-butyl) 1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (4.00 g, 8.05 mmol), prepared as described in Example 615, α-chlorobenzaldoxime (2.51 g, 16.1 mmol), prepared as described in Example 596, anhydrous triethylamine (1.7 mL, 12.1 mmol), and anhydrous dichloromethane (25 mL) was heated at 40° C. for 18 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with potassium carbonate, water, and brine, dried over sodium sulfate, and filtered. The filtrate was loaded onto a silica gel column (250 g) and eluted with a gradient of 30-40% ethyl acetate in hexanes. The fractions containing product were combined and concentrated under reduced pressure to provide 2.97 g of di(tert-butyl) 1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a pale yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:25][C:12]2([CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>N1C=CC=CC=1>[CH2:27]([O:29][N:30]=[C:21]1[CH2:20][CH2:19][CH:18]([N:15]2[CH2:14][CH2:13][C:12]3([C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:25]3)[CH2:17][CH2:16]2)[CH2:23][CH2:22]1)[CH3:28]
Reactant: CCON
Reactant: CC(=O)N1Cc2ccccc2C2(CCN(C3CCC(=O)CC3)CC2)C1
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C1CCC(N2CCC3(CC2)CN(C(C)=O)Cc2ccccc23)CC1
Temperature: 60 °C

Procedure:
4-(2-Acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)cyclohexanone 6e (100 mg; 0.29 mmol) was dissolved in pyridine (1 mL) and treated with O-ethyl hydroxyamine hydrochloride (34 mg; 0.35 mmol). The vial was sealed and heated to 60° C. for 1 hr. The solvent was evaporated under reduced pressure and the residue was dissolved in DMSO (2 mL) and purified by LC/MS (10-99% CH3CN—H2O gradient, with 0.05% TFA, 9 min) to provide 1-(1′-(4-(ethoxyimino)cyclohexyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)ethanone. LC/MS m/z [M+H]+ 384.4 retention time 1.80 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). 1H-NMR (400 MHz, CDCl3) δ7.69 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.3 Hz, 1H), 7.19-7.15 (m, 1H), 7.01 (d, J=7.5 Hz, 1H), 4.63 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.79 (dd, J=13.4, 18.1 Hz, 2H), 3.41 (d, J=13.0 Hz, 1H), 3.33 (d, J=9.3 Hz, 2H), 3.17 (m, 2H), 3.04-2.98 (m, 2H), 2.59-2.47 (m, 4H), 2.14 (s, 3H), 1.76-1.69 (m, 6H), 1.21-1.14 (t, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[Li]CCCC.[I:18]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([I:18])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: II
Reactant: Clc1nccc2ccc(Br)cc12
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccc2ccc(I)cc12
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7-bromo-1-chloroisoquinoline (15 g, 62 mmol) in THF at −78° C., n-BuLi (123.7 mmol) was added. The resulting solution was stirred for 15 min. and, I2 (31.4 mg, 123.7 mmol) in THF was slowly added by syringe over a period of 5 min. The solution was then allowed to reach room temperature and treated with a saturated aqueous Na2S2O3 solution. The resulting mixture was extracted with diethyl ether (2×). The extracted organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1cncc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cccc(CNc2cncc(Cl)n2)c1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To a solution of 2-amino-6-chloropyrazine (100 mg, 0.77 mmol) in 7.7 mL of anhydrous toluene was added 3-chlorobenzaldehyde (87.4 μL, 0.77 mmol) followed by 50 mg of activated, powdered 4 Å molecular sieves. The reaction was refluxed under nitrogen for 3 h, then cooled to ambient temperature and treated with sodium borohydride (43.0 mg, 1.16 mmol). The resultant slurry was heated to reflux under nitrogen overnight. After cooling to ambient temperature the reaction was filtered through a pad of Celite®, and the flitrate was concentrated in vacuo to a brown residue. Chromatography on a silica gel preparatory TLC plate (1:1 hexane:ethyl acetate) provided 71.0 mg of the title compound I-2a.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:19][N:18]=1.Cl>C1COCC1.CO>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccnc(Br)c1)c1cccc(F)c1C#N
Reactant: FC(F)c1cc(Br)ccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
n-Butyllithium (2.5 M in hexane) (0.353 mL, 0.88 mmol) was added to 4-bromo-2-(difluoromethyl)pyridine (183 mg, 0.88 mmol) in THF (7 mL) at −78° C. under argon atmosphere. The reaction was stirred for 30 min before N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. Methanol (5 mL) was added followed by hydrochloric acid (1 M in diethylether) (2.204 mL, 2.20 mmol) and the reaction was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate. The aqueous phase was extracted with EtOAc (×3). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (64 mg, 20%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:30])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=3)=[CH:13][C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:9]=2[N:10]=1)[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CO>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:11][C:9]=2[N:10]=1)=[O:30])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3cc(C)ccn3)c2s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cc(C)ccn3)c2s1
Temperature: 80 °C

Procedure:
A stirred mixture of the crude Trifluoro-methanesulfonic acid 2-(3-ethyl-ureido)-7-(4-methyl-pyridin-2-yl)-benzothiazol-5-yl ester (44 mg, 0.096 mmol), 3-pyridineboronic acid (13 mg, 0.106 mmol), powdered potassium phosphate tribasic (25 mg, 0.115 mmol), anhydrous 1,4-dioxane (0.7 ml) and anhydrous methanol (1.2 ml) was purged with nitrogen for 15 min. 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex (12 mg, 0.0144 mmol) was added and the mixture heated at 80° C. for 16 h under an atmosphere of nitrogen. After cooling to ambient temperature, the mixture was filtered through celite and washed through with methanol. The filtrate was evaporated in vacuo to give the crude 1-Ethyl-3-[7-(4-methyl-pyridin-2-yl)-5-pyridin-3-yl-benzothiazol-2-yl]-urea.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]>O.CO>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: COC(=O)CCCCBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCC#N
Yield: 74.3 %

Procedure:
Potassium Cyanide (4 g, 61.44 mmol) is dissolved in 70 mL water and 200 mL methanol. To the solution 10 g (51.2 mmol) of methyl 5-bromopentanoate is added and the mixture is refluxed overnight. The reaction mixture is concentrated to dryness. To the residue, 100 mL of EtOAc is added to extract the product. The organic is washed with water three times, dried and concentrated to yield 5.37 g (74%) of methyl 5-cyanopentanoate as an oil.
Reaction SMILES: C[O:2][C:3]1[CH2:7][CH:6]([OH:8])[C:5](=O)[C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].CO.Cl>O1CCCC1>[OH:8][CH:6]1[CH2:7][C:3](=[O:2])[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5]1
Reactant: COC(=O)CCCCCCC1=C(OC)CC(O)C1=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC1=CC(O)CC1=O
Reaction time: 4 h

Procedure:
10 Parts of sulfuric acid is treated with 9 parts of 20% fuming sulfuric acid and allowed to stand at room temperature for 10 minutes. 1.25 Parts by volume of that solution then is added dropwise to 28.5 parts by volume of 1M lithium aluminum hydride in tetrahydrofuran. After the addition is complete, the temperature is maintained at -60° for 15 minutes and then allowed to rise to room temperature. The aluminum hydride solution so obtained is cooled to -60° and added rapidly to a solution of 6.92 parts of methyl 2-methoxy-4-hydroxy-5-oxocyclopent-1-eneheptanoate dissolved in 310 parts of redistilled tetrahydrofuran which is cooled to -40°. The temperature is lowered to -70° after the addition is complete and the reaction mixture is stirred at that temperature for 33/4 hours. Then 7.9 parts of methanol in 17.8 parts of tetrahydrofuran is added slowly and the temperature is allowed to rise to -20° at which time 120 parts by volume of a 1 N aqueous hydrochloric acid solution is added. The mixture is allowed to stand at about 4° for 16 hours and then the solvent is removed under reduced pressure. The aqueous residue which remains is diluted with ethyl acetate and the organic and aqueous layers separated. The organic layer is washed with water, potassium bicarbonate and water. Then it is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure to afford methyl 3-hydroxy-5-oxocyclopent-1-eneheptanoate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:42])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH:39]3[CH2:41][CH2:40]3)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:39]1([C:34]2[CH:33]=[C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:42])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)[CH:37]=[C:36]([CH3:38])[N:35]=2)[CH2:41][CH2:40]1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C4CC4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C4CC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M238) (244 mg, 0.41 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (150 mg, 76%).
Reaction SMILES: C([Cl:4])(=O)N.[CH3:5][NH:6][C:7]([NH:9][CH3:10])=[O:8].Cl.[CH3:12][NH:13][C:14](NC)=[O:15]>ClC1C=CC=CC=1>[ClH:4].[CH3:5][NH:6][C:7]([NH:9][CH3:10])=[O:8].[CH3:12][N:13]=[C:14]=[O:15]
Reactant: NC(=O)Cl
Agent: CNC(=O)NC
Agent: Cl
Solvent: Clc1ccccc1
Product: CN=C=O

Procedure:
A solution of carbamoyl chloride in a suitable solvent such as chlorobenzene is introduced by line 1 into reactor 3 and a slight excess of 1,3-dimethylurea in chlorobenzene usually containing some 1,3-dimethylurea hydrochloride in chlorobenzene is added by line 2 to reactor 3 which is operated at 30° to 40° C. A slurry of 1,3-dimethylurea hydrochloride (solid phase) and methyl isocyanate in chlorobenzene (liquid phase) is formed and the slurry is removed by line 4 to filter 5. The liquid phase from the filter is removed by line 6 to distillation column 7 wherein the solution is distilled to remove methyl isocyanate by line 8 after condensation in condensor 9. The chlorobenzene solvent from distillation column 7 is passed by line 10 to wash the filter and obtain a slurry of chlorobenzene and 1,3-dimethylurea hydrochloride.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13](C)[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].FC1C([Cl:32])=CC=CC=1C(O)=O.CNCCN.C(N)CN>>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][NH:13][C:12]2[C:18]([Cl:32])=[CH:19][CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Reactant: O=C(O)c1cccc(Cl)c1F
Agent: CNCCN
Solvent: NCCN
Product: CCOP(=O)(C=C1NCCNc2c(Cl)cccc21)OCC

Procedure:
(9-chloro-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester was prepared in an analogous fashion to (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester, prepared in Example 1, by replacing 2-fluorobenzoic acid with 2-fluoro-3-chlorobenzoic acid and N-methylethylenediamine with ethylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][C:14](=[O:16])[NH:13][N:12]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:17]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][C:14](=[O:16])[N:13]([CH:24]3[CH2:25][CH2:26][N:21]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]3)[N:12]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CCCCN1CCC(O)CC1
Reactant: O=c1[nH]nc(-c2cc(Cl)cc3c2OCC3)o1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCN1CCC(n2nc(-c3cc(Cl)cc4c3OCC4)oc2=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
2.38 g (0.01 mol) of 5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,3,4-oxadiazol-2(3H)-one, in suspension in 80 ml of tetrahydrofuran, are introduced into a 250 ml three-necked round-bottomed flask, cooled to 0° C. and placed under magnetic stirring, 1.57 g (0.01 mol) of 1-butylpiperidin-4-ol, 3.41 g (0.013 mol) of triphenylphosphine and then 2.44 g (0.014 mol) of ethyl azodicarboxylate are added and the mixture is stirred at room temperature for 3 h and then at 40° C. for 3 h. The solvent is evaporated under reduced pressure and the residue is taken up in water and extracted five times with diethyl ether. The organic phase is dried over magnesium sulphate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with an 80/20 mixture of ethyl acetate and heptane. 3 g of compound are obtained. Melting point: 133.8-134° C.
Reaction SMILES: C(S)CCS.[CH2:6]([O:8][P:9]([CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])([CH:11]([N:24]=[N+]=[N-])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[CH3:7].C(N(CC)CC)C>CO>[CH2:6]([O:8][P:9]([CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])([CH:11]([NH2:24])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[O:10])[CH3:7]
Reactant: CCOP(=O)(COC(=O)CCC(C)C)C(CCCCNC(=O)OC(C)(C)C)N=[N+]=[N-]
Agent: SCCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOP(=O)(COC(=O)CCC(C)C)C(N)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.04 ml of 1,3-propanedithiol were added dropwise to a stirred solution of 3.65 g of benzyl 2(R or S)-[[(RS)-(ethoxy)[1-(RS)-azido-5-tert.butoxycarbonylaminopentyl]phosphinyl]methyl]-4-methylvalerate and 2.83 ml of triethylamine in 80 ml of methanol. The mixture was stirred at room temperature overnight, the solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using 4% methanol/dichloromethane for the elution to give 3.25 g of benzyl 2(R or S)-[[(RS)-(ethoxy)[1-(RS)-amino-5-tert.butoxy carbonylaminopentyl]phosphinyl]methyl]-4-methylvalerate as an off-white foam; nmr (CDCl3): 7.36 (s,5H); 5.2-5.08 (m,2H); 4.6 (brs,1H); 4.2-3.98 (m,2H); 3.17-3.08 (m,2H); 3.0-2.76 (m,2H); 2.4-2.13 (m,1H): 2.0-1.25 (m,25H); 0.98-0.86 (m,6H); MS: 513 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][CH2:22][CH:23]([NH2:26])[CH2:24][CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH:23]([CH2:22][O:21][CH3:20])[CH2:24][CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCC(N)COC
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NC(CC)COC
Yield: 80 %

Procedure:
The compound prepared in Example 3 was reacted with 1-methoxy-2-aminobutane according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(CO)cc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccc(CO)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a mixture of 9.75 g of p-aminobenzyl alcohol and 19.27 g of pyridine in 230 ml of methylene chloride cooled to 0° C. is added over 35 minutes a solution of 21.5 g of 4-tetradecyloxybenzoyl chloride in 230 ml of methylene chloride. The mixture is stirred at room temperature for 2 hours and diluted with chloroform. The mixture is heated to dissolve insolubles, washed with hot water and hot dilute hydrochloric acid then dried. The mixture is filtered hot and the solvent evaporated to a residue which is crystallized from tetrahydrofuran:hexane to give 18.1 g of the desired product as a yellow powder, m.p. 140°-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:8]
Reactant: Cc1cc(F)c(C(=O)O)cc1Cl
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
To a solution of 5-chloro-2-fluoro-4-methylbenzoic acid (Preparation 21, 200 g, 1.06 mol) in DCM (1.4 L) were added methanesulphonamide (152 g, 1.6 mol), 4-(dimethylamino)pyridine (183 g 1.6 mol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (306 g, 1.6 mol). An exotherm of 30° C. was observed in the first 30 minutes, then the mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. The reaction mixture was washed with aqueous hydrochloric acid (4 M, 0.8 L). The organic layer was separated, washed with water (500 mL) and dried over sodium sulfate to yield a tan solid, which was recrystallised from hot EtOAc (0.9 L) by addition of n-heptane (100 mL) and cooling to afford the title compound (118 g, 45%).