Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=1.ClCCl>C(=O)(O)[O-].[Na+]>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:18]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)(=[O:20])=[O:19])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1cc(O)cc(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccnc2)c1
Yield: 58.1 %

Procedure:
A mixture of orcinol monohydrate (1.42 g, 0.01 mol) and 3-pyridylsulfonyl chloride hydrochloride (2.13 g, 0.01 mol), as prepared in J. Am. Chem. Soc., 114:4889 (1992), in saturated aqueous sodium bicarbonate (17.5 mL) and dichloromethane (50 mL) was stirred rapidly at ambient temperature for 2 days. The dichloromethane was separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The ethyl acetate and dichloromethane extracts were combined and washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was recrystallized from ether and hexane, collected by filtration, and dried under high vacuum to give 1.54 g of a white solid (58% yield). 1H-NMR (300 MHz, CDCl3) δ 9.03 (d, 1H), 8.88 (dd, 1H), 8.16 (dt, 1H), 7.5 (m, 1H), 6.57 (d, 1H), 6.42 (s, 1H), 6.32 (t, 1H), 2.24 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2cccc(F)c2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2cccc(F)c2)cc1

Procedure:
In a manner similar to Example 4, Step (c), 4-(3′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (0.9258 g, 0.00340 mol) was allowed to react with hydroxylamine hydrochloride (0.284 g, 0.00409 mol) in the presence of sodium carbonate (0.434 g, 0.00409 mol) in absolute ethanol (19 mL) to give 4-(3′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a pale gray solid; mp 155-157° C.
Reaction SMILES: [BrH:1].O[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>O>[Br:1][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: Br
Reactant: OCCCc1ccc(O)cc1
Solvent: O
Product: Oc1ccc(CCCBr)cc1
Yield: 83.8 %

Procedure:
To 48% hydrobromic acid solution (110 g) was added 4-(3-hydroxypropyl)phenol (25 g) and heated on a steam bath for 3 hours. After cooling, water (500 ml) was added, the oil was extracted with ether, washed with water and then with dilute sodium bicarbonate solution. The etheral extract was dried over potassium carbonate, evaporated and the residue was distilled in a Kugelrohr apparatus giving 29.6 g (84%) of 4-(3-bromopropyl)phenol, bp 180° (2 mm). The product was 92.6% pure by gas chromatography and mass spectrum was compatible with 4-(3-bromopropyl)phenol.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[O:13][C:12]([C:14]([O:16]C)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:21][CH2:20][CH2:19]1>CO>[N:18]1([C:14]([C:12]2[O:13][C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:7])=[O:8])=[CH:10][CH:11]=2)=[O:16])[CH2:21][CH2:20][CH2:19]1
Reactant: C1CNC1
Reactant: COC(=O)c1ccc(S(=O)(=O)NC(C)(C)C)o1
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc(C(=O)N2CCC2)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 5-[(tert-butylamino)sulfonyl]-2-furoate (the product of step i) (2.15 g) in methanol (80 mL) was added azetidine (1.15 mL). After stirring at room temperature for 5 h the mixture was evaporated to dryness in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and H2O (50 mL). The separated organic layer was dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude material was purified by column chromatography (EtOAC as eluent) to give the subtitle compound as a pale yellow oil. Yield: 3 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>O1CCOCC1>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH:24][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)=[CH:22][CH:21]=2)[CH2:18][CH2:19]1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ccn4ncc(C=O)c4n3)cc2)CC1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 4-(4-methylpiperazin-1-yl)aniline (264 mg, 1.381 mmol). The mixture was heated in microwave for 20 minutes at 120° C. The solid formed was isolated by filtration to yield 5-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. The residue was used in the next step without further purification. LCMS (M+1=337).
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])(=O)C.[OH2:19]>O1CCCC1.[OH-].[K+].C(O)C>[OH:4][CH2:5]/[C:6](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:17])=[CH:11]/[CH2:12][OH:19]
Reactant: O
Reactant: CC(=O)OCC(=O)CC/C=C(\C)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Temperature: -20 °C
Reaction time: 2 h

Procedure:
In 30 ml of anhydrous tetrahydrofuran was suspended 5.4 g of (E)-4-methyl-6-acetoxy-4-hexen-1-yltriphenylphosphonium iodide, and to this suspension was added dropwise two molar equivalents of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The mixture was stirred at -20° C. for 2 hours, and to this was further added 2.5 g of (E)-6,10-dimethyl-2-oxo-5,9-undecadien-1-ol acetate (prepared in Referential example 2) in 10 ml of anhydrous tetrahydrofuran. The resulting mixture was again stirred at room temperature for 3 hours and, after addition of ice-water, extracted with ether, and from the extract was obtained an oil. The so obtained crude oil was dissolved in 25 ml of a 5% potassium hydroxide-ethanol solution under ice-cooling, and allowed to stand for 2 hours. This was, after addition of water, extracted with ether and treated in the usual way. The resultant was then chromatographed on silica gel to yield 0.95 g of the desired product.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[SH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(S)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(S)c1
Yield: 50 %

Procedure:
2-(3-mercaptophenyl)acetic acid (1.0 g, 6.0 mmol) was dissolved in dry methanol (40 mL). To this solution 10 drops concentrated sulfuric acid was added and the reaction mixture was heated to reflux for 36 hours. The reaction mixture was then concentrated to about half the volume, diluted with ethyl acetate, and the organic layer washed with saturated sodium bicarbonate solution, then dried over sodium sulfate and concentrated to an oil, 0.55 g, 3.0 mmol, 50% yield. 1H NMR 500 MHz (CDCl3) 7.05 ppm, 3H, m; 6.88 ppm, 1H, m; 3.53 ppm, 3H, s; 3.38 ppm, 2H, s.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH:16]([CH2:18][CH3:19])[CH3:17])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[SH:8].[CH:20](O)=O>>[CH:16]([NH:15][C:3]1[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:9])[N:6]=[C:7]2[S:8][CH:20]=[N:1][C:2]=12)([CH2:18][CH3:19])[CH3:17]
Reactant: CCOC(=O)c1c(C)nc(S)c(N)c1NC(C)CC
Reactant: O=CO
Product: CCOC(=O)c1c(C)nc2scnc2c1NC(C)CC

Procedure:
2.8 g. of 5-amino-4-sec.butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester are refluxed in 10 ml. of formic acid for 12 hours. After this time, the excess acid is removed in vacuo and the residue is dissolved in 10 ml. of water. The aqueous solution is made alkaline with sodium hydroxide and extracted twice, each time with 10 ml. of ether. The ether layer is collected, dried over calcium chloride and evaporated to dryness. The residue, 7-sec.butylamino-5-methylthiazolo[5,4-b]pyridine-6-carboxylic acid, ethyl ester is distilled in vacuo, b. p.0.01 180°-185°, yield 1.8 g. (62%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].Cl.[CH3:13]O>>[CH3:13][O:4][C:3](=[O:5])[C@@H:2]([NH2:1])[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CO
Reactant: N[C@@H](CC1CCCC1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)CC1CCCC1
Temperature: 65 °C
Yield: 73 %

Procedure:
(S)-2-Amino-3-cyclopentyl-propionic acid (Chemimpex, 1.0 g, 6.36 mmol), methanol (15 mL) and concentrated hydrochloric acid (2 mL) was placed in a reaction flask and heated at 65° C. for 16 h. After such time, the reaction mixture was concentrated in vacuo and then dissolved in water. The resulting solution was then treated with a saturated aqueous sodium bicarbonate solution until pH ˜7-9. It was then extracted with ethyl acetate and the organic layers combined, dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo to afford (S)-2-amino-3-cyclopentyl-propionic acid methyl ester (796 mg, 73%) as a clear colorless oil: HR-ES(+) m/e calcd for C9H17NO2 [M+H]+ 172.1332, observed 172.1332; 1H NMR (300 MHz, DMSO-d6) δ ppm 3.60 (s, 3H), 3.25 (dd, J=6.04, 7.85 Hz, 1H), 1.34-1.96 (m, 9H), 0.92-1.14 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH:10](OS(C)(=O)=O)[CH3:11])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O.C(OC(C)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH:10]([N:25]=[N+:26]=[N-:27])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(OS(C)(=O)=O)C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 70 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-methylsulfonyloxybutane (1.1 kg, 2.9 mol) in N,N-dimethylformamide (4.1 L) was added sodium azide (378 g, 5.8 mol), and the reaction was heated at 70° C. for 7 h. After cooling to room temperature, the reaction mixture was diluted with isopropyl acetate (11 L) and was washed with sodium bicarbonate (50% saturated aqueous solution) and water (5.5 L). The organic layer was separated and treated with Darco KB (254 g) overnight. The mixture was filtered over solka floc, washed with toluene and concentrated. The residue was diluted with toluene (1 L) and was loaded onto a silica gel pad, which was eluted with 90:10 hexane/ethyl acetate to give the title compound.
Reaction SMILES: [OH2:1].[C:2](#[N:9])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8]>>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH2:9])=[O:1])#[N:8]
Reactant: O
Reactant: N#CCCCCC#N
Product: N#CCCCCC(N)=O
Yield: 10 %

Procedure:
A process as claimed in claim 1, wherein at least 5 mol of water are employed per mole of adiponitrile and a yield of at least 10% of 5-cyanovaleramide is obtained.
Reaction SMILES: [CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7]Br)[CH:2]=[CH2:3].C([O-])=[O:16].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7][OH:16])[CH:2]=[CH2:3]
Reactant: C=CC[Si](CC=C)(CC=C)CCCBr
Reactant: O=C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: C=CC[Si](CC=C)(CC=C)CCCO

Procedure:
Triallyl(3-hydroxylpropyl)silane was prepared from triallyl-3-bromopropyl silane prepared in Example 7 via the formyloxypropyl intermediate. A 100 ml flask equipped with stir bar and reflux condenser was charged with 10.0 grams (36 millimoles) of triallyl 3-bromopropyl silane (prepared as described in Example 7), 4.90 grams (72 millimoles) sodium formate (commercially available from Aldrich Chemical Co. of Milwaukee, Wis.) and 0.60 grams of tetrabutyl ammonium bromide (commercially available from Aldrich Chemical Co.). The suspension was stirred at 110° C. for two days. The solution was then filtered and combined with equal volumes of deionized water and cyclohexane (commercially available as Omnisolve from E. Merck of Gibbstown, N.J.). The organic extract was flash chromatographed on silica using first cyclohexane, followed by 80/20 cyclohexane/acetone to collect the triallyl formyloxypropyl silane intermediate.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:35])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:35])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[C:11]1[O:12][C:15]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 100.6 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyanophenylamino)butanoyl)-4-cyanobenzohydrazide (1.02 g, 1.98 mmol) in CH2Cl2 (30 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (1.04 g, 3.97 mmol), iodine (1.01 g, 3.97 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 25 min and quenched with sat, aq. sodium thiosulfate (300 mL). The solution was extracted with CH2Cl2 (200 mL). The organic extract was washed with sat. aq. sodium thiosulfate (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20% EtOAc in hexanes) to provide the title compound as a light yellow oil (984 mg, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.22 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.92 (dd, J=2.3, 8.8 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H), 5.10 (dd, J=7.2, 9.2 Hz, 1H), 4.52 (dq, J=6.1, 7.2 Hz, 1H), 1.45 (d, J=6.1 Hz, 3H), 0.75 (s, 9H), 0.09 (s, 3H), −0.07 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[F:26][C:27]1[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=1[C:29](N(OC)C)=[O:30].Cl.O>CCOC(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:29](=[O:30])[C:28]3[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=3[F:26])=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CON(C)C(=O)c1ccccc1F
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of 2-fluoro-N-methoxy-N-methyl-benzamide (140 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl (in dioxane) (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude sulfonamide was finally purified via preparatory TLC (20% EtOAc/hexanes) and recrystallization from MeCN/H2O to afford 98 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ 10.6 (s, 1H), 8.3 (d, 1H), 8.2 (d, 1H), 7.74 (d, 2H), 7.6 (d, 1H), 7.5 (d, 1H), 7.43 (d, 2H), 7.42-7.37 (m, 2H), 1.26 (s, 9H); MS (ES) M+H expect 447.1. found 447.5.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([NH:22][CH2:23][P:24](=[O:29])([O:27]C)[O:25]C)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.Br>>[NH2:11][C@H:12]([C:20]([NH:22][CH2:23][P:24](=[O:25])([OH:29])[OH:27])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COP(=O)(CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OC
Agent: Br
Product: N[C@@H](Cc1ccccc1)C(=O)NCP(=O)(O)O

Procedure:
In a manner analogous to Example 13(b), but with reaction of dimethyl [(N-benzyloxycarbonyl-L-phenylalanyl)-amino]-methylphosphonate and hydrogen bromide/glacial acetic acid for 2 hours, there was obtained (L-phenylalanylamino)methylphosphonic acid of melting point 266°-268° C (decomposition); [α]D20 = +74.5° (c = 0.8% in water).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Cl:11][C:12]1[C:13]([NH2:20])=[C:14]([NH2:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:19]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(Cl)cc(Cl)c1N
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound (Leeson, P. D. et al., J. Med. Chem 34:1243 (1991)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (4.12 g, 28.2 mmol) and 3,5-dichloro-1,2-diaminobenzene (500 mg, 2.82 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale yellow shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 286 mg (44%). mp 326°-328° C. (dec) Lit 337°-340° C.). 1H NMR (d6 -DMSO) δ7.05 (d, 1H, J=1.8, H-8), 7.32 (d, 1H, J=1.8, H-6), 11.5 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/e 234 (M+4, 12), 232 (M+2, 67), 230 (M+, bp), 204 (52), 202 (77), 141 (19), 142 (59) EIHRMS calc. for C8H4Cl2N2O2 229.9650, found 229.9646.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])[CH2:21][CH2:20]2)[N:6]=1)=O.[BH4-].[Na+]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:19]2([CH2:18][C:17]([C:31]([F:32])([F:33])[F:34])([OH:35])[CH2:16][NH:15][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH:13]=[CH:14][C:5]([CH2:3][OH:2])=[N:6]4)[CH2:21][CH2:20]2)[CH:27]=1
Reactant: COC(=O)c1ccc2c(N=CC(O)(CC3(c4cc(F)ccc4OC)CC3)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3nc(CO)ccc23)C(F)(F)F)CC1

Procedure:
Analogously to Example 40, 200 mg (0.41 mmol) of 5-{3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propylidenamino}-quinoline-2-carboxylic acid methyl ester is reacted with 156 mg (4.1 mmol) of sodium borohydride. After working-up and purification on silica gel with hexane-ethyl acetate (0–75%), 119 mg (63% of theory) of the product is obtained.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])[CH3:3].[CH3:14][S:15][C:16](SC)=[CH:17][N+]([O-])=O.C(N(CC)CC)C>C(O)C>[CH3:14][S:15][C:16]1[CH:17]=[C:13]2[N:8]([C:7]=1[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CCOC(=O)C[n+]1ccccc1
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(SC)cc2ccccn12
Yield: 91.8 %

Procedure:
A solution of 1-ethoxycarbonylmethylpyridinium bromide 5 (6.15 g, 25 mmol), 1,1-bis(methylsulphanyl)-2-nitroethylene (8.2 g, 50 mmol) and 25 g of triethylamine in 150 ml of ethanol was heated at reflux for 12 h. Following evaporation of the solvents and of the excess triethylamine, 150 ml of water were added to the residue, and the organic phase was extracted with petroleum ether (75 ml×3). The combined extracts were dried over anhydrous magnesium sulphate, filtered and then concentrated under vacuum. The residual oil was chromatographed on a neutral alumina column, with hexane as the eluting solvent, to give ethyl 2-(methylsulphanyl)-3-indolizinecarboxylate 9 (5.4 g).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:11]1[C:15]2[C:16](=[O:33])[N:17](CCS(C3C=CC=CC=3)(=O)=O)[N:18]([CH3:21])[C:19](=[O:20])[C:14]=2[N:13]=[C:12]1[N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35]1)[C:8]#[C:9][CH3:10]>O1CCCC1.O>[CH2:7]([N:11]1[C:15]2[C:16](=[O:33])[NH:17][N:18]([CH3:21])[C:19](=[O:20])[C:14]=2[N:13]=[C:12]1[N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35]1)[C:8]#[C:9][CH3:10]
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(C)n(CCS(=O)(=O)c3ccccc3)c(=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(C)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.11 g potassium-tert-butoxide are added to a solution of 0.52 g of (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-6-(2-phenylsulphonyl-ethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione in 5 ml of tetrahydrofuran. The solution is stirred for 10 min at ambient temperature and then diluted with water. It is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is then removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate).
Reaction SMILES: [C:1]([O:6]CC)(=O)[C:2]([CH3:4])=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]([NH2:27])=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:17]3[C:18](=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)[N:27]=[C:2]([CH3:4])[C:1]2=[O:6])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1ccc(Cl)cc1
Product: Cc1nc2cc(C(F)(F)F)ccc2n(-c2ccc(Cl)cc2)c1=O

Procedure:
Preparation as in Example 1 but using ethyl pyruvate and N-(4-chlorophenyl)-4-trifluoromethylbenzene-1,2-diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1N1CCCC1
Product: Cc1c(C(=O)Nc2ccc(N3CCCC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 23.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.3 g) and 5-amino-2-pyrrolidinobenzonitrile (0.8 g), the title compound (0.4 g) was obtained, melting point: 205° C.