Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([CH3:32])=[CH:19][C:20]([OH:31])=[C:21]([CH:30]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[C:18]([CH3:32])=[CH:19][C:20]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(C(=O)c2ccccc2)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(Cl)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 7 h
Yield: 90.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-chloro-2-hydroxy-4-methylbenzophenone (443 mg), and 4-dimethylaminopyridine (220 mg) were suspended in o-dichlorobenzene (1 ml), and the mixture was stirred at 140° C. for 7 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (175 mg, yield 90%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH3:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:34]=1[C:35](O)=[O:36].[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47]>C(Cl)Cl>[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47].[CH3:30][N:29]([CH:26]1[CH2:27][CH2:28][N:23]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25]1)[C:35](=[O:36])[C:34]1[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:33]=1[O:32][CH3:31]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CNC1CCN(Cc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)N(C)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-dicyclohexylcarbodiimide (10.3 g; 0.05 moles) and 1-benzyl-4-methylaminopiperidine (10.2 g; 0.05 moles) were added successively to a solution of 2-methoxy-5-chlorobenzoic acid (9.3 g; 0.05 mole) in methylene chloride (250 ml). After stirring overnight at room temperature, the insoluble N,N'-dicyclohexylurea was filtered off, the solution was washed with water, dried (Na2SO4) and the solvent removed in vacuo to give an oil. It was salified with fumaric acid as described in Example 1 to give 10.3 g of N-methyl-N-(1-benzylpiperid-4-yl)-2-methoxy-5-chlorobenzamide fumarate, m.p. 192°-194° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>C(O)C>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH2:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(N2CCOCC2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCc1ccc(N2CCOCC2)cc1
Temperature: 25 °C

Procedure:
Step 2 A solution of 2-[2-(4-morpholin-4-ylphenyl)ethyl]-1H-isoindole-1,3(2H)-dione (193 mg, 0.57 mmol) and hydrazine monohydrate (70 mg, 1.4 mmol) in ethanol (6 ml) was heated at reflux for 2 hr. The reaction was cooled to ambient temperature, and the solvent was removed in vacuo. The residue was taken up in ether, washed with 2M aqueous sodium hydroxide, and then extracted with 1M aqueous hydrochloric acid (2×10 mL). The acidic extracts were combined and the pH raised to 10-11 with 4M aqueous sodium hydroxide. This was then extracted thrice with ether, the organics combined, and dried (Na2SO4). Filtration and removal of solvent in vacuo left a brown oil, 110 mg, 0.57 mmol, 100 percent crude yield. The material was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12](=[O:14])[CH3:13].[C:15](=[S:17])=[S:16].CN(C)C=O.[H-].[Na+]>C1C=CC=CC=1.O.C(O)(=O)C>[OH:14][C:12]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][C:4]=2[C:8]([F:11])([F:10])[F:9])[S:17][C:15](=[S:16])[CH:13]=1
Reactant: S=C=S
Reactant: CC(=O)c1c(F)cccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(=S)sc2cccc(C(F)(F)F)c12
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2'-fluoro-6'-(trifluoro-methyl)acetophenone (3.0 g, 14.5 mmol), carbon disulfide (1.5 mL, 26.7 mmol) and dimethylformamide (DMF) (12.5 mL) in benzene at 15°-25° C. is treated portion-wise with a 60% dispersion of sodium hydride in mineral oil (1.15 g, 28.8 mmol NaH) over a 1.5 hour period, stirred for 0.5 hour, heated at 125° C. for 1 hour, cooled to room temperature and diluted with water. The resultant mixture is treated with acetic acid and extracted with ether. The aqueous phase is acidified to pH 3 with HCl and extracted with ethyl acetate. The ethyl acetate extracts are combined, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give an orange oil residue. The residue is crystallized from diethyl ether/hexanes to give the title product as a white solid, 3.0 g (79% y), mp 142°-144° C., identified by IR, 1HNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[O:8][C:9]1[CH:14]=[CH:13][N+:12]([CH2:15][CH2:16][CH2:17][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1.[C:34]([OH:41])(=[O:40])[CH:35]=[CH:36][C:37]([OH:39])=[O:38].CC1C=C(C=CC=1)OC1CCN(CCCN(C2C=CC=CC=2)C2C=CC=CC=2)CC1>CO>[C:34]([OH:41])(=[O:40])[CH:35]=[CH:36][C:37]([OH:39])=[O:38].[CH3:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[O:8][C:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:11][CH:10]=1
Reactant: Cc1cccc(Oc2cc[n+](CCCN(c3ccccc3)c3ccccc3)cc2)c1
Agent: Cc1cccc(OC2CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1
Agent: O=C(O)C=CC(=O)O
Agent: [BH4-]
Solvent: CO
Product: Cc1cccc(OC2=CCN(CCCN(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
5.0 g. of sodium borohydride, (0.131 moles) is added portionwise to a solution of 13 g. (0.032 moles) of 4-(3-methylphenoxy)-1-[3-(N,N-diphenylamino)propyl]pyridinium iodide in 200 ml. of methanol over a 10 minute period, allowing the temperature to reach reflux. The reaction is refluxed another 20 minutes. Solvent is evaporated. The residue is dissolved in chloroform, washed with sodium carbonate solution, and dried. Solvent is evaporated. The residue is converted to the maleate in ether and recrystallized from acetonitrile to give 10.9 g. of 3,5-dihydro-4-(3-methylphenoxy)-N,N-diphenyl-1(2H)-pyridinepropanamine butenedioate (1:1), mp. 164°-166° C.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>>[CH3:27][N:28]1[CH:32]=[C:31]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])[N:30]=[CH:29]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC(=O)O
Product: Cn1cnc(S(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)c1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 1-methyl-1H-imidazole-4-sulfonyl chloride. Off-white solid. MS (ESI): 459.3 (MH+)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOCC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of N2-butyl-8-(methyloxy)-9-[3-(tetrahydro-2H-pyran-4-yl)propyl]-9H-purine-2,6-diamine (93.13 mg, 0.257 mmol) in methanol (10 ml) was added 4M HCl in dioxane (1.5 ml, 6 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated under a steam of nitrogen and the residue was redissolved in methanol (5 ml) and loaded onto a 5 g aminopropyl SPE cartridge and eluted with methanol. The eluant was evaporated under a stream of nitrogen to give the title compound (64 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[O:14])[CH:10](N(C)C)[NH:9]2)=[CH:4][CH:3]=1.ClC1C=CC(N2[C:29](=[O:30])[C:28](=O)C(N(CC)CC)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(NC(=O)C)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(C(O)=O)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(C(OC)=O)N2)=CC=1.ClC1C=CC(N2C(=O)C(=O)C(C(OCC)=O)N2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[O:14])[CH:10]([O:30][CH2:29][CH3:28])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)C1NN(c2ccc(Cl)cc2)C(=O)C1=O
Reactant: CN(C)C1NN(c2ccc(Cl)cc2)C(=O)C1=O
Agent: CC(=O)NC1NN(c2ccc(Cl)cc2)C(=O)C1=O
Agent: CCOC(=O)C1NN(c2ccc(Cl)cc2)C(=O)C1=O
Agent: COC(=O)C1NN(c2ccc(Cl)cc2)C(=O)C1=O
Product: CCOC1NN(c2ccc(Cl)cc2)C(=O)C1=O

Procedure:
1-(4′-chlorophenyl)-3-dimethylamino-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-diethylamino-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-acetamido-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-carboxy-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-methoxycarbonyl-4,5-pyrazolinedione; 1-(4′-chlorophenyl)-3-ethoxycarbonyl-4,5-pyrazolinedione;
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][O:25][C:24]4=[O:28])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:29])[O:11]1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][O:25][C:24]4=[O:28])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:29])[O:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(-n4ccoc4=O)cc3OC[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)[C@@H]2COc3cc(-n4ccoc4=O)ccc3N12
Yield: 105.4 %

Procedure:
Using compound (3R,3aS)-3-((t-butyldimethylsiloxy)methyl)-7-(2-oxooxazol-3-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (0.38 g, 0.904 mmol), and TBAF (0.47 g, 1.807 mmol) as starting materials, THF as solvent, preparation following the method as described in Example 1(b) afforded white solid 0.29 g, yield 99.9%.
Reaction SMILES: O=C1NC2C=CC=CC=2S[C@H](C2C=CC=CC=2)[C@@H]1NC(=O)[C@H](C)NC(=O)CC1C=CC=CC=1.Br.[NH2:35][C@H:36]1[C:42](=[O:43])[NH:41][C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[S:38][C@H:37]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:77](O)=[O:78])[CH2:67][C:68]2[NH:69][C:70]3[C:75]([CH:76]=2)=[CH:74][CH:73]=[CH:72][CH:71]=3)=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1>>[F:61][C:59]1[CH:58]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:77]([NH:35][C@@H:36]2[C:42](=[O:43])[NH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[S:38][C@@H:37]2[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:78])[CH2:67][C:68]2[NH:69][C:70]3[C:75]([CH:76]=2)=[CH:74][CH:73]=[CH:72][CH:71]=3)=[O:64])[CH:56]=[C:55]([F:54])[CH:60]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)O
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Agent: Br
Agent: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: O=C(Cc1cc(F)cc(F)c1)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that (2,3-cisS)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (105 mg) was used as the amine component and N-[(3,5-difluorophenyl)acetyl]-3-(1H-indol-2-yl)-L-alanine (110b) (119 mg) was used as the acid component to afford the title compound as a 1:1 mixture with the 2S,3S diastereomer (173 mg), white solid, m.p.85-90° C. 1H NMR (300 MHz, d6-DMSO) δ 2.40 (m, 2H), 3.03 (m, 4H), 4.26 (m, 1H), 4.72 (m, 1H), 5.17(d, 1H, J=7 Hz), 5.82(d, 1H, J=6 Hz), 6.89-7.79 (m, 12H), 8.21(m, 1H), 10.53 (m, 1H). MS APCI, m/z=611(M+1). LC/MS: 2.66.min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)(C)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C@H:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C@H:25]([NH:27][C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:16])[CH3:26])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: COc1cccc([C@@H](C)N)c1
Product: COc1cccc([C@@H](C)NC(=O)C2CNCCO2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Step-2 of Intermediate-2 by using 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (Step-1 of Intermediate-2) and (R)-1-(3-methoxyphenyl)ethanamine followed by deprotection of resultant Boc protected compound by following the similar procedure as described in Step-3 of Intermediate-2.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:31])C(=O)C1.O>CN(C=O)C>[I:31][C:22]1[C:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A solution of Example 10A (1.69 g, 5.3 mmol) in DMF (20 mL) was treated with NIS (1.26 g, 5.6 mmol), stirred at room temperature for 3 hours, poured into water, and filtered. The filter cake was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 1.64 g (70% yield) of the desired product. MS (ESI(+)) m/e 444.8 (M+H)+.
Reaction SMILES: [Li].[H-].C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1)=O)C.[OH-].[Na+]>CCOCC>[CH3:6][N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1
Reactant: CCOC(=O)N1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Agent: [H-]
Agent: [Li]
Agent: [Na+]
Solvent: CCOCC
Product: CN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1

Procedure:
To a solution of lithium aluninum hydride (155 mg) in anhydrous ether was added a solution of 5-(4-ethoxycarbonylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene (600 mg) in anhydrous ether under ice-cooling, and the resulting mixture was stirred under ice-cooling for 1 hour and under reflux for 2.5 hours. The reaction mixture was cooled, admixed with 10% aqueous sodium hydroxide solution and extracted with ether. The ether extract was dried over anhydrous sodium sulfate and evaporated to afford 5-(4-methylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 243°-244° C. (decomp.) (oxalate).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[O-]CC.[Na+].[Na].[C:17](Cl)(=O)[C:18](C)([CH3:20])[CH3:19]>C1(C)C(C)=CC=CC=1.C(O)C>[C:3]([CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[C:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)C(=O)Cl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
Ethyl pivaloylacetate was prepared from diethyl malonate in the following manner. Diethyl malonate (64 g, 0.4 mol) was dissolved in 350 ml of a mixture of xylene isomers. A solution of sodium ethoxide, prepared by dissolving sodium (9.66 g, 0.42 g at) in absolute ethanol (150 ml), was then added with stirring at ambient temperature. Ethanol was removed by distillation. After the mixture was cooled to 50° C., pivaloylchloride (53 g, 0.4 mol) was added with stirring over a period of one hour and the resulting slurry stirred for a further hour. The mixture obtained was then filtered to remove sodium chloride and the filtrate added to dry sodium ethoxide, which had been prepared by dissolving sodium (9.29 g; 0.4 g at) in 250 ml of absolute ethanol and evaporating to dryness. After stirring for 90 minutes at 50° C., the mixture was acidified with dilute hydrochloric acid and the organic phase separated and dried over anhydrous magnesium sulphate. Evaporation of the solvent in a rotary evaporator followed by vacuum distillation afforded essentially pure ethyl pivaloylacetate product as a colorless liquid (b.p. 167° C. at 65 mbar). Structure of the product was confirmed with NMR analysis. The product yield, determined by GLC, was 0.343 mol (86%).
Reaction SMILES: [CH3:1][O:2][C:3]1C=C(O)[CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:28])[C:14]([C:26]#[N:27])=[CH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)[CH3:11]>>[C:26]([C:14]1[C:13](=[O:28])[O:12][C:10]2[C:6]([C:15]=1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:11]=2)#[N:27]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1
Product: COc1cc(OC)cc(-c2c(C#N)c(=O)oc3cc(OC)ccc23)c1
Yield: 4.2 %

Procedure:
The title compound was prepared from 3-methoxyphenol and 2-cyano-3-(3,5-dimethoxy-phenyl)-acrylic acid ethyl ester by a procedure similar to that described for Example 1 in 4.2% yield. 1H NMR (CDCl3): 7.36 (d, J=9.0, 1H), 6.89-6.83 (m, 2H), 6.65-6.63 (m, 1H), 6.55-6.54 (m, 2H), 3.93 (s, 3H), 3.85 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][N:7]1[CH2:11][C@@H:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@@:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])([C:17]#[N:18])[C@H:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[F:34])C.[Li+].[OH-]>C1COCC1.O>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([C@@H:8]2[C@:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])([C:17]#[N:18])[C@H:10]([CH2:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH2:11][N:7]2[CH2:6][CH2:5][C:4]([OH:35])=[O:3])[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CCN1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(CCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 94.5 %

Procedure:
To a mixture of rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-propionic acid ethyl ester (12.3 mg, 0.0235 mmol) in THF (2 mL) was added a solution of LiOH (Aldrich, 6.7 mg, 0.16 mmol) in water (1 mL) and the reaction mixture was stirred at rt for 22 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 6-7), extracted with EtOAc, washed with water (2×), and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-propionic acid (11 mg, 100%). HRMS (ES+) m/z Calcd for C25H26Cl2F2N2O2+H [(M+H)+]: 495.1412; Found: 495.1413.
Reaction SMILES: [N:1]1[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=[C:3]([CH2:11][N:12]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[N:2]=1>C(O)C.[Pd]>[N:1]1[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=[C:3]([CH2:11][N:12]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:2]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(nn1)OCCO2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cc2c(nn1)OCCO2)C1CCNCC1
Yield: 97 %

Procedure:
Phenylmethyl 4-((6,7-dihydro[1,4]dioxino[2,3-c]pyridazin-3-ylmethyl) {[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinecarboxylate (11.89 g. 25 mmol) in ethanol (90 ml) was hydrogenated with 10% palladium on charcoal (aqueous paste, 2 g) for 21 h. The mixture was filtered and evaporated to give a white solid (8.5 g, 97%).
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[CH2:20][C:21]3[CH:26]=[C:25]([OH:27])[C:24]([OH:28])=[C:23]([OH:29])[CH:22]=3)=[CH:14][C:13]=2[N+:31]([O-])=O)=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]>CO.[Pd]>[NH2:31][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:30])[CH2:20][C:21]2[CH:22]=[C:23]([OH:29])[C:24]([OH:28])=[C:25]([OH:27])[CH:26]=2)[CH:16]=[CH:17][C:12]=1[C:6]1[O:5][C:4]([CH3:3])=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: Cc1oc(-c2ccc(NC(=O)Cc3cc(O)c(O)c(O)c3)cc2[N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: Cc1oc(-c2ccc(NC(=O)Cc3cc(O)c(O)c(O)c3)cc2N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.1 %

Procedure:
(The following reaction is done in an N2 atmosphere.) Dissolve 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trihydroxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid (61) (21 mg, 0.05 mmol) in MeOH (1.5 mL) and add Pd on carbon (10% (w/w) Pd content, 11.5 mg, 0.005 mmol) followed by NH4CO2H (68 mg, 1.08 mmol) at rt. Degas the reaction mixture carefully (flush with N2) and stir it for 17 h at rt. Filtrate reaction mixture through a short pad of celite and remove solvent. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain 5-{2-Amino-4-[2-(3,4,5-trihydroxy-phenyl)-acetylamino]phenyl}-2-methyl-furan-3-carboxylic acid (62) (4.6 mg, 23%) as a white solid. 1H NMR (400 MHz, CD3OD): 2.69 (s, 3H); 3.50 (s, 2H); 6.39 (s, 2H); 6.91 (s, 1H); 7.13 (br.d, 1H, J=8.6 Hz); 7.57 (d, 1H, J=8.6 Hz) 7.65 (br.s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][C@@H:14]([N:16]=[N+]=[N-])[CH2:13][C@@H:12]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C:29]3=[O:34])=[CH:24][CH:23]=2)=[O:20])=[O:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@@H:12]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C:29]3=[O:34])=[CH:24][CH:23]=2)=[O:20])=[O:10])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
9.4 A solution of 25 mg (0.052 mmol) of “A9” and 20.46 mg (0.08 mmol) of triphenylphosphine in a mixture of 0.5 ml of tetrahydrofuran and 0.5 ml of water is stirred at room temperature for 12 hours. After the precipitated triphenylphosphine oxide has been filtered off, the filtrate is evaporated to dryness, and the residue is purified by preparative HPLC (acetonitrile/water/0.1% trifluoroacetic acid), giving 12 mg (40%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-aminopyrrolidine-1,2-dicarboxamide (“10”) as colourless crystals, ESI 458.