Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C(=O)C>[C:19]([C:18]1[CH:27]=[CH:28][C:29]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:16]([Cl:15])[CH:17]=1)(=[O:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1Cl
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.46 g) in N,N-dimethylacetamide (6 mL) was rapidly added thionyl chloride (0.35 g) and the mixture stirred at -15° to -20° C. for 1 hour. 3-Chloro-4-aminobenzophenone (0.45 g) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into ice water and filtered through diatomaceous earth. The diatomaceous earth was washed with methylene chloride, the organic solution dried and the solvent removed. Chromatography (eluent methylene chloride, then 5% ethyl acetate in methylene chloride) gave the title compound (0.31 g) as a white solid; mp 142°-144° C. Analysis for C17H13ClF3NO3 : Calculated: C, 54.92; H, 3.53; N, 3.77; Found: C, 54.89; H, 3.63; N, 3.68.
Reaction SMILES: N[CH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1.C=O.[C:28](O)(=O)C.[C:32]([BH3-])#[N:33].[Na+]>C(#N)C>[CH3:28][N:33]([CH3:32])[CH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=3[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][CH2:13][C:7]2=[N:6][N:5]=1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: NCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 22, a mixture of 1-(2-aminoethyl)-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, 37% aqueous formaldehyde and acetic acid in acetonitrile is treated with sodium cyanoborohydride and the resulting boron complex is warmed with aqueous ethylenedizmine to give 1-[2-(dimethylamino)ethyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:65][CH2:66][CH:67]([OH:70])[CH2:68][OH:69]>CN(C=O)C.CCOC(C)=O>[OH:70][CH:67]([CH2:68][OH:69])[CH2:66][NH:65][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)=[CH:10][C:2]=1[F:1]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Reactant: NCC(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(-c2nc(-c3ccc(C(=O)NCC(O)CO)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoic acid (75 mg, 0.18 mmol) was dissolved in anhydrous DMF (1 mL). N-ethyldiisopropylamine (65 μl, 0.38 mmol) was added followed by HATU (72 mg, 0.19 mmol) and the reaction was stirred at RT for 15 minutes. 3-Amino-1,2-propanediol (17 mg, 0.19 mmol) was added and the reaction stirred at RT overnight. EtOAc was added and the organic phase was washed three times with a 1N aqueous solution of HCl and brine. It was dried on MgSO4, filtered and concentrated. It was purified on preparative HPLC to afford the title compound as a brown solid. LC/MS (Method B): 492.2 (M+H)+, 490.3 (M−H)−. HPLC (Method A) Rt 4.82 min (Purity: 95.9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:14]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:20][CH:21]=3)=[N:13][CH:12]=[N:11][C:10]=2[N:9](COCC[Si](C)(C)C)[CH:8]=1.C(C(O)=O)(F)(F)F.C(N)CN.[OH-].[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:14]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:20][CH:21]=3)=[N:13][CH:12]=[N:11][C:10]=2[NH:9][CH:8]=1
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(-c2ccccn2)cn3COCC[Si](C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(-c4ccccn4)c23)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-(5-(pyridin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide (170 mg, 0.350 mmol) in dichloromethane (2.0 mL), was added CF3CO2H (2.0 mL). The resulting solution was stirred for 2 hours at 50° C. and then concentrated in vacuo. The residue was dissolved in methanol (2 mL), and ethane-1,2-diamine (42 mg, 0.70 mmol) and sodium hydroxide (98 mg, 1.6 mmol) were added. The resulting solution was stirred for 30 minutes at room temperature before being concentrated in vacuo. The resulting solution was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the crude product by reverse phase HPLC using an acetonitrile gradient in water with 0.5% TFA modifier afforded N-(3-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a white solid. LRMS (ESI) calc'd for C21H18N5O [M+H]+: 356, found 356. 1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 8.27 (s, 1H), 8.12-8.16 (m, 1H), 7.90 (s, 1H), 7.64-7.68 (m, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.50 (d, J=6.8 Hz, 1H), 7.37-7.40 (m, 2H), 5.72 (s, 1H), 5.52 (s, 1H), 1.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:3]([CH2:12][Br:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(Br)c1C
Solvent: CC#N
Product: COC(=O)c1cccc(Br)c1CBr
Temperature: 25 °C
Yield: 107.2 %

Procedure:
A mixture of methyl 3-bromo-2-methylbenzoate (17.0 g, 74.22 mmol) and N-bromosuccinimide (15.85 g, 89.06 mmol) in acetonitrile (200 mL) was heated under gently refluxing for 17 hours while a 200 W bulb situated 2 cm away was shining on the reaction flask. The mixture was cooled to room temperature and solvent was removed. The residue was dissolved in ethyl acetate (200 mL) and washed with water (3×80 mL), brine (80 mL) and dried (MgSO4). Solvent was removed to give methyl 3-bromo-2-bromomethylbenzoate (24.5 g, 97% by HPLC): 1H NMR (CDCl3) δ 7.90-7.86 (dd, J=1.0 and 7.9 Hz, 1H), 7.78-7.74 (dd, J=1.2 and 8.2 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 5.12 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(F)cc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-(bromomethyl)-2,4-difluorobenzene (0.70 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.82 g, 50%).
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][C:10]2[S:14][N:13]=[C:12]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]=2[C:21](=[O:23])[NH2:22])C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[OH-].[Na+]>O1CCCC1>[CH2:16]([S:15][C:12]1[C:11]([C:21]([NH2:22])=[O:23])=[C:10]([NH:9][C:8]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:24])[S:14][N:13]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NCCCN1CCCC1
Reactant: CCCCCSc1nsc(NC(=O)Oc2ccccc2)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCSc1nsc(NC(=O)NCCCN2CCCC2)c1C(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
To a mixture of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid phenyl ester (0.10 g, 0.27 mmol) and 1 mL of tetrahydrofuran was added N-3-aminopropylpyrollidine (0.175 g, 1.4 mmol). After stirring for 72 hours at ambient temperature, the mixture was poured into 1M NaOH, extracted twice with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated. Purification of the residue by radial chromatography (2 mm plate, 3% ethanol-CH2Cl2-30% ethanol-CH2Cl2 containing 0.5% NH4OH), followed by concentration and trituration of the residue with ether-hexane afforded 0.076 g (78%) of 3-pentylsulfanyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylic acid amide as a colorless solid 1H NMR (400 MHz, CDCl3) a 7.57 (bs, 1H), 7.06 (bs, 2H), 3.35 (m, 2H), 3.26 (m, 2H), 2.53 (t, 2H, J=6.8 Hz), 2.47 (m, 4H), 1.73 (m, 8H), 1.4-1.2 (m, 4H), 0.88 (t, 3H, J=7.2 Hz) ppm; MS (APCI, m/z): 400 [M+H]F.
Reaction SMILES: C(CCC(O)=S)(=O)C.S(Cl)(Cl)=O.[C:13]([S:16][CH2:17][CH2:18][C:19](Cl)=[O:20])(=[O:15])[CH3:14].Cl.[NH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH:24]1[C:33]([OH:35])=[O:34].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:13]([S:16][CH2:17][CH2:18][C:19]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH:24]1[C:33]([OH:35])=[O:34])=[O:20])(=[O:15])[CH3:14]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: O=C(O)C1CCc2ccccc2N1
Agent: CC(=O)CCC(O)=S
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)SCCC(=O)N1c2ccccc2CCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Acetylthiopropanoic acid (132 g) in toluene (200 ml) was treated with thionyl chloride (300 ml). The resulting solution was warmed on the steam bath for two hours, stirred overnight at room temperature then evaporated to dryness under reduced pressure, and finally distilled, to yield 139 g, b.p. (0.35-0.50 mm) 64°-66° of 3-acetylthiopropanoyl chloride. A solution of (±)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid hydrochloride (32.05 g) in pyridine (300 ml) was treated dropwise with 3-acetylthiopropanoyl chloride (25 g) with vigorous stirring. After stirring overnight, the reaction mixture was added to ice (600 g), acidified with concentrated hydrochloric acid, and extracted with ether. The combined ether extracts were concentrated under vacuum to a solid product, which was washed with cold ether (50 ml). This product, 1-(3-acetylthio-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, was crystallized from ethyl acetate-hexanes; yield 19 g, m.p. 89°-91°.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([NH:17][C:18]3([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7](NC(N)=N)=[N:6][CH:5]=1.Cl.Cl.NC1(C(N2CCN(C)CC2)=O)CCCC1.[Cl:53]C1C2C(=CC=C(S(Cl)(=O)=O)C=2)C(Cl)=CN=1>C(Cl)Cl>[Cl:53][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([S:14]([NH:17][C:18]3([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])[CH:9]=2)[C:4]([Cl:3])=[CH:5][N:6]=1
Reactant: CN1CCN(C(=O)C2(NS(=O)(=O)c3ccc4c(Cl)cnc(NC(=N)N)c4c3)CCCC2)CC1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: CN1CCN(C(=O)C2(N)CCCC2)CC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)C2(NS(=O)(=O)c3ccc4c(Cl)cnc(Cl)c4c3)CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.5 %

Procedure:
4-Chloro-1-guanidino-N-{1-[(4-methylpiperazino)carbonyl]cyclopentyl}-7-isoquinolinesulphonamide dihydrochloride ##STR90## Triethylamine (1.36 ml, 10.0 mmol) was added to a solution of (1-aminocyclopentyl)(4-methyl-1-piperazinyl)methanone dihydrochloride (567 mg, 2.0 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (592 mg, 2.0 mmol) in CH2Cl2 (25 ml), and the reaction stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and water, and the layers separated. The organic phase was washed with water, extracted with HCl (2N), and these combined acidic extracts washed with EtOAc, and re-basified using Na2CO3. This aqueous solution was extracted with EtOAc, the combined organic extracts washed with brine, dried (Na2SO4) and evaporated in vacuo to give a foam. This was crystallised from CH2Cl2 -i-Pr2O to afford 1,4-dichloro-N-{1-[(4-methyl-1-piperazinyl)carbonyl]cyclopentyl}-7-isoquinolinesulphonamide (153 mg, 0.33 mmol) as a solid.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18]CC(O)=O)(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(N[C@H]2CC[C@H](C)CC2)CCCCC1.C([O:46][C:47](=[O:60])[CH2:48][CH2:49]NS(C1SC(N)=NC=1)(=O)=O)C>>[CH:24]1([N:7]([C@H:1]2[CH2:6][CH2:5][C@H:4]([CH3:30])[CH2:3][CH2:2]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:49][CH2:48][C:47]([OH:60])=[O:46])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)CCNS(=O)(=O)c1cnc(N)s1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and 3-(2-amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][N+:17]([O-:19])=[O:18].C(C1C=CC=C(C(C)(C)C)C=1[O-])(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:16]2[N+:17]([O-:19])=[O:18])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: O=[N+]([O-])CBr
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Temperature: -19 °C
Reaction time: 0.25 h
Yield: 319.7 %

Procedure:
A stirred mixture of 9.4 g of 4A bead molecular sieves, 9.4 g of dry Celite, (trademark), 5.62 g (30 mmol) of N-benzylmaleimide, and 120 mL of dry toluene under nitrogen was cooled to -19° C. and treated with 2.7 mL (3.9 mmol, 1.3 equivalents) of bromonitromethane. Tetrabutylammonium 2,6-di-t-butylphenoxide, the title product of Example 1, 23.38 g, was added, via a solid addition funnel, over 1.75 hours to the stirred reaction mixture at -19° C. After 15 minutes of further stirring, the reaction mixture was warmed to -1° C. and treated with 60 mL of 2N hydrochloric acid with vigorous stirring. The mixture was stirred for 1 hour and filtered through a Celite pad. The filtered solids were washed two times with 100 mL of toluene and the combined toluene solutions were washed two times with 60 mL of 2N hydrochloric acid, two times with 50 mL of water and once with brine. The resulting solution was stirred with 3.0 g of Darco (trademark) KBB overnight and filtered. The recovered Darco was washed two times with 50 mL of toluene, the toluene solutions were combined and the toluene was removed under vacuum to yield 14.95 g of a partially solidified orange-brown oil. This material was dissolved in 30 mL of toluene at 50° C. The toluene was removed by distillation under reduced pressure at 50° C., using a heated oil bath, while maintaining a constant volume by adding a total of 120 mL of isopropanol. This resulting slurry was stirred at 50° C. for 3 hours. Heating of the mixture was discontinued and the mixture was allowed to slowly cool to room temperature overnight. The mixture was then cooled to 0° C. for 3 hours and filtered. The filtered solids were washed with 10 mL of cold isopropanol followed by hexanes, and dried under vacuum giving 3.07 g (42% yield) of the title compound as a light tan solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.C(N(CC)CC)C.[C:41](=[O:44])([O-])O.[Na+]>ClCCl>[C:14]([OH:16])(=[O:15])[CH3:13].[Cl:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([NH:29][C:41](=[O:44])[CH2:12][C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[CH2:27][CH2:28]1
Reactant: O=C(O)CCc1nnc(-c2ccccc2)o1
Reactant: O=C([O-])O
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O
Product: O=C(Cc1nnc(-c2ccccc2)o1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h

Procedure:
3-(5-Phenyl-1,3,4-oxadiazol-2-yl)propanoic acid (0.175 g) and N,N′-carbonyldiimidazole (0.148 g) in dichloromethane was stirred under nitrogen for 30 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.263 g), and triethylamine (0.126 g) was then added and allowed to stir for 2 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid. This solid was purified by chromatography using 2.5% ethanol/dichloromethane. The solvent was removed under reduced pressure and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile) followed by 1 ml of glacial acetic acid being added and the solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(5-phenyl-1,3,4-oxadiazol-2-yl)acetamide acetate (0.024 g).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[C:7]([Br:15])=[CH:6][C:5]=1[Cl:16].O.[OH-].[Li+]>CO>[Br:15][C:7]1[C:8]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([Cl:16])[CH:6]=1
Reactant: COC(=O)c1cc(OC(F)(F)F)c(Br)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(OC(F)(F)F)c(Br)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a mixture of 4-bromo-2-chloro-5-trifluoromethoxy-benzoic acid methyl ester (1.0 g, 3.0 mmol, Preparation 48) dissolved in methanol (4 mL) and water (4 mL) was added lithium hydroxide (360 mg, 15 mmol). The reaction mixture was stirred at 60° C. for 1 h and concentrated. The reaction mixture was adjusted to acidic pH with 1 N HCl, dissolved in EtOAc (60 mL) and washed with water (60 mL). The aqueous layer was extracted with EtOAc (60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to produce the title intermediate (966 mg, 100% yield) as a white powder.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 56.9 %

Procedure:
Next, 0.73 g (1.37 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[(4-chlorophenyl)(methyl)phosphono]butanoate and 0.89 g (8.22 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.55 g (4.11 mmol) of aluminum trichloride. After stirring was carried out at room temperature for 1 hour, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of ether three times and the water layer was separated and methanol was added to adjust the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, the eluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with 40% methanol at a flow rate of 6 mL/min and the fractions of the compound were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[(4-chlorophenyl)(methyl)phosphono]butanoic acid (0.24 g, yield 57%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]=[P:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:30][I:31]>C1C=CC=CC=1>[I-:31].[CH3:30][N:10]([P+:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: CI
Reactant: CC(=O)c1cccc(N=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: c1ccccc1
Product: CC(=O)c1cccc(N(C)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [I-]
Yield: 63 %

Procedure:
A solution of 140.2 gm of 3-acetylphenyliminotriphenyl phosphorane and 56.9 gm of methyl iodide in 525 ml of dry benzene was refluxed for 8 hours in an atmosphere of nitrogen. The mixture was cooled, and the precipitate was filtered off, washed with benzene and dried, yielding 120 gm of the title compound, m.p. 178°-180° C.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][C:12](=[CH2:14])[C:11]([CH:15]([CH3:18])[CH:16]=[CH2:17])=[CH:10]1)(C(C)(C)C)(C)C.CCOCC>O1CCCC1>[CH3:18][CH:15]([C:11]1[C:12](=[CH2:14])[CH2:13][CH:9]([OH:8])[CH:10]=1)[CH:16]=[CH2:17]
Reactant: C=CC(C)C1=CC(O[Si](C)(C)C(C)(C)C)CC1=C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(C)C1=CC(O)CC1=C
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
2.02 Grams of (RS)-3-(1-methyl-2-propenyl)-4-methylidenecyclopent-2-en-1-yl t-butyldimethylsilyl ether was dissolved in 20 ml of tetrahydrofuran. Under ice-water cooling, 7.7 ml of a tetrahydrofuran solution of 1M n-tetrabutylammonium fluoride was added to the ether solution, and then stirred at an ambient temperature for six hours. The reaction solution was poured into ice-water and extracted with ether. The ether layer was washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the oily substance obtained was subjected to silica gel column chromatography to yield 1.05 g of (RS)-3-(1-methyl-2-propenyl)-4-methylidenecyclopent-2-en-1-ol. Yield 91%