Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C[O:10][C@@H:11]1[C@@H:15]([CH2:16][O:17]CC2C=CC(Cl)=CC=2Cl)[O:14][C@@H:13]([N:27]2[CH:39]=[C:31]3[CH:32]=[CH:33][C:34]4[CH2:35][NH:36][N:37]=[CH:38][C:29]([C:30]=43)=[N:28]2)[C@:12]1([CH3:41])[OH:40].B(Cl)(Cl)Cl.CO>C(Cl)Cl>[CH3:41][C@@:12]1([OH:40])[C@H:11]([OH:10])[C@@H:15]([CH2:16][OH:17])[O:14][C@H:13]1[N:27]1[CH:39]=[C:31]2[CH:32]=[CH:33][C:34]3[CH2:35][NH:36][N:37]=[CH:38][C:29]([C:30]=32)=[N:28]1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc2ccc3c-2c(n1)C=NNC3
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c-2c(n1)C=NNC3
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 20.1 %

Procedure:
To compound 24.1 (160 mg, 0.25 mmol) in CH2Cl2 (10 mL) at −78° C. was added 1M solution of boron trichloride in CH2Cl2 dropwise over 5 minutes and the solution stirred at −78° C. for 2.5 h and then at −25° C. for 3 hr. To this mixture was added 25 mL of 1:1 v/v CH2Cl2:MeOH and the solution stirred at −15° C. for 30 minutes. The mixture was brought to room temperature and the solvent was evaporated under reduced pressure. The residue was co-evaporated with MeOH (5×10 mL) and a 10 mL MeOH solution was neutralized with NH4OH and evaporated again. The residue was adsorbed on 2 g silica gel and loaded on a silica column and eluted successively with 50:1,20:1 and 15:1 CH2Cl2:MeOH. Fractions eluting at 20:1 and 15:1 were collected, Pooling of fraction and evaporation gave 16 mg product 24.2. 1H NMR (DMSO-d6) δ 8.10 (s, 1H), 7.51 (s, 1H), 7.30 (t, 1H), 6.61 (d, J 9 Hz, 1H), 6.11 (s, 1H), 5.71 (dt, J 6, 12 Hz, 1H), 5.08 (m, 3H), 3.86 (m, 5H), 3.78 (m, 1H), 0.72 (s, 31).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Br.O.[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([OH:14])([CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.05 mmol) in diethyl ether (20 mL) at −25 to −30° C. was added methyl magnesium bromide (3M in diethyl ether, 3.35 mL, 10.05 mmol) dropwise under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (20 mL) was then added dropwise, followed by saturated ammonium chloride (20 mL) and the ether layer was separated. The aqueous phase was further extracted with ether (50 mL) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (2.09 g, 97%). 1H NMR (CDCl3, 300 MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m, 2H), 2.48-2.39 (m, 1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>CO.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([C:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:19])(=[O:1])[CH2:7][CH2:6]2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCS(=O)(=O)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: Nc1cccc(C(=O)N2CCS(=O)(=O)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a stirred solution of (1,1-dioxidothiomorpholino)(3-nitrophenyl)methanone (3.5 g, 12.31 mmol) in MeOH (20 ml) was added Pd—C (10%, 350 mg) followed by slow addition of triethylsilane (8.5 ml) at RT. Reaction was stirred at RT for 1 h. Reaction mixture was filtered through celite and washed with methanol (50 ml). Filtrate was concentrated under vacuum and triturated in hexane to get crude product (2.8 gm).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:21][O:20][N:19]([CH3:18])[C:13]([CH:10]1[CH2:9][CH2:8][N:7]([C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:16])=[O:6])[CH2:12][CH2:11]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 89.5 %

Procedure:
A solution of 1-(1,1-Dimethylethyloxycarbonyl)-4-piperidine carboxylic acid (11.3 g, 49.3 mmol), N,O-dimethylhydroxylamine hydrochloride (5.77 g, 59.1 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (11.33 g, 59.1 mmol), 4-dimethylaminopyridine (602 mg, 4.93 mmol) and triethylamine (14.96 g, 148.0 mmol) in dichloromethane (200 mL) was stirred at room temperature for 18 h. The mixture was concentrated to ca. 25 mL, then was poured into 1M hydrochloric acid (75 mL) and extracted with ethyl acetate (3×75 mL). The organic extracts were washed sequentially with 1M hydrochloric acid (50 mL), 10% (w/v) aqueous sodium carbonate (2×50 mL) and brine (50 mL), combined, dried over Na2SO4, filtered and evaporated to afford the title compound as a clear syrup (12.0 g, 44.1 mmol, 89%). 1H NMR CDCL3 : δ4.2 (brm, 2H, eq-H--C(2)), 3.72 (s, 3H, ° CH3), 3.19 (s, 3H, NCH3), 2.8 (brm, 3H, ax-H--C(2), H--C(4)), 1.7 (brm, 4H, H--C(3)), 1.46 (s, 9H, (CH3)3C).
Reaction SMILES: [CH3:1]C1C=C2NC(=O)C3C=NC=CC=3N2N=1.[Cl:16][C:17]1[N:31]=[CH:30][C:20]2[C:21](=[O:29])[NH:22][C:23]3[N:24]([N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]=2[CH:18]=1>>[CH3:28][C:26]1[CH:27]=[C:23]2[N:22]([CH3:1])[C:21](=[O:29])[C:20]3[CH:30]=[N:31][C:17]([Cl:16])=[CH:18][C:19]=3[N:24]2[N:25]=1
Reactant: Cc1cc2[nH]c(=O)c3cnccc3n2n1
Reactant: Cc1cc2[nH]c(=O)c3cnc(Cl)cc3n2n1
Product: Cc1cc2n(C)c(=O)c3cnc(Cl)cc3n2n1
Yield: 73 %

Procedure:
When in Example 3 the 2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one is replaced by the 8-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one pf Example 1b, 2,4-dimethyl-8-chloropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one is obtained, yield: 73%; m.p. 253.8° (DMF).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[C:17]([N:27]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.CC(C)([O-])C.[Na+].[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:15][C:16]1[C:17]([N:27]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[C:8]1[N:13]=[CH:12][C:11]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[CH:10][N:9]=1
Reactant: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(Br)cn3)c(N(CC3CC3)CC3CC3)nc12
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(N4CCOCC4)cn3)c(N(CC3CC3)CC3CC3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.2 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine (0.32 g,0.47 mmol), tris(dibenzylideneacetone)dipalladium (0.07 g, 0.08 mmol), (2-biphenyl)-di-tert-butylphosphine (0.02 g, 0.06 mmol), sodium tert-butoxide (0.09 g, 1 mmol), morpholine (0.08 ml, 0.9 mmol) in toluene was stirred at ambient temperature for 24 h. Thereafter, the reaction mixture is quenched with water and extracted with ethyl acetate (2×30 mL). The combined organic extracts was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified by chromatography using silica gel to afford the title compound as a colorless solid (0.11 g, 35%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]([O:20]CC)=O.C(N1C2C(=CC=CN=2)C(O)=C(C(OCC)=O)C1=O)C1C=CC=CC=1.[NH2:47][C:48]1[CH:53]=[CH:52][C:51](Br)=[CH:50][C:49]=1[S:55]([NH2:58])(=[O:57])=[O:56]>>[NH2:58][S:55]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[NH:47][C:18]([C:3]1[C:4](=[O:17])[N:5]([O:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:20])(=[O:56])=[O:57]
Reactant: CCOC(=O)c1c(O)c2cccnc2n(OCC(C)C)c1=O
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Agent: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: CC(C)COn1c(=O)c(C(=O)Nc2ccccc2S(N)(=O)=O)c(O)c2cccnc21

Procedure:
The title compound was prepared according to the procedure of Example 84C substituting the product of Example 158C for the product of Example 84B and substituting 2-aminosulfonamide for the product of Example 84A (0.225 g, 86%). MS (DCI) m/z 433 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].Cl.CCOCC.[N:34](OCCC(C)C)=[O:35]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:27])[C:4](=[N:34][OH:35])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: COC(=O)CC(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)CC1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)C(=NO)C(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)CC1
Reaction time: 0.17 h

Procedure:
To 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-piperidin-1-yl]-3-oxo-propionic acid methyl ester (5.3 mmol, 2.0 g) was added a solution of HCl/Et2O (1N, 55 mL) and isoamyl nitrite (6.36 mmol, 0.854 mL) at room temperature. After 10 minutes, the reaction mixture had become homogenous, and a white precipitate formed after and additional 30 minutes. After 3 hours, the reaction mixture was diluted with EtOAc and washed with H2O. The aqueous phase was extracted with EtOAc, the organics dried (Na2SO2) and concentrated in vacuo. The residue was triturated in Et2O/hexane to yield the title compound as a white solid, mp=159°-160° C. (4.7 mmol, 1.89 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4](I)=[C:5]([CH3:9])[C:6]=1[CH2:7][OH:8].[Na].[CH3:12][OH:13]>>[CH3:1][C:2]1[S:3][C:4]([O:13][CH3:12])=[C:5]([CH3:9])[C:6]=1[CH2:7][OH:8]
Reactant: Cc1sc(I)c(C)c1CO
Reactant: CO
Agent: [Na]
Product: COc1sc(C)c(CO)c1C

Procedure:
12.0 G. (0.151 mol) of cupric oxide and 12.5 g. (0.0466 mol) of 2,4-dimethyl-3-hydroxymethyl-5-iodothiophene were added to a solution of 12.5 g. (0.543 mol) of sodium in 100 ml. of dry methanol. The reaction mixture was heated to 80°-82° C. (internal temperature) for 20 hrs. with vigorous stirring, then cooled. The cold solution was diluted with 150 ml. of methanol, filtered, poured into ice water and extracted with ether/hexane (ratio 4:1). The organic layers were washed with 5% sodium carbonate solution, dried and evaporated. The residue which resulted was recrystallized from hexane to yield 2,4-dimethyl-3-hydroxymethyl-5-methoxythiophene, m.p. 55°-60° C. This product contained about 10% of 2,4-dimethyl-3-hydroxymethylthiophene which is formed in this reaction by reduction of the iodide. Fraction recrystallization of a sample from hexane yielded pure 2,4-dimethyl-3-hydroxymethyl-5-methylthiophene, m.p. 64°-65° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1)#[N:2].Br.[Br:13][CH2:14][CH2:15][CH2:16][NH:17][C@H](C(O)=O)C.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:17][CH2:16][CH2:15][CH2:14][Br:13])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@H](NCCCBr)C(=O)O
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NC(=O)NCCCBr)cc1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To 10.0 g (0.07 mole) 4-cyanophenyl isocyanate in mL methylene chloride at 23° C. was added with stirring 15.2 g (0.07 mole) 3-bromopropylalanine hydrobromide. To this was added 7.08 g (0.07 mole) triethylamine via syringe. After the addition was complete the reaction was allowed to proceed for one hour. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate (2×50 mL), dilute aqueous hydrochloric acid, dried (Na2SO4) and concentrated to give 13.8 g (85%) of desired N-4-cyanophenyl-N'-3-bromopropyl urea contaminated with 15% isocyanate dimer.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH:12]2[N:17](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:16][CH2:15][N:14]([C:31]([C@@H:33]3[CH2:37][C@H:36]([S:38][C:39]4[C@H:40]([CH3:63])[C@@H:41]5[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]5[C:43]=4[C:44]([O:46]CC4C=CC([N+]([O-])=O)=CC=4)=[O:45])[CH2:35][N:34]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:32])[CH2:13]2)=[O:11])=CC=1)([O-])=O>O1CCCC1.O>[C:10]([CH:12]1[NH:17][CH2:16][CH2:15][N:14]([C:31]([C@@H:33]2[CH2:37][C@H:36]([S:38][C:39]3[C@H:40]([CH3:63])[C@@H:41]4[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]4[C:43]=3[C:44]([OH:46])=[O:45])[CH2:35][NH:34]2)=[O:32])[CH2:13]1)([OH:11])=[O:9]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(C(=O)O)C4)C3)[C@H](C)[C@H]12
Yield: 51.2 %

Procedure:
160 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3-(4-nitrobenzyloxycarbonyl)-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 3 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 160 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 35 mg of the title compound, as a powder.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[C:20]#[C:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>ClCCl>[F:1][C:20]#[C:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(C#CCl)cc2)CC1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CF)cc2)CC1
Reaction time: 24 h

Procedure:
110 ml of 1 molar solution of tetrabutylammonium fluoride in dichloromethane are added at 0° C. to a solution of 28.85 g (0.1 mol) of 1-(2-chloroethynyl)-4-(trans-4-pentylcyclohexyl)benzene in 150 ml of dichloromethane. The reaction mixture is boiled for 24 hours and evaporated in vacuo, and the residue is then extracted with 3×150 ml of petroleum ether (30°-50° C.). The combined petroleum ether phases are dried over magnesium sulphate and evaporated. The product is obtained from the resultant residue by chromatography using petroleum ether as eluent.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[N:28]1([C:32]([C@@H:34]2[CH2:38][CH:37]([F:39])[CH2:36][NH:35]2)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:32]([C@@H:34]2[CH2:38][CH:37]([F:39])[CH2:36][N:35]2[C:2]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=3)[NH:4][C:3]2=[O:12])=[O:33])[CH2:31][CH2:30][CH2:29]1
Reactant: O=C([C@@H]1CC(F)CN1)N1CCC1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N2CC(F)C[C@H]2C(=O)N2CCC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 2.37 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 10-3 (3.82 g, crude form) as starting materials, respectively 874 mg (Isomer A: colorless solid) and 1.45 g (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[C:15]1([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cccc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2cccc3ccccc23)cc1
Yield: 80.4 %

Procedure:
A mixture of 4-[[2-(1-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.7 g) in methanol and 0.5N sodium hydroxide (6 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from dichloro-methane-diethyl ether to give 0.54 g of colorless 4-[[2-(1-naphthalenyloxy) ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 124°-125° C. after drying over phosphorus pentoxide at 60° C. and 0.1 mm.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](#[N:17])[C:14]([CH3:16])=[CH2:15].[H-].[Na+].C(O)(=O)C>C(O)C>[CH2:10]([O:9][P:8]([CH2:15][CH:14]([C:13]#[N:17])[CH3:16])([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[O:12])[CH3:11]
Reactant: C=C(C)C#N
Reactant: CCOC(OCC)P([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(C)C#N)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 23.5 g of ethyl (diethoxymethyl)phosphonite and 6.7 g of methacrylonitrile in 30 ml of ethanol is added dropwise to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl-2-cyanopropyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+40.4 and +40.3 ppm (CDCl3).
Reaction SMILES: C(OO)(=[O:3])C.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([O:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[N:8]=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(O)C>[NH2:6][C:7]1[N+:12]([O-:3])=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([O:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[N:8]=1
Reactant: CC(=O)OO
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6.75 ml of 40% peracetic acid are added dropwise at 0° to a suspension of 3.4 g (10 mmol) of methyl 2-amino-6-([p-toluenesulfonyl)oxy]-4-pyrimidinecarbamate in 120 ml of absolute ethanol. The mixture is stirred at room temperature for 48 hours and thereafter poured into an aqueous solution of sodium sulfite. Ethyl acetate is added thereto, the organic phase is separated, dried over sodium sulphate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride/methanol, there being obtained methyl 2-amino-6-[(p-toluenesulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide of melting point 144°-145°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][C:15]([CH3:17])([CH3:18])[C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:32]5[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]5)=[O:25])=[CH:21][CH:20]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (50 mg, 0.137 mmol), 4-hydroxypiperidine (15 mg, 0.15 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (57 mg, 0.15 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in 3 mL of anhydrous DMF was stirred at room temperature. The mixture was poured into 75 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-fluoro-3-[4-{4-[(4-hydroxypiperidin-1-yl)carbonyl]phenyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as orange solid. Yield: 52 mg, 85%.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH3:21])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22]S(O)(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH3:21])([C:18]([NH2:19])=[O:22])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vigorously stirred solution of 1-benzhydryl-3-methylaminoazetidine-3-carbonitrile (I-3A-2a; 2.10 g, 7.57 mmol) in methylene chloride (25 ml) cooled in an ice bath was treated with H2SO4 (4.0 ml, 76 mmol), dropwise. After the reaction mixture was allowed to warm to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with concentrated aqueous NH4OH to pH 11. The mixture was extracted with methylene chloride; the combined organic layers were dried (Na2SO4) and then concentrated, in vacuo, to afford I-3A-2b (1.2 g, 54%) as an off-white solid: +ESI MS (M+1) 296.3; 1H NMR (400 MHz, CD3OD) δ 7.41 (d, J=7.5 Hz, 4H), 7.25 (t, J=7.5 Hz, 4H), 7.16 (t, J=7.1 Hz, 2H), 4.48 (s, 1H), 3.41 (d, J=8.7 Hz, 2H), 3.09 (d, J=8.7 Hz, 2H), 2.24 (s, 3H).