Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:31])(=[O:30])[NH:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:24]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCNS(=O)(=O)c1cccc(NC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c1
Yield: 27 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-amino-N-butyl-benzenesulfonamide (53 mg, 0.21 mmol) as the coupling partner. Chromatography (1:1 ethyl acetate:dichloromethane) through SiO2 yielded 23 mg (27%) of the titled compound. ESI-MS m/z 502 (MH+), 500 (M−H−).
Reaction SMILES: C(=O)([O:10][C:11]1[C:16]2[NH:17][C:18](=[O:20])[S:19][C:15]=2[C:14]([C:21](=[O:24])[CH2:22]Br)=[CH:13][CH:12]=1)OCC1C=CC=CC=1.[CH2:26]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[CH2:26]([N:33]([CH2:22][C:21]([C:14]1[C:15]2[S:19][C:18](=[O:20])[NH:17][C:16]=2[C:11]([OH:10])=[CH:12][CH:13]=1)=[O:24])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)CBr)c2sc(=O)[nH]c12
Reactant: c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CN(CCCCCCOCCCCc1ccccc1)Cc1ccccc1)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a solution of benzyl 7-(bromoacetyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl carbonate (50 mg) in dry DMF (1 ml) stirring under nitrogen was added N-benzyl-6-(4-phenylbutoxy)hexan-1-amine (Tetrahedron Letters. 1994, 35, 9375) (60 mg) and N,N-diisopropylethylamine (32 μl). After stirring at 40° C. for 2 h, 2N HCl was added and the mixture extracted with ethyl acetate. The solution was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with a stepped gradient of 2% to 10% methanol-dichloromethane mixtures to give the title compound (50 mg). LCMS RT=3.14 min.
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:22]([NH:26][C:27]([NH:21][S:18]([CH2:17][C:8]1[C:7]([S:4]([N:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:12][CH:11]=[CH:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:19])=[O:20])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)Cc1c(C(=O)OC)cccc1S(=O)(=O)N(C)C
Temperature: 0 °C
Yield: 70.1 %

Procedure:
A mixture of 8.7 g of the product from Example 14, 2.7 g of n-butyl isocyanate, and 3.2 g anhydrous potassium carbonate in 75 ml methyl ethyl ketone was stirred at reflux temperature for 4.5 hours. The resulting suspension was then poured into 250 ml ice-water and the aqueous layer washed with diethyl ether. Concentrated hydrochloric acid was added to the water layer until a yellow solid formed. The crude product was collected by filtration, washed with n-butyl chloride and dried to give 7.9 g of the title compound as a pale yellow solid, m.p. 118°-134°; IR(nujol): 3400, 1725, 1700 cm-1 ; NMR (CDCl3): δ 0.8-1.6 (7H, m), 2.85 (6H, s, SO2N(CH3)2), 3.0 (2H, q), 3.95 (3H, s, CO2CH3), 5.75 (2H, s, --CH2 --), 6.25 (1H, t, NH), 7.2-8.2 (4 H, m).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N([CH2:42][C:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:46]=[CH:45][CH:44]=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:42][C:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:46]=[CH:45][CH:44]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(Cc3cccc4ccccc34)c(-c3ccc(Cl)cc3)c2CC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3cccc4ccccc34)c3c2CCNCC3)cc1

Procedure:
The title compound (0.015 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 1-naphthalen-methyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also provided 3-(4-chloro-phenyl)-2-naphthalen-1-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C24H22ClN3, 387.15. found, m/z 388.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.79-7.18 (m, 11H), 5.74 (d, J=7.3 Hz, 2H), 3.42 (s, 2H), 3.21-3.19 (br m, 2H), 3.10-3.08 (br m, 2H), 2.92-2.90 (br m, 2H), 2.84-2.82 (br m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([NH:8][NH2:9])[CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.O>ClCCl>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:10])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1cc(Cl)ccc1F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)=NNc1cc(Cl)ccc1F
Temperature: 25 °C
Yield: 63 %

Procedure:
(5-Chloro-2-fluoro-phenyl)-hydrazine (22.5 g, 140 mmol) was dissolved in dichloromethane (80 mL). Ethyl pyruvate (16.3 mL, 140 mmol) was added slowly to this solution at room temperature. The mixture was stirred for another1 h at room temperature, added to water and extraxcted with dichloromethane. Organic phases were pooled, washed subsequently with hydrochloric acid (1 N) and brine and dried with MgSO4. Solvents were removed in vacuo and the residue was triturated with n-hexane to yield the title product as beige solid (22.8 g, 62.9%), ISP-MS: m/e=259.1 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]C)=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])(=O)=O>CC(N(C)C)=O>[CH3:30][O:29][CH2:28][CH2:27][CH2:26][CH2:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]
Reactant: COCCCCOS(C)(=O)=O
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(C(=O)O)cc2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
Methyl 1H-indole-2-carboxylate (0.67 g), cesium carbonate (1.9 g) and 4-methoxybutyl methanesulfonate (0.70 g) were suspended in DMA (20 ml), and the suspension was stirred at 60° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-4:6) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (10 ml), 4N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was heated at 80° C. for 2 hr. The mixture was allowed to cool to room temperature, acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the object product (0.77 g).
Reaction SMILES: [O:1]1[CH2:3][C:2]21[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:7]=[CH:6][C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]2=1.[NH2:18][NH2:19]>>[NH:18]([CH2:3][C:2]1([OH:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[NH2:19]
Reactant: NN
Reactant: C1=Cc2ccccc2C2(CO2)c2ccccc21
Product: NNCC1(O)c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 10.5 g. of spiro [dibenzo[a,d]cycloheptene-5,2'-oxirane] and 100 ml. of anhydrous hydrazine is refluxed for 3 hours, the resulting mixture evaporated in vacuo to about 50 ml., cooled, the resulting crystals filtered off and washed generously with water. The crude solid is taken up in methylene chloride, extracted with water and then with saturated sodium chloride solution, dried and evaporated in vacuo. The residue is crystallized from ethyl acetate to obtain 5-hydrazinomethyl-5H-dibenzo[a,d]cyclo-hepten-5-ol, m.p. 128°-131° C.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(N(CC)CC)C>C(#N)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([O:17][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
The crude carboxylic acid is suspended in anhydrous acetonitrile (150 ml) and treated with p-nitrobenzyl bromide (7.56 g, 35 mμol) and triethylamine (4.9 ml, 35 mμol). The resulting solution is kept at room temperature for 2 days and then in a refrigerator for 3 days. The reddish orange solution is evaporated under vacuum and the residue shaken with ethyl acetate (100 ml, 2×50 ml) and filtered to remove triethylammonium bromide. The ethyl acetate filtrate is washed with water (3×100 ml) and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to an amber oil (13.62 g). Crystallization from diethyl ether affords N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]azetidin-2-one (6.84 g) as an off-white powder. Chromatography of the mother liquors on a silica gel column using 1:1 toluene-ethyl acetate as eluting solvent affords addition product (3.14 g) as an oil which solidifies.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[OH:27])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[OH:27])[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCCO2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc3c(cc2O)CCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
A 500 mL round-bottom flask was charged with chroman-6-ol (9.2 g, 61 mmol) and tetrahydrofuran (120 mL). A 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (32.5 mL, 65.0 mmol) was added at 5° C. and the reaction mixture was stirred for 15 min and concentrated in vacuo. To the residue was added dichloromethane (180 mL), followed by a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (18.8 g, 60.0 mmol) in dichloromethane (180 mL) at 5° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 24 h. Saturated aqueous ammonium chloride (7 mL) was added and the reaction mixture was concentrated in vacuo. Trituration of the residue in methanol/water (1/100, 200 mL) afforded 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one. A mixture of the 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one, triethylsilane (23.2 g, 200 mmol), trifluoroacetic acid (50.0 g, 438 mmol) and dichloromethane (200 mL) was stirred at ambient temperature for 20 h and concentrated in vacuo. Trituration of the residue in diethyl ether (150 mL) afforded 1-(diphenylmethyl)-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one (24.3 g, 90%) as an off-white solid: MS (ES+) m/z 448.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C@H:18]([CH3:22])[CH2:19][CH:20]=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.[OH-:26].[Na+].O>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C@H:18]([CH3:22])[CH2:19][C:20]([OH:26])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c([C@H](C)CC=O)c(C)n2Cc1ccc(Br)cc1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)c([C@H](C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Yield: 97 %

Procedure:
A solution of (R)-3-[1-(4-Bromo-benzyl)-5-methoxy-2-methyl-1H-indol-3-yl]-butanal (110 mg, 0.250 mmol) and silver nitrate (59.7 mg, 0.275 mmol) in 1.3 ml absolute ethanol was treated with a solution of 5N NaOH in ethanol (1:5, 0.9 ml, 0.75 mmol NaOH). After 45 min this was treated with 10 ml water, acidified to pH 3 and extracted with CHCl3 (5×20 ml) rinsing each extract with brine. The combined organics were dried over Na2SO4 and concentrated in vacuo to provide, after silica gel chromatography the title compound as a pale yellow solid (101 mg, 97% yield). IR (film) 3425, 2961, 2934, 2833, 1706, 1483, 1451, 1405, 1228, 1156, 1010, 796, 755 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J=9.0 Hz, 2H, ArH), 7.11 (d, J=2.4 Hz, 1H, ArH), 7.04 (d, J=8.7, 1H, ArH), 6.77-6.73 (m, 3H, ArH), 5.18 (s, 2H NCH2), 3.86 (s, 3H, OCH3) 3.56 (dt, J=7.2, 21.9 Hz, 1H ArCH), 2.86 (d, J=3.6 Hz, 1H, CH2CO); 2.83 (d, J=3.3 Hz, 1H, CH2CO); 2.27 (s, 3H, ArCH3) 1.49 (d, J=7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 178.0, 153.7, 137.3, 133.8, 133.0, 132.0, 127.7, 126.7, 121.2, 118.8, 114.6, 110.1, 109.9, 102.4, 56.3, 46.3, 41.5, 28.6, 21.1, 10.9; HRMS (CI) exact mass calcd for (C21H23BrNO3) (M+1) requires m/z 416.0861, found m/z 416.0867. [α]D=−30.9 (c=1.0, CHCl3).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:28]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH3:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(C)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 1-Bromo-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (434 mg, 1 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), trimethylboroxine (140 μl, 1 mmol), K2CO3 (414 mg, 3 mmol), and 1,4-dioxane (8 ml) was refluxed with stirring for 2 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (10 ml). The mixture was acidified by the addition of aqueous 6N HCl and then extracted with EtOAc (40 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:EtOAc=94:6 as the eluent gave the title compound as white solid (229 mg); MS-(+)-ion M+1=370.1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6](=O)[C:5]([NH:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[O-]CC.[Na+].[Na].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CO>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:10]1[C:11](=[O:16])[C:12]([C:13](=[O:15])[CH3:14])=[C:6]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]12)[CH3:28]
Reactant: CC(=O)CC(=O)Nc1ccc(Cl)ccc1=O
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCOC(=O)Cn1c2ccc(Cl)ccc-2c(C(C)=O)c1=O
Reaction time: 0.17 h

Procedure:
A mixture of 1-[(4-chloro-7-oxo-1,3,5-cycloheptatrien-1-yl)amino]-1,3-butanedione (5.8 g) and sodium ethoxide solution, prepared by dissolving 1.1 g of sodium in 200 ml of anhydrous, methanol-free ethanol, was heated at reflux for 5 hr. Thereafter, ethyl bromoacetate (10 ml) was added dropwise to the hot solution and refluxing was continued for an additional 10 min. The reaction mixture was evaporated to dryness. The residue was dissolved in chloroform and the solution filtered through a column of silica gel. Evaporation of the eluate gave 3.75 g of 3-acetyl-6-chloro-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester, identical to the compound obtained from method A. Crystallization of the latter compound gave the product with mp 183.5° C.; nmr (CDCl3) δ1.27 (t, 3H), 2.7 (s, 3H), 4.2 (q, 2H), 4.85 (s, 2H), 6.85-9.3 (m, 4H); ir (white mineral oil) 1725, 1685 cm-1 ; uvλmax (MeOH) 293 nm (ε21,995), 256 (14,630), 231 (16,945); Anal Calcd for C15H14ClNO4 : C, 58.55% H, 4.59% N, 4.55%; Found: C, 58.53% H, 4.60% N, 4.54%.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48 %

Procedure:
0.60 g (2 mmol) of Z-Phe-OH, 0.51 g (2 mmol) of H-D-Trp-OMe.HCl, 0.46 g (2.4 mmol) of EDCI, 0.32 g (2.4 mmol) of HOBT and 0.44 ml (4 mmol) of NMM are dissolved at -10° C. in 10 ml THF and stirred at room temperature for 15 hours. The THF is distilled off under vacuum, the residue dissolved in 50 ml ethyl acetate and the organic phase washed three times with 10 ml 0.5 N HCl, 10% NaHCO3 solution and water respectively. The organic phase is dried with MgSO4 and the solvent distilled off under vacuum. 0.48 g (48%) of thin-layer chromatographically identical Z-Phe-D-Trp-OMe are obtained as a colourless powder.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([NH:20][C@@H:21]([C:23]([OH:25])=O)[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29]>C(Cl)Cl>[C:16]([O:15][C:13]([NH:20][C@@H:21]([C:23]([NH:26][CH2:27][CH:28]([OH:30])[CH3:29])=[O:25])[CH3:22])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A mixture of CDI (19 g, 0.12 mol), Boc-D-alanine (20 g, 0.11 mol) and DCM (300 ml), was stirred at r.t. for 1 h, before 1-amino-2-propanol (14 ml, 0.18 mol) was added. The reaction mixture was stirred at r.t. overnight. After concentration, the residue was purified by column, and 13 g (46.3%) of N2-(tert-butoxycarbonyl)-N-(2-hydroxypropyl)-D-alaninamide as solid was obtained. ES-MS [M+1]+: 247.01.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:23][C:22]([CH3:24])=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]=1[CH3:29])=O>>[CH3:24][C:22]1[NH:23][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:20]([CH3:29])[C:21]=1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c(C)c1CC(=O)O

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid (40 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14]C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH3:14])[CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A mixture of 3-ethylaminomethyl-azetidine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol), dihydrofuran-3-one (0.155 mL, 2.0 mmol), diisopropylethylamine (0.347 mL, 2.0 mmol) and 4 Å molecular sieves (600 mg) in DCM (10 mL) was stirred at RT for 30 min. Sodium triacetoxyborohydride (424 mg, 2 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (257 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 4.04-3.92 (3 H, m), 3.83 (1 H, dd, J=8.89, 6.90 Hz), 3.75 (1 H, q, J=8.07 Hz), 3.64 (1 H, dd, J=8.87, 6.21 Hz), 3.56-3.55 (2 H, m), 3.14 (1 H, m), 2.67-2.66 (2 H, m), 2.51 (1 H, dd, J=12.33, 7.20 Hz), 2.17 (3 H, s), 2.05 (1 H, s), 1.89-1.79 (1 H, m), 1.44 (9 H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.[CH:16]1[C:21]([CH:22]=[O:23])=[CH:20][C:19]2[O:24][CH2:25][O:26][C:18]=2[CH:17]=1.O>O1CCCC1>[O:8]1[C:5]2[CH:6]=[CH:7][C:2]([CH:22]([C:21]3[CH:16]=[CH:17][C:18]4[O:26][CH2:25][O:24][C:19]=4[CH:20]=3)[OH:23])=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 933.6 %

Procedure:
A solution of 4-bromo-1,2-(methylenedioxy)benzene (5.02 g, 2.5 mmol) in 100 mL of dry tetrahydrofuran is cooled to -78° C. n-Butyllithium (15.6 mL, 2.5 mmol) is added dropwise to the reaction. The white suspension is stirred for another hour. Piperonal (4.12 g, 2.4 mmol) in 20 mL of tetrahydrofuran is added. The reaction is warmed to room temperature and stirred overnight. Water (50 mL) is added to quench the reaction. Layers are separated and the aqueous phase is extracted with 3×40 mL of ethyl acetate. The combined organics are dried (magnesium sulfate) and filtered. Solvent is removed in vacuo and the residue is purified by silica gel chromatography eluting with 20% ethyl acetate-hexane to give 6.1 g (90%) of product as a white solid;