Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CCN=C=NCCCN(C)C.[NH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].S(C1C=CC(C)=CC=1)([O-])(=O)=O.CN1CCOCC1>C(Cl)(Cl)Cl.C(#N)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
Boc-Gly-OH (17.52 g, 0.1 mole) in a mixture of CHCl3 (50 ml) and acetonitrile (50 ml) was cooled to -15° C. and EDCI (19.17 g, 0.1 mole) was added and stirred for 20 minutes. To this, a pre-cooled solution of H-Gly-OBzl.tosylate (37.1 g, 0.11 mole), NMM (12.09 ml, 0.11 mole) in CHCl3 (100 ml) was added and stirred overnight at room temperature. After removing the solvent, the residue was taken in CHCl3 and extracted with acid and base. Chloroform was removed under reduced pressure, triturated with pet. ether, filtered, washed with pet. ether and dried to obtain 30.2 g of I (yield: 93.7%), m.p. 82°-83° C. Rf2, 0.52; Rf4, 0.82. Anal. Calcd. for C16H22N2O5:C, 59.61; H, 6.88; N, 8.69%. Found: C, 59.43; H, 6.88; N, 8.35%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[F:10].[Na].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>O1CCCC1>[F:10][C:4]1[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][CH:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Fc1cccc(CBr)c1F
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc(F)c1F)C(C)=O
Yield: 78.8 %

Procedure:
A solution of 1-(bromomethyl)-2,3-difluorobenzene (1.6 g) and ethyl acetoacetate sodium salt (2.36 g) in tetrahydrofuran (20 mL) was stirred for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.56 g, 79%) as a colorless viscous oil.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14](=[O:18])/[CH:15]=[CH:16]/[CH3:17]>C(OCC)C>[CH2:1]([S:13][CH:15]([CH2:16][CH3:17])[CH:14]=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C/C=C/C=O
Reactant: CCCCCCCCCCCCS
Solvent: CCOCC
Product: CCCCCCCCCCCCSC(C=O)CC
Temperature: 25 °C

Procedure:
Lauryl mercaptan (1 mole) was stirred with diethyl ether (150 ml) at 10° C and to this was added dropwise crotonaldehyde (1 mole) over a period of 2 hours. After the completion of the addition, the reaction mixture was warmed to room temperature and reacted for a further 22 hours. The reaction mixture was then distilled to give a laurylmercaptobutyraldehyde product fraction (0.90 moles) of boiling range 147°-150° C at 1.5 mm Hg. The reaction mixture was maintained under nitrogen at all times.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([S:17][CH2:18][C:19]([NH:21][C:22]2[C:31]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=3)=[C:25]3[N:26]=[CH:27][C:28]([CH3:30])=[CH:29][N:24]3[N:23]=2)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH:12]1([S:17]([CH2:18][C:19]([NH:21][C:22]2[C:31]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=3)=[C:25]3[N:26]=[CH:27][C:28]([CH3:30])=[CH:29][N:24]3[N:23]=2)=[O:20])=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc2c(-c3ccc(F)c(C)c3)c(NC(=O)CSC3CCCC3)nn2c1
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(-c3ccc(F)c(C)c3)c(NC(=O)CS(=O)C3CCCC3)nn2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Solid m-chloroperoxybenzoic acid (30 mg, about 50% titre, 0.10 mmol) was added to an ice-cooled solution of the product from Example 143D (37 mg, 0.093 mmol) in CHCl3 (7 mL). The yellow solution was stirred with ice cooling for 15 minutes, then transferred to a test tube and washed with 20% Na2CO3 (4 mL). The organic phase was concentrated under vacuum, and the residue purified by HPLC (30×100 mm XBridge column eluted with aqueous 0.1 M (NH4)2CO3-MeOH, 80:20-0:100 over 15 min), then by flash chromatography (silica gel eluted with EtOAc-MeOH, 100:0-80:20) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.38-1.54 (m, 1H), 1.64-1.86 (m, 4H), 1.90-2.23 (m, 3H), 2.30 (d, J=1.6 Hz, 3H), 2.38 (s, 3H), 3.34-3.49 (m, 2H), 3.88 (d, J=14.3 Hz, 1H), 7.22-7.31 (m, 1H), 7.34-7.48 (m, 2H), 8.39 (s, 1H), 8.42-8.55 (m, 1H), 9.51 (s, 1H); MS (ESI) m/z 415 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[S:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:52]/[O:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)/[C:49](O)=[O:50])[N:47]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl.Cl>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:49](=[O:50])/[C:48](/[C:46]4[N:47]=[C:43]([NH:42][C:40]([O:39][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:41])[S:44][CH:45]=4)=[N:52]\[O:53][C:54]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)[C@H:22]3[S:21][CH2:20][C:19]=2[CH2:28][S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[S:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CSc3c[nH]nn3)CS[C@H]12
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a suspension of 7β-amino-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (110 mg: 0.2 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (122 mg: 0.23 mMol.) in dichloromethane (3 ml) are added N-methylmorpholine (72 μl: 0.66 mMol.) and phenyl dichlorophosphate (33 μl: 0.22 mMol.) at -30° C. After stirring for 2 hours, the reaction mixture is diluted with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, purified by silica gel chromatography, and crystallized from toluene to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (110 mg). m.p. 190°-200° C. (decomp.).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH2:24][CH3:25])[C:22]([CH3:26])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:27]([O:29][CH2:30][CH2:31][NH2:32])[CH3:28].C(N(CC)C)C.Cl.CCOCC>S(Cl)(Cl)=O.CO>[CH2:24]([N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([S:2](=[O:5])(=[O:3])[NH:32][CH2:31][CH2:30][O:29][CH2:27][CH3:28])=[CH:9][CH:8]=3)[N:18]=2)=[CH:20][N:21]=[C:22]1[CH3:26])[CH3:25]
Reactant: O=S(=O)(O)Cl
Reactant: CCOCCN
Reactant: CCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C
Agent: CCN(C)CC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCOCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3CC)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
Chlorosulphonic acid (280 μl, 4 mmol) was added dropwise to solution of 2-anilino-4-(1-ethyl-2-methylimidazol-5-yl)pyrimidine (Method 30; 279 mg, 1 mmol) in thionyl chloride (5 ml) cooled at 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of 2-ethoxyethylamine (356 mg, 4 mmol) and diethylmethylamine (1 ml, 15 mmol) in MeOH (3 ml) added. The mixture was stirred for 15 minutes and the volatiles were evaporated in vacuo. Water (20 ml) was added and extracted DCM (2×25 ml). DCM was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with DCM:MeOH (100:0 increasing in polarity to 97:3) to yield a white foam. The white foam was dissolved in MeOH (3 ml) and treated with 1M HCl in ether (0.55 ml, 0.55 mmol). The solvent was evaporated in vacuo and the resultant solid triturated with ether, collected by filtration and dried-under vacuum at 60° C. to yield the title compound (128 mg, 47%) as a yellow solid. NMR: 1.05 (t, 3H), 1.30 (t, 3H), 2.76 (s, 3H), 2.88 (m, 2H), 3.32 (m, 4H), 4.76 (m, 2H), 7.37 (d, 1H), 7.52 (m, 1H), 7.73 (d, 2H), 7.90 (d, 2H), 8.43 (s, 1H), 8.65 (d, 1H), 10.14 (brs, 1H); m/z 431.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[CH:22][C:21]=3[Cl:34])[C:15]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:34][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][C@@H:16]1[CH2:17][CH2:18][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCNCC1
Yield: 85 %

Procedure:
Treat a solution of 4-[(R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 17) (0.85 g, 0.18 mmol) in CH2Cl2 (10 mL) with Trifluoroacetic acid (2 mL). Stir the reaction 1 hr at room temperature. Concentrate the reaction in vacuo. Purify the crude on a SCX column using 2M NH4 in MeOH to elute the pure product. Remove the solvent to afford 0.59 g (85%) of product. MS (m/e): 421 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25].CCOC(C)=O.C(Cl)(Cl)Cl>CN(C=O)C.[I-].[Na+]>[CH2:3]([O:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CCCCCCl
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
Sodium iodide (84 mg, 0.56 mmol) and then sodium hydride (80% oil dispersion, 0.49 g, 16.3 mmol) were added to (A) (2.68 g, 12.0 mmol) in dry DMF (40 mL). After stirring 15 min, 5-chlorovaleronitrile (1.5 mL, 13.3 mmol) was added, and the suspension heated at 80°-85° C. for 4 h under argon. After cooling, the reaction was quenched with H2O (100 mL), then extracted with ether (4×75 mL). The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine and then concentrated to give 4.39 g crude product. Column chromatography with 4.5% EtOAc/CHCl3 produced 3.17 g of (B) (87% yield): NMR δ 1.5-1.75 (s+m, 13 H), 2.3 (t, 2 H), 3.4 (t, 2 H), 4.77 (s, 2 H), 7.3 (s, 5 H). Anal. Calcd for C17H24N2O3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.19; H, 7.99; N, 9.11.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]N)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH2:27]=O.[C:29]([BH3-])#[N:30].[Na+]>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:30]([CH3:29])[CH3:27])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(C)C)CC1

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.0 g) as starting compound, 37% formalin (0.45 ml) and sodium cyanoborohydride (0.34 g) were reacted and treated in the same manner as in Example 136 to give 0.48 g of 4-amino-5-chloro-N-((1-(5-dimethylaminopentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1(O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:5])C.C(O)(=[O:34])C>[Zn]>[CH2:27]([N:24]([CH2:25][CH3:26])[CH2:23][CH2:22][N:13]1[CH:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:4]([OH:5])=[O:34])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:21])[CH3:28]
Reactant: CCN(CC)CCN1C(=O)c2ccccc2C1(O)c1ccccc1C(=O)N(CC)CC
Reactant: CC(=O)O
Agent: [Zn]
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccccc1C(=O)O

Procedure:
To a solution of 2.18 g of Compound 29 in 25 ml of acetic acid was added 5 g of zinc powders activated by washing with 2N-hydrochloride. After heating at reflux for 3.5 hours, the mixture was filtered and concentrated under reduced pressure. To the residue was added 20 ml of water, and pH was adjusted to 7 with 10N-sodium chloride solution. Then, filtration was performed and the mother liquor was concentrated under reduced pressure. The residue was subjected to HP-10 high porous polymer column-column chromatography (eluting solvent, water:methyl alcohol=1:3). A major fraction was concentrated to dryness under reduced pressure to give 1.56 g of 2-[2-(2-diethylaminoethyl)isoindolin-1-on-3-yl]benzoic acid (Compound 27).
Reaction SMILES: [CH3:1][CH2:2][C:3]([OH:5])=O.[Cl:6][S:7]([N:10]=C=O)(=[O:9])=[O:8]>C1C=CC=CC=1>[C:3]([NH:10][S:7]([Cl:6])(=[O:9])=[O:8])(=[O:5])[CH2:2][CH3:1]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCC(=O)O
Solvent: c1ccccc1
Product: CCC(=O)NS(=O)(=O)Cl
Yield: 99.6 %

Procedure:
n-Propionic acid (0.741 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (1.71 g, quantitative) as a crystalline, hygroscopic solid.
Reaction SMILES: [CH2:1]([C:8](=[CH:11]OCC)[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH2:1]([C:8](=[CH:11][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCOC=C(C#N)Cc1ccccc1
Product: N#CC(=CN1CCOCC1)Cc1ccccc1
Yield: 40.3 %

Procedure:
9.35 g (0.05 mol) of 2-benzyl-3-ethoxyacrylonitrile and 17.4 g (0.2 mol) of morpholine are refluxed for 20 h. Subsequent vacuum distillation yields 4.6 g of 2-benzyl-3-morpholinoacrylonitrile (81% with respect to the reacted 2-benzyl-3-ethoxyacrylonitrile (50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[N:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH3:12])[CH:6]=1.C(N(CC)CC)C.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:13]=[CH:14]/[C:15]([N:39]=[N+:40]=[N-:41])=[O:17])[N:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH3:12])[CH:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@H]1CCC[C@H]1n1cc(Br)cc1/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CCC[C@H]1n1cc(Br)cc1/C=C/C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of (2E)-3-(4-bromo-1-(cis-2-methylcyclopentyl)-1H-pyrrol-2-yl)acrylic acid (700 mg) in DMF (7 mL) was added a solution of triethylamine (0.36 mL) and diphenylphosphoryl azide (0.678 g) in DMF (1 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (685 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C:8](=O)[C:9]=2[CH:10]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:8]1[CH2:7][CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][C:4]2[NH:3][C:2]([CH3:1])=[CH:10][C:9]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1cc2c([nH]1)CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc2c([nH]1)CC(c1ccccc1)CC2=NNC(=N)N
Yield: 81.5 %

Procedure:
A mixture of 2-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.41 g), concentrated hydrochloric acid (0.18 ml), water (0.18 ml) and ethanol (50 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated. The residue was suspended in ethyl acetate, and the suspension was washed with water. Under reduced pressure, the solvent was evaporated. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-2-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 4) (0.92 g) as colorless crystals.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24]C=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[Cl:46][C:47]1[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:48]=1[CH2:49][N:50]1[CH2:55][CH2:54][N:53](CCCN)[CH2:52][CH2:51]1>>[Cl:46][C:47]1[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:48]=1[CH2:49][N:50]1[CH2:51][CH2:52][N:53]([CH2:24][CH2:25][CH2:20][NH:19][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)[CH2:54][CH2:55]1
Reactant: NCCCN1CCN(Cc2c(F)cccc2Cl)CC1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(NCCCN2CCN(Cc3c(F)cccc3Cl)CC2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-[4-(2-chloro-6-fluorobenzyl)piperazino]propylamine were reacted to yield N2-[3-[4-(2-chloro-6-fluorobenzyl)piperazino]propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=3.0 Hz), 7.37 (d, 1H, J=2.4 Hz), 7.19–7.15 (m, 2H), 7.00–6.93 (m, 2H), 6.81 (d, 1H, J=8.7 Hz), 6.56 (d, 1H, J=2.7 Hz), 5.48 (bs, 1H), 4.27–4.21 (m, 4H), 3.70 (d, 2H, J=31.8 Hz), 3.36 (q, 2H, J=6.3 Hz), 2.68–2.35 (m, 10H), 1.75 (q, 2H, J=6.3 Hz); 19F NMR (CDCl3): −31693, −48483; LCMS: ret. time: 18.20 min.; purity: 97%; MS (m/e): 532 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.C([O:13][C:14]([C:16]1[CH:29]=[C:19]2[C:20](=[O:28])[N:21](CC3CC3)[CH2:22][CH2:23][N:18]2[N:17]=1)=O)C.C1(CN2CCN3N=C(CO)C=C3C2=O)CC1>>[OH:13][CH2:14][C:16]1[CH:29]=[C:19]2[C:20](=[O:28])[N:21]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:22][CH2:23][N:18]2[N:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cc2n(n1)CCN(CC1CC1)C2=O
Agent: O=C1c2cc(CO)nn2CCN1CC1CC1
Product: COc1ccc(CN2CCn3nc(CO)cc3C2=O)cc1

Procedure:
The compound was prepared from 1-(3-tert-butoxycarbonylaminoethyl)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester and 4-methoxybenzyl chloride using the methods described in the preceding examples 49 (5-cyclopropylmethyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester) and 50 (5-cyclopropylmethyl-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:17]([C:20]3[CH:24]=[C:23](C)O[C:21]=3C)(=[O:19])=[O:18])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:29][N:30]1C=C(S(Cl)(=O)=O)C(C)=[N:31]1.FC1C=CC(OC)=C(C2C=CC(C(N)C)=CC=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:17]([C:20]3[C:24]([CH3:23])=[N:31][N:30]([CH3:29])[CH:21]=3)(=[O:19])=[O:18])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Reactant: Cc1nn(C)cc1S(=O)(=O)Cl
Agent: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cn(C)nc2C)cc1

Procedure:
Prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) starting with 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.41, 7.20 (a/b, 4H), 7.39 (s, 1H), 7.05-6.88 (m, 3H), 4.70 (d, 1H), 4.55 (m, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 2.33 (s, 3H), 1.52 (d, 3H) ppm; MS (ESI) m/z: 404 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]([NH2:13])C2C=CC=CC=2)=CC=1.COC1CCCCCN=1.[F:25][C:26]1[CH:39]=[CH:38][C:29]([CH:30]([NH2:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][CH:27]=1.COC1CCCCN=1>>[ClH:1].[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:30]([N:37]=[C:6]2[CH2:5][CH2:14][CH2:15][CH2:2][NH:13]2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:38][CH:39]=1
Reactant: NC(c1ccccc1)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: COC1=NCCCC1
Agent: COC1=NCCCCC1
Product: Cl
Product: Fc1ccc(C(N=C2CCCCN2)c2ccccc2)cc1

Procedure:
By the procedure of Example 1, only substituting respectively for 4-chlorobenzhydrylamine and O-methylcaprolactim, appropriate amounts of 4-fluorobenzhydrylamine and O-methylvalerolactim the title compound was obtained, m.p. 211°-213°C.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1)(=O)=O.C1(O)C=CC=CC=1.[OH:24][C@@H:25]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](O)[CH:37]=1)[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>>[OH:24][C@@H:25]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]2)[CH:41]=1)[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)OCC1CCN(S(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCN(S(C)(=O)=O)CC2)c1

Procedure:
Reaction between (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate and phenol (7, Intermediate I) gives (R)-tert-butyl (3-hydroxy-3-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propyl)carbamate.