Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:22]#[N:23])[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:22]#[N:23])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCNCC1
Yield: 88.5 %

Procedure:
4-(4-Nitro-phenyl)-1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonitrile (1.28 g, 3.91 mmol) was suspended in Methanol (50.0 mL) and treated with 2.00 M of Sodium carbonate in Water (20.0 mL, 40.0 mmol) at rt overnight. Water was added to the heterogenous mixture to achieve a solution, then the mixture was partitioned between DCM and brine (50 mL each). Ext. of the aq. with DCM (3×50 mL), followed by washing the org. with brine (50 mL), drying and conc. in vacuo afforded 4-(4-Nitro-phenyl)-piperidine-4-carbonitrile (0.800 g; Yield=88.4) as a white solid. 1H-NMR (DMSO-d6): 8.30 (d, 2H, J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 3.07 (m, 2H), 2.82 (m, 2H), 2.36 (br s, 1H), 2.05 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: [OH-:1].[Li+].[Cl:3][C:4]1[N:9]=[C:8](SC)[N:7]2[CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:6]2[CH:5]=1>O.C1COCC1.C(Cl)Cl>[Cl:3][C:4]1[NH:9][C:8](=[O:1])[N:7]2[CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:6]2[CH:5]=1
Reactant: [OH-]
Reactant: CSc1nc(Cl)cc2nc(COc3ccccc3)cn12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c(Cl)cc2nc(COc3ccccc3)cn12
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A solution of lithium hydroxide (66 mg, 2.75 mmol) in H2O (10 mL) was added to a solution of 7-chloro-5-methylsulfanyl-2-phenoxymethyl-imidazo[1,2-c]pyrimidine (0.70 g, 2.29 mmol) in THF (10 mL). The mixture was stirred at 50° C. for 4 hours and then diluted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 7-chloro-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.62 g, 98% yield) as a white solid that was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[NH2:1][CH:2]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4]([O:6][CH2:18][CH3:19])=[O:5]
Reactant: CCO
Reactant: NC(CC(=O)O)c1cccnc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC(N)c1cccnc1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a stirred suspension of 114 g (0.69 mole) of β-amino-β-(3-pyridyl)propionic acid in 2,850 ml of ethanol was added a 5° C. solution of 417 g of sulfuric acid in 240 ml of ethanol. After stirring for 1 hour, the resultant clear solution was left standing at room temperature for 48 hours and then concentrated to incipient crystallization in vacuum at a temperature below 50° C. The solution was added to a suspension of 715 g of sodium bicarbonate in 1430 ml of water over 1 hour. The temperature of the solution was maintained between 0° to 5° C. After stirring an additional 30 minutes, 300 ml of carbon tetrachloride was added and the admixture stirred for 10 minutes. The by-product salt was removed by filtration and the aqueous layer was extracted thoroughly with carbon tetrachloride. The combined organic extracts were dried and concentrated under vacuum to yield 87.11 g (65% yield) of crude ethyl β-amino-β-(3-pyridyl)propionate as a slightly viscous green liquid.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH:4]=[CH:5][CH2:6][CH2:7][CH3:8].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[CH2:6]([C@H:5]1[C@@H:12]2[CH2:13][C@H:14]([CH:10]=[CH:11]2)[C@H:4]1[C:3](=[O:9])[CH2:2][CH3:1])[CH2:7][CH3:8]
Reactant: C1=CCC=C1
Reactant: CCCC=CC(=O)CC
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CCC[C@@H]1[C@H](C(=O)CC)[C@H]2C=C[C@H]1C2
Yield: 84 %

Procedure:
Prepared according to general procedure A from oct-4-en-3-one (112 μL, 0.75 mmol), cyclopentadiene (93 μL, 1.13 mmol), 70% aqueous perchloric acid (12.9 μL, 0.15 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (40.5 mg, 0.15 mmol) in water (150 μL) for 32 hours at 0° C. Purification by silica gel chromatography (15:1 pentane:ether) provided the title compound as a colorless oil in 84% yield (120 mg, 0.62 mmol); 15:1 endo:exo, endo 92% ee. IR (film) 3060, 2961, 2872, 1710, 1459, 1413, 1377, 1333, 1216, 1106, 1017, 935.7, 904.3, 716.7 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.22 (dd, J=6.0, 3.3 Hz, 1H, CH═CH), 5.84 (dd,J=5.4, 2.7 Hz, 1H, CH═CH), 3.12 (m, 1H, CHCH═CH), 2.57 (m, 1H, CHCH═CH), 2.45 (m, 3H, CH2CO and CHCO), 1.83 (m, 1H, CH(nPr)), 1.59-1.19 (br m, 6H, CH3CH2CH2, and CHCH2CH), 1.02 (dd, J=6.0, 6.0 Hz, 3H, CH3), 0.89 (dd, J=7.2, 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 211.7, 138.8, 132.4, 59.5, 47.3, 47.2, 46.6, 41.4, 38.7, 35.1, 22.3, 14.7, 8.3; HRMS (CI) exact mass calc'd for (CH13H20O) requires m/z 192.1514, found m/z 192.1512. [α]D=+91.5 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (150° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=6.0 min, and (1S, 2S, 3R, 4S) endo isomer tr=5.6 min, exo isomers tr=5.1, 5.4 min.
Reaction SMILES: [CH2:1]([S:8][C:9]1([CH2:15][N+:16]([O-])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH2:16][CH2:15][C:9]1([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])CC1(SCc2ccccc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC1(SCc2ccccc2)CCOCC1
Yield: 55.6 %

Procedure:
A solution of 4-benzylthio-2,3,5,6-tetrahydro-4-nitromethyl-4H-pyran (8 g) in dry ether (25 cm3) was added dropwise over a period of about 45 min to a stirred suspension of lithium aluminium hydride (3.8 g) in dry ether (200 cm3), cooled in an ice bath. When the addition was complete the mixture was heated under reflux for an additional hour. Excess lithium aluminum was destroyed by the careful addition of water, and then an aqueous solution of sodium potassium tartrate (200 cm3, 20% w/w) was added. The mixture was stirred until the solids had dissolved and the ether layer was then separated. The aqueous solution was then extracted with ether and the combined extracts then dried (MgSO4). Removal of the ether under reduced pressure gave the crude product which was purified via the recrystallisation of its hydrochloride salt using isopropanol. The purified amine (3.95 g, 59%) was obtained as a colourless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:16][CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: COc1ccc2nc(Cl)c(N)nc2c1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2nc(OC)c(N)nc2c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.3 %

Procedure:
To 3-amino-2-chloro-6-methoxyquinoxaline (1.50 g, 7.16 mmol) dissolved in tetrahydrofuran (60 ml), 25 wt % sodium methoxide (15.5 g, 71.6 mmol) in methanol was added at room temperature and stirred further at room temperature for 21 hours. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.18 g of the titled compound (yield, 80%).
Reaction SMILES: [Br-].[C:2]([CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[OH-].[Na+].[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH:30]=O>C(Cl)Cl.O>[Br:26][C:27]1[CH:28]=[C:29](/[CH:30]=[CH:4]/[C:2]#[N:3])[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#C/C=C/c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.9 %

Procedure:
To a mixture of (cyanomethyl)triphenylphosphonium bromide (70.6 g, 185 mmol) and sodium hydroxide (7.39 g, 185 mmol) in DCM (100 mL) and water (300.00 mL) at 0° C. was added 3-bromo-4-fluorobenzaldehyde (25.0 g, 123 mmol). It was allowed to warm to room temperature and stirred for 2 h. The organic layer was separated, and the water layer was extracted with DCM twice. The combined organic phases were dried over Na2SO4 and concentrated to give a crude product, which was washed with diethyl ether. The residue was purified to give the title compound as a white solid (35 g, 88% yield). LCMS: rt=1.50 min, [M+H+]=226
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([SH:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>C(COC)OC>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH2:15][CH:14]=[CH2:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)[nH]n1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCSc1cc(C(C)(C)C)n[nH]1
Yield: 88 %

Procedure:
To a slurry of 3-t-butylpyrazole-5-thiol (10 g) in dry dimethoxyethane (100 ml) was added portionwise, with stirring, sodium hydride (1.6 g). Stirring at room temperature was continued for a few minutes, and then allyl bromide (7.8 g) was added. The reaction mixture was stirred for 2 hours, filtered, and evaporated. The residue was dissolved in ether and washed with water, and the ether layer separated, dried, and evaporated to give 3-t-butyl-5-(allylthio)pyrazole, as a pale brown oil (11.0 g), 88% yield.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([C:12]([O:14]C)=[O:13])=[C:4]2[N:3]=1>[OH-].[Na+]>[SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cnn2c(C)cc(S)nc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(S)nc2c(C(=O)O)cnn12

Procedure:
7.20 g of methyl 5-mercapto-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate were heated to 100° in 2N sodium hydroxide solution until almost all had dissolved. The solution was cooled, filtered and the filtrate was adjusted to pH 2. The product was filtered off under suction, washed with water and acetone and dried. There was obtained 5-mercapto-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid of m.p. 225° (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(S(C)(=O)=O)cc1N
Yield: 73 %

Procedure:
A solution of ethyl 2-nitro-4-methylsulphonylbenzoate (10.0 g) in methanol was hydrogenated over 5% palladium on charcoal catalyst (1.2 g) at room temperature and atmospheric pressure. The resultant slurry was filtered and the filtrate was evaporated to dryness to give ethyl 2-amino-4-methylsulphonylbenzoate (6.5 g) as a yellow solid NMR (CDC3) 1.4(t,3H) 3.1(s,3H) 4.35(q,2H) 6.1(bs,2H) 7.0(d, 1H) 7.2(s, 1H) 7.95(d, 1H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][OH:16]>O1CCCC1>[Cl:13][C:6]1[N:5]=[C:4]([O:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
2.0 g of sodium hydride was added to a mixture of 9.65 g of 2,6-dichloro-3-nitropyridine, 4.95 g of methyl glycolate and 100 ml of tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 10.86 g of 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.[C:24]([O:34][CH2:35][CH3:36])(=[O:33])/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.C(OCC)(=O)C>[C:24]([C:25]1[C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][NH:22][CH:21]=1)([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)/C=C/c1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.5 %

Procedure:
To a 1.0 M solution of lithium hexamethyldisilazide in THF (41 mL, 41 mmol) at 78° C. was added dropwise over 45 min. a solution of tosylmethyl isocyanide (8.1 g, 41 mmol) in THF. After the reaction was stirred for an additional 45 min. a solution of trans-ethyl cinnamate (7.3 g, 41 mmol) in THF (40 mL) was added over 40 min. The reaction was warmed to 25° C. and stirred for 5 h. The reaction was diluted with ethyl acetate and washed with sat. aqueous NaHCO3. The aqueous layer was extracted three times with ethyl acetate, dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with a gradient of 20–30% ethyl acetate in hexanes to provide 3.4 g (41%) of 3-carboethoxy-4-phenylpyrrole as an off-white solid. 1HNMR (CDCl3): δ 8.62 (br s, 1H), 7.5 7–7.12 (m, 6H), 6.73 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H)
Reaction SMILES: [Na].[C:2]([NH:4][C:5]([CH:9]1[CH2:11][CH2:10]1)=[N:6][C:7]#[N:8])#[N:3].[ClH:12].CCCCCC>CC(=O)CC>[NH2:8][C:7]1[N:3]=[C:2]([Cl:12])[N:4]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:6]=1
Reactant: N#CN=C(NC#N)C1CC1
Reactant: Cl
Agent: [Na]
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: Nc1nc(Cl)nc(C2CC2)n1
Temperature: 10 °C

Procedure:
33 g of the sodium salt of N,N'-dicyano-cyclopropanecarbamidine (crude product) is suspended in 100 ml butanone. A solution of 20 g HCl in 400 ml butanone is dropped under stirring into this solution at 10° C. After the addition has been completed it is stirred for 1 h at ambient temperature. The reaction mixture is concentrated by evaporation and 200 ml of saturated aqueous NaHCO3 -solution and 300 ml diethylether are added. The organic phase is separated, washed, dried and concentrated by evaporation. One isolates 21 g of crude product which is treated with hexane to leave the pure title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([O:30][CH2:31][CH2:32][CH3:33])[C:9]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:12]C(OCC1C=CC=CC=1)=O)=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]([O:30][CH2:31][CH2:32][CH3:33])[C:9]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH2:12])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCON(C(=N)N(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCON(C(=N)N(N)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 3-(benzyloxycarbonylamino)-1-propoxyguanidine (760 mg, 1.7 mmol), as prepared in the preceding step, and 10% Pd/C (80 mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon) for 30 min. The catalyst was removed by filtration through Celite, the filtrate was concentrated in vacuo, and the residue was purified by Waters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless oil (160 mg,:28%). 1H-NMR (300 MHz, CDCl3) δ4.12 (t, J=6.1 Hz, 2H), 2.85 (t, J=6.7 Hz, 2H), 1.84 (pentet, J=6.2 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[C:9]1=[S:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]1=[S:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccn(Cc2ccccc2)c1=S
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccn(Cc2ccccc2)c1=S
Yield: 74.5 %

Procedure:
Reaction of 143b (0.050 g, 0.21 mmol) with 1M BBr3 (0.66 mL) in dry CH2Cl2 (5 mL) within 48 h according to procedure 142a afforded pure 144b (0.034 g, 72%) as olive green solid. 1H NMR (400 MHz, cd3od) δ 7.34 (m, 3H), 6.84 (m, 1H), 5.83 (d, J=49.5 Hz, 1H). 13C NMR (100 MHz, CD3OD) δ 128.12, 127.61, 127.27, 126.94, 113.77. HRMS (EI) calcd for C12H11NOS [M]+ 217.0561. found 217.0762.
Reaction SMILES: [BH4-].[Na+].Cl[C:4]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:5]1[F:7].O.Cl>CN1C(=O)CCC1.O.O.O.O.O.O.[Co](Cl)Cl.C1(C)C=CC=CC=1>[F:7][CH:5]1[CH2:6][CH:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)C1(Cl)CC1F
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Sodium borohydride (8.75 g, 231.21 mmol) was dissolved in NMP (95 mL) under stirring with a stirring blade at room temperature. Subsequently, to the resultant solution was added an NMP solution (20 mL) of tert-butyl 1-chloro-2-fluoro-cyclopropane-1-carboxylate (cis/trans=62/38) (hereinafter the compound will be referred to as “compound (1a)”) (30 g, 154.14 mmol). An NMP solution (35 mL) of cobalt chloride hexahydrate (1.1 g, 4.62 mmol) was gradually added to the resultant reaction mixture under ice cooling. After completion of dropwise addition, the resultant mixture was stirred with a stirring blade at room temperature for 30 minutes, and at 40° C. for three hours. After completion of reaction, water (120 mL) was added to the resultant reaction mixture at the same temperature, followed by addition of 5 N hydrochloric acid (30 mL). Subsequently, toluene was added to the reaction mixture for extraction. The resultant toluene layer was washed with water, and then dried over sodium sulfate, to thereby yield a toluene solution containing 24.3 g (yield: 98%) of the title compound. Yield was determined by means of high performance liquid chromatography (HPLC) (the same shall apply hereinafter).
Reaction SMILES: [C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[C:8]=2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35].[C:36](OCC)(=O)C>>[ClH:35].[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[C:8]=2[CH2:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:36]3)=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Reaction time: 0.01 h
Yield: 89 %

Procedure:
To a solution of the product of Example 7 (8.7 g, 18.5 mmol) stirring in ethyl acetate (100 mL) was added a saturated solution of hydrochloric acid gas in ethyl acetate (250 mL). After 0.5 min, the resulting solution was concentrated to give 8.0 g (89%) of the desired product as a white foam which was used without further purification: 1H-NMR (300 MHz, DMSO) δ 7.70-7.85 (m, 4H), 7;.30-7.50 (m, 7H), 7.10 (s, 1H), 6.80-7.00 (m, 2H), 4.25-4.40 (m, 4H), 4.00-4.20 (br s, 3H), 3.35-3.55 (m, 4H), 2.85-3.55 (m, 2H), 1.70-1.90 (m, 4H), 1.30-1.45 (m, 2H);
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:19]=[CH:20][C:21]3[C:26]([C:4]=2[NH:3]1)=[CH:25][CH:24]=[CH:23][CH:22]=3.CCN=C=NCCCN(C)C.Cl.[CH:39]1[CH:40]=[CH:41][C:42]2N(O)N=[N:45][C:43]=2[CH:44]=1.CN1CCOCC1.NC1C=CC=CC=1>CN(C=O)C>[C:43]1([NH:45][C:14]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[C:7](=[O:9])[CH2:8][C:2](=[O:1])[NH:3][C:4]4[C:26]5[C:21]([CH:20]=[CH:19][C:5]3=4)=[CH:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][CH:17]=2)=[O:15])[CH:44]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 49.4 %

Procedure:
4-[2,4-Dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid (50 mg, 0.144 mmol) obtained in Example 102, (4), WSC.HCl (39 mg, 0.202 mmol), HOBt (31 mg, 0.202 mmol), N-methylmorpholine (47 μL, 0.432 mmol), and aniline (14 L, 0.158 mmol) were stirred at room temperature for 16 hours in anhydrous DMF (1.5 mL). The reaction mixture was post-treated in a conventional manner to give the title compound (30 mg, yield 49%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[C:12]([NH:16][C:17]([CH:19]1[CH2:21][C:20]1([CH3:23])[CH3:22])=[O:18])[C:13]([OH:15])=[O:14]>O>[CH3:22][C:20]1([CH3:23])[CH2:21][CH:19]1[C:17]([NH:16]/[C:12](=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:3][C:2]([NH2:4])=[NH:1])/[C:13]([OH:15])=[O:14])=[O:18]
Reactant: N=C(N)N
Reactant: CC1(C)CC1C(=O)NC(=CCCCCCBr)C(=O)O
Solvent: O
Product: CC1(C)CC1C(=O)N/C(=C\CCCCCNC(=N)N)C(=O)O
Temperature: 70 °C
Yield: 34.5 %

Procedure:
To a solution of 2 mmoles of guanidine (prepared from 432 mg of guanidine sulfate and 630 mg of barium hydroxide octahydrate) in 7 ml of water was added 332 mg (1 mmole) of 8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid, and the solution was heated at 70° C. in a nitrogen atmosphere for 1 hr. The reaction mixture was applied to a 2×25 cm column of Dowex 50W-X8 (H+, 100-200 mesh) After elution with water the fractions containing the product were pooled and evaporated under reduced pressure. The residue was dissolved in several ml of warm ethanol and added dropwise to 100 ml of ether with rapid stirring. Filtration and washing with ether gave 107 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino-2-octenoic acid as an amorphous electrostatic powder. Homogeneous by TLC (n-BuOH, HOAc, H2O; 4:1:1). ##STR72##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([P:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: CCOP(OCC)OCC
Product: CCCCCCC(C(=O)OCC)P(=O)(OCC)OCC
Yield: 80.6 %

Procedure:
2-Bromo octanoic acid ethyl ester (50 g, 0.2M) was heated at 150° with triethyl phosphite (75 g, 0.44M) and the distillate, Bpt 37°-60° condensed as the temperature was raised to 200° over 6 h. The reaction mixture was cooled and distilled under high vacuum (1.00 mm Hg) to afford 2 main fractions (a) Triethyl phosphite b.p. 40°-70° and (b) 2-(diethylphosphono)octanoic acid ethyl ester (49.5 g, 0.16M); b.p. 120°-130° at 0.5 mm Hg. (Found: C, 52.9; H, 9.4. C14H29O5P+0.5H2O requires: C, 53.0; H, 9.5%; δ(CDCl3) 0.88 (3H, m, CH3); 1.32 (17H, m, (CH2)4, 3×CH3); 1.9 (2H, m, CH2); 2.92 (1H, d, d, d, J= 22 Hz, J=10 Hz, J=4 Hz, CH--P); 4.18 (6H, m, 3×CH2O).