Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:8]2[C:9](=[O:26])[N:10]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:7]=2[N:6]([CH3:27])[C:5]=1[C:28]([NH:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:29].C(N(CC)CC)C.[C:45]([O:48][CH2:49][C:50](Cl)=[O:51])(=[O:47])[CH3:46]>C1COCC1.C(=O)([O-])O.[Na+]>[C:45]([O:48][CH2:49][C:50]([N:35]1[CH2:34][CH2:33][CH:32]([CH2:31][NH:30][C:28]([C:5]2[N:6]([CH3:27])[C:7]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]([CH2:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:9](=[O:26])[C:8]=3[C:4]=2[O:3][CH3:2])=[O:29])[CH2:37][CH2:36]1)=[O:51])(=[O:47])[CH3:46]
Reactant: COc1c(C(=O)NCC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(=O)NCC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of the compound of Example 542 (400 mg, 0.76 mmol) and triethylamine (0.29 mL, 2.1 mmol) in THF (17 mL) was added acetoxyacetyl chloride (0.10 mL, 0.95 mmol) under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate, and filtered through aminosilica gel. The filtrate was concentrated, and the residue was recrystallized from ethanol-hexane to give the title compound (321 mg, 71%) as a white solid.
Reaction SMILES: [Cl-:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[Cl-:1].[Cl:1][CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:2])[CH2:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Product: O=C(CCCCCl)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution consisting of 18.5 parts of [(tetrahydro-2H-pyran-2-ylidene)methyl]triphenylphosphonium chloride in 100 parts by volume of concentrated hydrochloric acid is heated at the reflux temperature for about 36 hours, then is cooled to room temperature. The solvent is removed by distillation under reduced pressure to afford (6-chloro-2-oxohexyl)triphenyl-phosphonium chloride, identical with the product of Example 2.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)CCc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2
Temperature: 25 °C
Yield: 37.2 %

Procedure:
6-Bromo-1,1-dimethyl-indan (WO2005066115) 8g (4.32 g, 19.27 mmol) was dissolved in 40 mL of tetrahydrofuran and then butyllithium (15.67 mL, 1.6 mol/L, 25.05 mmol) was added dropwise at −78° C. After the reaction mixture was reacted for 40 minutes, a solution of di-tert-butyl azodicarboxylate (5.32 g, 23.12 mmol) in 30 mL of tetrahydrofuran was then added. The reaction mixture was reacted for another 3 hours at −78° C. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with 5 mL of methanol. The mixture was warmed up to room temperature and filtered by silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 8h (2.70 g, yield 37.2%) as a yellow solid.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[NH:5][C:6](=[O:19])[S:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.O>C(O)(=O)C>[CH3:3][C:4]1[NH:5][C:6](=[O:19])[S:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:1])=[CH:14][CH:15]=1
Reactant: CSc1ccc(C(=O)c2sc(=O)[nH]c2C)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c(=O)sc1C(=O)c1ccc(S(C)=O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Hydrogen peroxide (1 equivalent, 30%) is added to a solution of 4-methyl-5-[4-(methylthio)benzoyl]-2(3H)-thiazolone (2.7 g) in glacial acetic acid (80 ml). The mixture is stirred for 3 hours at 50° C. The precipitate obtained on addition of water is recrystallized from ethanol to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28]C(=O)OC(C)(C)C)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.Cl>C(Cl)Cl.O1CCOCC1>[NH2:28][C@H:26]([CH3:27])[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]=2[F:24])=[N:9]1
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](N)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a solution of tert-butyl N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]carbamate (2.56 g, 5.35 mmol) in DCM (20 mL) was added 4N HCl in dioxane (15 ml). After stirring 18 h at room temperature, the reaction was diluted with DCM (100 mL) and extracted with water (200 mL). The aqueous layer was washed again with DCM (50 mL). The aqueous layer was placed in a 2 L beaker along with ethyl acetate (50 mL) and stirred while adding NaOH (beads) to adjust the pH to ˜11. More ethyl acetate (100 mL) was added and then the layers were separated and the aqueous layer was washed with ethyl acetate. The combined organic layers were washed with brine and then dried (MgSO4), filtered and concentrated to obtain 1.8 g (90%) of 1-[(2R)-2-aminopropyl]-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine as a solid.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>[OH-].[Na+].O1CCOCC1.C(OCC)(=O)C>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:17][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[C:18]([OH:20])=[O:19])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81024.5 %

Procedure:
Nε -Carbobenzyloxy-L-lysine (30.0 g, 0.107 mmol) was dissolved in a solution of 2N NaOH (60 mL) and dioxane (150 mL) under nitrogen. After about 15 minutes at room temperature, the mixture was cooled to about 0° C. and subsequently treated with additional 2N NaOH (60 mL) and p-toluenesulfonyl chloride (20.4 g, 0.107 mmol) in 5 g portions over about 15 minutes. The mixture was stirred at about 0° C. for about 1 hour and at room temperature for about 18 hours before it was neutralized to pH 6 with 1N HCl. The mixture was then diluted with ethyl acetate and the organic phase was separated and washed with brine. The aqueous phase was extracted twice more with ethyl acetate and the combined organic phases were treated further as mentioned above. Following drying and solvent evaporation of the combined organic phases, the residue was first pre-columned on silica gel (elution with 10% methanol in dichloromethane) and subsequently recrystallized from ethyl acetate/hexanes (2:1) to give 37.67 g (81%) of the title compound as a white solid, m.p. 120°-121° C.; 1H NMR (CDCl3) δ 8.37 (v br s, 0.5H), 7.71 (d, J=8.0 Hz, 2H), 7.32 (s, 5H), 7.23 (d, J=7.6 Hz, 2H), 6.49 and 4.89 (2m, 1H), 5.73 (d, J=8.4 Hz, 1H), 5.10 and 5.04 (2s, 2H), 3.91 (m, 1H), 3.17-3.02 (m, 2H), 2.35 (s, 3H), 1.73-1.66 (m, 2H), 1.40-1.24 (m, 4H); 13C NMR (CDCl3) ppm 199.88, 175.06, 174.57, 158.37, 156.89, 143.66, 136.86, 136.32, 129.66, 128.54, 128.10, 127.19, 67.47, 66.89, 55.28, 40.95, 40.44, 32.25, 29.10, 28.75, 21.77, 21.46; IR (KBr, cm-1) 3382, 3264, 2950, 1738, 1656 1550, 1334, 1286, 1160, 1092, 818, 678, 568; MS m/z (MH+) 435.1590, obsd 435.1595.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C.Cl>O>[C:4]([C:3]1[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:2]=1[N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([OH:6])=[O:5]
Reactant: CCOc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCN(C)c1cc(OCC)c([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 24.5g 2-chloro-4-ethoxy-5-nitrobenzoic acid, 22.7g methyl tetradecylamine (distilled) and 35.0 ml triethylamine were heated on a steam bath for 5 hours and then poured into two liters of water and made acid with HCl. The reaction product was filtered and washed with water, and recrystallized twice from methanol/water.
Reaction SMILES: NC1C=CC=CC=1[S:8][C:9]1[CH:28]=[CH:27][C:26]2C3=C4[C:25]5[C:16]([C:17](=[O:53])[N:18]([C:41]6[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:44]=[CH:43][C:42]=6[CH:50]([CH3:52])[CH3:51])[C:19](=[O:40])[C:20]=5C=C3OC3C=CC(C(C)(C)C)=CC=3)=[CH:15][C:14]([O:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:57][CH:56]=3)=[C:13]4[C:12]3=[CH:65][CH:66]=[CH:67][C:10]=1[C:11]=23.N([O-])=O.[Na+].CC(O[CH2:76][C:77]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)C(COC(C)=O)=C2[C:78]=1[CH:79]=CC=C2)=O>O>[C:61]([C:58]1[CH:57]=[CH:56][C:55]([O:54][C:78]2[C:77]3[C:90]4[CH:89]=[CH:88][C:87]5[S:8][C:9]6[C:10](=[CH:11][CH:26]=[CH:27][CH:28]=6)[C:67]6=[CH:66][CH:65]=[C:12]([C:13]7[C:76]=3[C:25]3[C:16](=[CH:15][C:14]=7[O:54][C:55]7[CH:60]=[CH:59][C:58]([C:61]([CH3:63])([CH3:64])[CH3:62])=[CH:57][CH:56]=7)[C:17](=[O:53])[N:18]([C:41]7[C:42]([CH:50]([CH3:51])[CH3:52])=[CH:43][CH:44]=[CH:45][C:46]=7[CH:47]([CH3:48])[CH3:49])[C:19](=[O:40])[C:20]=3[CH:79]=2)[C:85]=4[C:86]=56)=[CH:60][CH:59]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4cccc5c(Sc6ccccc6N)ccc(c6c(Oc7ccc(C(C)(C)C)cc7)cc(c2c36)C1=O)c54
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1-n1c(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4ccc5sc6ccccc6c6ccc(c7c(Oc8ccc(C(C)(C)C)cc8)cc(c1=O)c2c37)c4c56
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 8-bromo-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (3.0 g), 2-aminobenzenthiol (0.48 g, 10% excess) and anhydrous potassium carbonate (0.24 g) were added to 30 mL of N-methyl-2-pyrrolidinone (NMP). The solution was heated rapidly and refluxed for 30 min. After a minute the liquor was added to 2% aqueous hydrochloride acid (250 ml) and after standing overnight, filtered and dried at 105° C. to give a red-blue solid of 8-((2-aminophenyl)thio)-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (2.06 g) with a nominal yield of 60.0%. 8-((2-aminophenyl)thio)-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (2.06 g) was dissolved in warm glacial acetic (12 mL) and concentration hydrochloride acid (1.3 mL) giving a fine suspension. The suspension was cooled to 0° C. and a solution of sodium nitrite (0.16 g) in water (3.6 mL) added and stirred continuously till clear. The prepared solution was added to a boiling solution of hydrated cupric sulphate (2.6 g) in water (60 mL) with good stirring within 1 hour. After boiling a further 1 hour, the solution was cooled, filtered and a blue-red solid was given. The solid was washed with a warm solution of sodium hydroxide (20 mL, 3%) three times and purified on Chromatography Column to eliminate by-products. The blue solid of 5,15-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-thioxantheno[2′,1′,9′:10,5,6]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (0.69 g) was given with a nominal yield of 34.2%. MS: base peak 884.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:36])[CH2:32][CH2:33][C:34]#[CH:35].CCN(CC)CC>C(Cl)(Cl)Cl.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.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:35]=[C:34]([CH2:33][CH2:32][CH2:31][OH:36])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CCCO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (800 mg), PdCl2(PPh3)2 (104.6 mg), CuI (34.1 mg), 4-pentyn-1-ol (0.17 mL), and Et3N (0.42 mL) in CHCl3 (14.9 mL) is stirred at room temperature overnight. Reaction condensed to remove CHCl3. The solvent is replaced with EtOH (15 mL) and additional Et3N (0.38 mL) is added to the reaction mixture. N2 is passed over the surface and the reaction is heated at 76° C. for 6 h, then allowed to cool to room temperature. Reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2. Product-containing fractions are combined, condensed, and recrystallized from hot acetonitrile to afford 408.9 mg (56%) of N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a yellow solid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:61]([O:63][CH3:64])=[O:62])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1.Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCN(CC)CC>[NH:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:12]([C:20]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:61]([O:63][CH3:64])=[O:62])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 18 h

Procedure:
9.5 ml NEt3, 13 g HOBT and 17 g BOC-Phe-OH are added to 35 g H-(D)Trp-Lys(Z)-OMe hydrochloride in 350 ml DMF. The solution is cooled to -20° C. and 14.5 g DCCI dissolved in 50 ml DMF are added. The reaction mixture is stirred for ca. 18 hrs. at 0° C. and then for 1 day at room temperature. The precipitated dicyclohexyl-urea is filtered off and the filtrate is concentrated, diluted with methanol and H2O added until precipitation occurs. After filtration the residue is washed with MeOH/H2O (4:1) and dried to yield the title compound:
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][N:6]([CH2:28][C:29]1[N:34]=[CH:33][C:32]2[O:35][CH2:36][CH2:37][O:38][C:31]=2[CH:30]=1)[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[CH:18]=[CH:17][C:16]2=[O:27])[CH2:9][CH2:8]1)C.[OH-].[Na+].Cl>CO.O1CCCC1>[O:38]1[C:31]2[CH:30]=[C:29]([CH2:28][N:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]3[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]4[C:24]5[C:19](=[N:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=5)[CH:18]=[CH:17][C:16]4=[O:27])[CH2:9][CH2:8]3)[N:34]=[CH:33][C:32]=2[O:35][CH2:36][CH2:37]1
Reactant: CCOC(=O)CN(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(OC)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(CC(=O)O)Cc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A solution of 90 mg of ethyl((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetate in 0.2 mL of methanol and 1 mL of tetrahydrofuran, 0.2 mL of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with a 1 mol/L aqueous hydrochloric acid solution and neutralized, and the solvent was distilled off under reduced pressure. The resultant residue was purified by a resin; HP-20, made by Mitsubishi Chemical Corporation and an eluent of acetone to obtain 54 mg of ((2,3-dihydro(1,4)dioxino(2,3-c) pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetic acid as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12]([CH3:16])[CH2:13][C:14]#[CH:15]>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[CH3:11][N:12]([CH3:16])[CH2:13][C:14]#[C:15][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C#CCN(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CC#Cc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a screw top tube, 8.1 mg (0.0425 mmoles) of CuI, 18 mg(0.0256 mmoles) of PdCl2(PPh3)2, and 207 mg (0.8483 mmoles) of 5-Bromo-1H-pyrrolo[2,3-b]pyridine were added. The dry solids were diluted with 1 ml of dry DMF and a stream of N2 was bubbled through the solution for 10 minutes and then 182.6 ul(1.7 mmoles) of Dimethyl-prop-2-ynyl-amine was added and the reaction was stirred in a sealed tube overnight at room temperature. The reaction was diluted with 10 ml of DCM and washed with saturated ammonium chloride solution. The organic layer was separated and dried with MgSO4, filtered, and concentrated to dryness yielding a crude material of 189 mg. MS showed a M+ ion of 200.05 which confirmed the structure above. The crude material was taken to the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:18]([CH3:20])[CH3:19])=[CH:13][C:14]([OH:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:18]([CH3:19])[CH3:20])=[CH:13][C:14]([O:17][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCn2c1cc1c(C(C)C)cc(O)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CCn2c1cc1c(C(C)C)cc(OCc3ccccc3)cc12
Reaction time: 1 h

Procedure:
To the compound of Step 3 (130 mg, 0.45 mmol) in DMF (2 mL) at 0° C., was added benzyl bromide (100 mL) and Cs2CO3 (300 mg, 0.92 mmol). The reaction mixture was warmed to r.t for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (130 mg).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([C:14](O)=[S:15])[C:11]([C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(OC(C)=O)=O>[CH2:1]([C:8]1[N:13]=[C:12]2[C:14]([O:19][C:17](=[O:18])[C:11]2=[CH:10][CH:9]=1)=[S:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)nc1C(O)=S
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=S)c2nc(Cc3ccccc3)ccc21

Procedure:
8.5 g (0.029 mol) 6-benzylthiopyridine-2,3-dicarboxylic acid are stirred into 150 ml acetanhydride 6 hours at 110° C. The substrate thereby dissolves completely. The solvent is distilled off in a vacuum and the residue is employed in the next stage without further purification.
Reaction SMILES: [N-]=C=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([CH2:36][C@@H:37]2[CH2:41][CH2:40][C:39](=[O:42])[NH:38]2)[CH:33]=[CH:32][C:31]=1[N:43]1[S:47](=[O:49])(=[O:48])[N:46](CC[Si](C)(C)C)[C:45](=[O:56])[CH2:44]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.O>[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([CH2:36][C@@H:37]2[CH2:41][CH2:40][C:39](=[O:42])[NH:38]2)[CH:33]=[CH:32][C:31]=1[N:43]1[S:47](=[O:49])(=[O:48])[NH:46][C:45](=[O:56])[CH2:44]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCC(=O)N3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [N-]=C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC[C@@H](Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of PS-isocyanate resin (0.500 g) in THF is added TBAF (1M in THF, 2.5 mL) and the mixture is stirred at RT for 2 h. The resin is filtered off and the TBAF solution is added to a stirring solution of 5-[2-benzyloxy-4-((S)-5-oxopyrrolidin-2-ylmethyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.660 g, 1.28 mmol) in THF (20 mL). The mixture is stirred at 50° C. for 18 h. The mixture is allowed to cool to RT then is diluted with water and extracted with EtOAc (3×). The organic layer is washed with brine, dried over Na2SO4 and concentrated. The residue is purified on a reverse phase silica cartridge eluting with EtOH/H2O (10-60%) to provide the title compound: (M−1)−=414.