Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[C:30]2[C:29]([NH2:31])=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][C:25]=2[N:24]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[N:23]=1>CN(C=O)C>[F:21][C:22]1[C:30]2[C:29]([NH2:31])=[CH:28][C:27]([C:2]3[CH:3]=[C:4]4[CH:10]=[N:9][N:8]([S:11]([C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:5]4=[N:6][CH:7]=3)=[CH:26][C:25]=2[N:24]([S:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)(=[O:37])=[O:38])[N:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3cc(Br)cnc32)cc1
Reactant: C[Sn](C)(C)c1cc(N)c2c(F)nn(S(=O)(=O)c3ccccc3)c2c1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3cc(-c4cc(N)c5c(F)nn(S(=O)(=O)c6ccccc6)c5c4)cnc32)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
5-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrazolo[3,4-b]pyridine (605 mg) in DMF (4 ml) was added to a solution of 3-fluoro-1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (650 mg) in DMF (6 ml), treated with Pd( )Ph3)4 (165 mg) and then heated at 120° C. for 21 h. The solution was allowed to cool, filtered, and then evaporated. The residue was dissolved in chloroform, loaded onto a 100 g silica cartridge which was eluted with 0-100% ethyl acetate:cyclohexane over 60 min using the Flashmaster II. Appropriate peaks were combined and evaporated to give the title compound as a white solid, 0.577 g.
Reaction SMILES: [CH2:1]=O.[CH3:3][C:4]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)=O>[CH3:3][C:4]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH3:1])[CH2:25][CH2:26]2)=[CH:17][CH:16]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N2CCNCC2)cc1
Reactant: C=O
Solvent: O=CO
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N2CCN(C)CC2)cc1
Yield: 70 %

Procedure:
A mixture of formaldehyde (2 ml), formic acid (2 ml) and diethyl 2-methyl-2-(4-(piperazin-1-yl)phenyl)malonate (4.80 g, 14.4 mmol) was heated at reflux for 2 h and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3.50 g (70.0%) of diethyl 2-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)malonate as brown oily liquid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:29][N:28]=2)=[C:21]([CH3:37])[N:20]=1)([O-])=O>>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[CH:29][N:28]=3)=[C:21]([CH3:37])[N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1Cc1ccc(CN(C)C)cn1
Product: Cc1nc(NCCSCc2ccc(CN(C)C)o2)[nH]c(=O)c1Cc1ccc(CN(C)C)cn1

Procedure:
Reaction of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethyl amine with 2-nitroamino-5-(5-dimethylaminomethyl-2-pyridylmethyl)-6-methyl-4-pyrimidone gives 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-pyridylmethyl)-6-methyl-4-pyrimidone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C)C=O>[CH2:18]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[CH3:19]
Reactant: CCI
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C=O)cc1O
Temperature: 0 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
Commercially available 3,4-dihydroxy benzaldehyde (35.8 g, 259 mmol) and potassium carbonate (37.6 g, 272 mmol) were dissolved in N,N-dimethylformamide (150 mL), then commercially available iodoethane (22 mL, 275 mmol) was added under nitrogen atmosphere at 0° C., and then the mixture was stirred for 2 days. The solvent was evaporated under vacuum, the resultant was cooled to 0° C., and then 5 M hydrochloric acid, ethyl acetate, and water were added for partition. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with water twice and then with a saturated saline solution, and the mixture was dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated, then dichloromethane was added, and then the precipitate was collected by filteration to obtain the title compound (25.8 g, 60%). The filtrate was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1-1:1). The target fraction was concentrated under vacuum, then diethyl ether and dichloromethane were added to the residue, and the precipitate was collected by filteration to obtain the title compound (3.45 g, 8.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Into a 500 mL round bottomed flask were added 5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.80 g, 20.96 mmol), 2-methoxyphenyl boronic acid (3.76 g, 24.74 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.756 g, 1.08 mmol), acetonitrile (100 mL) and 100 mL of 2M Na2CO3 (aq). The flask was fitted with a reflux condenser and heated at 60° C. with rapid stirring under N2 for 8 h. The reaction mixture was filtered to obtain a grey-tan precipitate, which was dissolved in EtOAc and washed with water followed by brine. Concentration of this solution afforded 7.70 g (80%) of the title compound as a tan powder. 1H-NMR (500 MHz, d6-DMSO) δ 8.50 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.54 (dd, J=1.5, 7.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.39 (m, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 3.80 (s. 3H), 2.34 (s, 3H); MS: m/z 456.9/458.9 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30](=[O:31])[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(CCl)N1CCCCC1
Product: O=C1OC2(CCN(C(=O)c3cn(CC(=O)N4CCCCC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which has been described in example 16) with commercially available 2-chloro-1-piperidin-1-yl-ethanone as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [CH2:1]([C@H:3]1[C:20](=O)[CH2:19][CH2:18][C@@:17]2([CH3:22])[CH:4]1[C@@H:5]([OH:24])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:23])[CH3:2].[ClH:25].Cl.[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32][NH2:33])[CH2:28]1>>[ClH:25].[NH:27]1[CH2:31][CH2:30][C@@H:29]([O:32]/[N:33]=[C:20]2/[C@H:3]([CH2:1][CH3:2])[CH:4]3[C@:17]([CH3:22])([CH2:18][CH2:19]/2)[C@@H:16]2[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]4)[CH2:6][C@@H:5]3[OH:24])[CH2:28]1
Reactant: CC[C@H]1C(=O)CC[C@@]2(C)C1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO[C@@H]1CCNC1
Agent: Cl
Product: CC[C@H]1/C(=N/O[C@@H]2CCNC2)CC[C@@]2(C)C1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
The title compound was obtained in 90% yield following the procedure described in Example 30 starting from 4β-ethyl-6α-hydroxyandrostan-3,17-dione (Preparation 27, 137 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 160 mg). The crude product was triturated with Et2O and the resulting precipitate was filtered to give the title compound I-bx.
Reaction SMILES: [CH:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24]>>[C:23]([C:25]1([C:28]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:17][CH:18]=2)=[O:29])[CH2:27][CH2:26]1)#[N:24]
Reactant: Nc1ccc(CCCCCCCOCC2CCCCC2)cc1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCOCC3CCCCC3)cc2)CC1
Yield: 95.8 %

Procedure:
General procedure E was used to convert 0.616 mmol of 13 and 0.924 mmol of 1-cyanocyclopropanecarboxylic acid to 0.590 mmol (96%) of the title compound.
Reaction SMILES: Cl[C:2](=[N:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:16]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)=[CH2:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[CH:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][C:2]([C:3]([O:5][CH3:6])=[O:4])=[N:7]2)=[CH:10][CH:11]=1
Reactant: C=Cc1ccco1
Reactant: COC(=O)C(Cl)=NNc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccco2)C1

Procedure:
The compound of Example 1 (2.0 g) was suspended in benzene (20 ml) and heated to reflux in the presence of 2-vinylfuran (2.5 ml). Triethylamine was added and the mixture was allowed to reflux for 1 hour longer. The mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated. Chromatography on silica gel (5:1 hexanes/ethyl acetate) gave the title compound (1.8 g). NMR (CDCl3) 7.3 to 6.9 (m, Ar-H, 5H); 6.2 (m, Furan-H, 2H); 5.5 (dd, CH, 1H); 3.9 (s, OCH3, 3H); 3.6 (m, CH, 1H); 3.4 (m, CH3, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:36]2[CH2:37][CH2:38][N:33]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([NH:23][C:17]4[C:16]5[C:21](=[CH:22][C:13]([Cl:12])=[CH:14][CH:15]=5)[N:20]=[CH:19][CH:18]=4)=[CH:25][CH:26]=3)(=[O:31])=[O:32])[CH2:34][CH2:35]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1

Procedure:
In the manner given in Example 13 but using 4-chlorophenylsulfonyl chloride in place of sulfamoyl chloride, and [[4-[(7-chloro-4-quinolinyl)amino]-phenyl]sulfonyl]piperazine, 1-[(4-chlorophenyl)sulfonyl]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]-piperazine is obtained.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.[Li+].[OH-]>C(O)C>[CH2:11]([C:6]1[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:12]
Reactant: CCc1ncccc1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ncccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of 2-ethylpyridin-3-yl acetate (5.1 g, 31 mmol) in ethanol (50 mL) was added 3M LiOH (50 mL, 150 mmol). The reaction mixture stirred at ambient temperature for 30 minutes. The mixture was concentrated to dryness and purified over silica gel (10% MeOH in Ch2Cl2) to afford 2-ethylpyridin-3-ol (2.5 g, 20 mmol).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SCCC)n1

Procedure:
A mixture of 5.75 g. 3-propylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 3 hours. The reaction mixture was worked up as described in Example 1 to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 134° - 135° C./0.1 mm. Gas-liquid chromatographic (GLC) assay indicated a content of 1-isomer of 94.2%. Elemental analysis satisfactory.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]3[CH2:27][CH2:26][S:25][C:24]([CH3:29])([CH3:28])[C@@H:23]3[C:30]([OH:32])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([N:22]3[CH2:27][CH2:26][S:25][C:24]([CH3:29])([CH3:28])[C@@H:23]3[C:30]([OH:32])=[O:31])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(-c3ccc(CO)cc3)cc2)[C@H]1C(=O)O
Reactant: NCCO
Solvent: C1CCOC1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(-c3ccc(CNCCO)cc3)cc2)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Crude product from (a) was diluted up in anhydrous THF (1 mL) in a dry environment and then cooled to ˜0° C. To this solution was added ethanolamine (1 mL of a 0.2 M solution in dry THF). This was allowed to warm to room temperature while stirring overnight. Concentration in vacuo, followed by hydrolysis of the ester as described in part (c) of Example 5 gave the title compound.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C(Cl)Cl>[CH:26]([O:25][C:23]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
To a solution of 4-(N-Boc amino)piperidine (2.61 g, 13 mmol) and triethylamine (3 mL, 21.5 mmol) in 25 mL of DCM, was added isopropyl chloroformate (1 M in toluene, 13.1 mL, 13.1 mmol). The mixture was stirred at room temperature for 20 h. It was then washed with a saturated solution of NaHCO3 (50 mL), followed by brine (50 mL). The solution was dried, filtered and evaporated to afford 3.26 g (87%) of 18a.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(OC([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:36]([CH:33]4[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]4)=[O:37])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCCN(C1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C1CCN(C(=O)C2CCNCC2)CC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 104.5 %

Procedure:
Under an inert atmosphere was combined ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (7.0 g, 23.14 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (5.3 g, 23.14 mmol), EDCI (4.43 g, 23.14 mmol), HOBT (3.13 g, 23.14 mmol), and triethylamine (65 mL, 46.3 mmol) in dichloromethane (140 mL). The mixture was stirred at room temperature for 48 h then concentrated in vacuo. The residue was taken-up in EtOAc (150 mL) and washed with water (100 mL), 1N NaOH (30 mL), and brine (30 mL), then dried (MgSO4). The solution was filtered, and concentrated. This was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine (10.0 g), which was deprotected with 10 mL trifluoroacetic acid as described herein to afford {4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone 39 (6.5 g ), [M+H]+=450.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Na+].[I-].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CCC(C)=O>[CH2:21]([O:20][P:19]([CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:6]=[CH:7][CH:8]=1)([O:23][CH2:24][CH3:25])=[O:26])[CH3:22]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1cn2cccc(CCl)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn2cccc(CP(=O)(OCC)OCC)c2n1
Yield: 45 %

Procedure:
By the method of Example 6, the product from Example 21 was dissolved in MEK (130 mL) and treated with NaI (3.4 g, 23 mmol) and triethyl phosphite (5.32 g, 32 mmol). Final purification via flash chromatography (95/4.5/0.5 EtOAc/EtOH/Et3N) provided 3.23 g (45%) of title compound.
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[C:12]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:7])C.Cl>O.O1CCOCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]2[O:10][C:9]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[C:8]([C:5]([OH:1])=[O:7])[C:12]=2[CH:13]=1)#[N:18]
Reactant: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(C)=O)cc1
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(=O)O)cc1
Yield: 34.6 %

Procedure:
5.2 g of sodium hydroxide was dissolved in 30 ml of water, and the solution was cooled to a temperature of 0° C. or below. With stirring, to this were added dropwise 2.7 ml of bromine and then 40 ml of a dioxane solution containing 4.14 g of 3-acetyl-2-[2-(4-methoxyphenyl)ethyl]-5-benzofurancarbonitrile obtained in the above step d). The resulting mixture was stirred at 0° C. for 45 minutes with ice cooling for 1 hour. The resulting reaction solution was mixed with water, adjusted to pH 2 with concentrated hydrochloric acid, and then extracted with chloroform. The resulting organic layer was washed with water and dried to distill off the solvent. Thereafter, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an eluant, thereby obtaining 1.44 g of 5-cyano-2-[2-(4-methoxyphenyl)ethyl]-3-benzofurancarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([OH:11])[CH:10]=1.Cl[CH2:24][P:25]([CH3:28])(=[O:27])[OH:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][P:25]([CH2:28][O:11][C:9]1[CH:10]=[C:5]([O:4][C:3]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:20])[F:22])=[CH:18][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:12]([O-:14])=[O:13])(=[O:26])[OH:27]
Reactant: CP(=O)(O)CCl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CP(=O)(O)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenol (2.5 mmol), chloromethyl methylphosphinic acid (3.8 mmol), potassium carbonate (5.0 mmol) and dimethylformamide (5 ml) is heated to 120° for 2 hours. The reaction mixture is then acidified and extracted with ether. The combined ether extracts are washed with water, dried and evaporated to dryness to yield P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinic acid.
Reaction SMILES: C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@H:13]([C:32]([OH:34])=O)[CH2:14][C:15]1[N:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[N+:29]([O-:31])=[O:30])[CH:16]=1)=O)(=O)=O)(C)(C)C.[NH2:42][C@@H:43]([CH2:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[C@@H:44]([OH:50])[C:45]([CH:47]1[CH2:49][CH2:48]1)=[O:46]>>[CH:52]1([CH2:51][C@H:43]([NH:42][C:32](=[O:34])[CH2:13][CH2:14][C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=3[N+:29]([O-:31])=[O:30])[CH:16]=2)[C@@H:44]([OH:50])[C:45]([CH:47]2[CH2:48][CH2:49]2)=[O:46])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)C1CC1
Product: O=C(CCc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)C1CC1

Procedure:
In an analogous manner to that described in Example 23, by condensing N-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamoyl]-1-(2,4-dinitrophenyl)-L-histidine and (2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-2-hydroxy-1-butanone there is obtained (S)-α-[(S)-α-(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R)-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxy-3-oxopropyl]-1-(2,4-dinitrophenyl)imidazole-4-propionamide as a yellow solid, MS: 795 (M+H)+.
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]1([C:11]23[CH2:22][CH:15]4[CH2:16][C:17]([C:19](=[O:21])C)([CH2:18]2)[CH:13]([CH2:14]4)[CH2:12]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[O:24]C(C)(C)C>O.O1CCOCC1>[C:5]1([C:11]23[CH2:22][CH:15]4[CH2:16][C:17]([C:19]([OH:24])=[O:21])([CH2:18]2)[CH:13]([CH2:14]4)[CH2:12]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Reactant: COC(C)(C)C
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C12CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 25 °C

Procedure:
Dioxane (1.81) was added to a solution, cooled to −22° C., of sodium hydroxide (724 g) in water (4.8 l). Bromine (578 g) was metered into this solution such that a temperature of −15° C. was not exceeded. A solution of 1-(2-phenylhexahydro-2,5-methanopentalen-3a-yl)ethanone (290 g) in dioxane (600 ml) was metered into this solution, and the reaction was allowed to warm up gradually to room temperature. tert-Butyl methyl ether was added. Subsequently, water was metered in (2.5 l). After phase separation, the aqueous phase was washed with tert-butyl methyl ether. Subsequently, after addition of tert-butyl methyl ether (5 l), hydrochloric acid (32%) was used to establish a pH of pH 1.5. After phase separation, the organic phase was washed repeatedly with water and clarified with activated carbon. The solvent was changed by distillation under reduced pressure with addition of diisopropyl ether. After extractive stirring with diisopropyl ether at reflux, 2-phenylhexahydro-2,5-methanopentalene-3a-carboxylic acid (292 g) was obtained as a solid with 95% purity.