Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:19]=1[O:20]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:25])([F:23])[F:24])[C:19]=1[OH:20])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CSc3ccccc32)cc(C(F)(F)F)c1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiazole (232 mg) was dissolved in N,N-dimethylformamide (3 mL), and lithium chloride (108 mg) was added to the solution, and then the mixture was stirred at 70° C. for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (131 mg) as a brown crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:29][CH2:30][C:31](Cl)=[O:32]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:31](=[O:32])[CH2:30][Cl:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)CCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCl)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and chloroacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][Br:13]
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(CCBr)c(Cl)c1
Temperature: 0 °C

Procedure:
2,4-Dichlorophenethyl alcohol (10 g, 52.0 mmol) was dissolved in 100 mL of methylene chloride, cooled to 0° C. under nitrogen atmosphere and 1.5 equiv of phosphorous tribromide (1M in CH2Cl2, 80 mmol, 80 mL) was added dropwise. The resulting reaction mixture was warmed to 23° C. and stirred for 2 h before the very slow addition of 200 mL of saturated aqueous sodium bicarbonate and extraction with methylene chloride (2×150 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by a SiO2 plug (5% EtOAc/hexanes) to yield 2,4-dichlorophenethyl bromide. The product was characterized by 1H NMR and HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][CH3:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=S)=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[N:22]([CH3:23])[C:21]3[CH:20]=[CH:19][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=4)=[CH:3][C:2]=3[N:1]=2)=[CH:27][CH:26]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(Br)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Temperature: 50 °C

Procedure:
A solution of the diamine from step 6 (1 eq) and 4-bromophenyl isothiocyanate (1 eq) in anhydrous tetrahydrofuran under nitrogen was stirred at 20° C. for 2-3 hours or when determined to be complete by HPLC. The solution was treated with 3 equivalents of 1-ethyl-(3-dimethylaminopropyl)carbodiimide HCl. The stirred solution was heated to 50° C. under nitrogen for 2-3 hrs or until the reaction is determined to be complete by HPLC. The reaction was evaporated under reduced pressure and then diluted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and later evaporated under reduced pressure. The crude material was purified by reverse high-pressure liquid chromatography to afford the product as a brown powder after lyophlization. MS: MH+=495.
Reaction SMILES: [C:1]1(=[O:14])[C:10]2[C:5](=CC(C(O)=O)=C[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=O.C1(N=C=NC2CCCCC2)CCCCC1.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[CH2:2]1[C:3]2[C:17](=[CH:18][C:19]([C:20]([NH2:16])=[O:21])=[CH:5][CH:4]=2)[CH2:9][CH2:10][C:1]1=[O:14]
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mmol) was co-dissolved in CH2Cl2 (50 mL) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0° C. and treated with a slight excess of 1,3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture was allowed to warm to ambient temperature over 30 minutes, during which time a fine white precipitate formed. Ammonium chloride (333 mg, 6.23 mmol) and triethylamine (1.58 mL, 12.5 mmol, d=0.797) were added. The solution was stirred at ambient temperature for 16 hours. The suspended urea and salts were filtered away and the solution concentrated in vacuo to a colorless oil. The oil was applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 250 mg (64%) of 2-tetralone-6-carboxamide, ethylene ketal as a white solid, clean by NMR, TLC. 2-Tetralone-6-carboxamide ethylene ketal (250 mg, 1.07 mmol) and catalytic p-toluenesulfonic acid were stirred in acetone (50 mL) at ambient temperature for 48 hours. The volatiles were removed in vacuo and the residue triturated in ethyl acetate. The solids were filtered, washed and dried to yield 77.5 mg (38%) of 2-Tetralone-6-carboxamide as a white powder, pure by NMR, TLC. MS.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>C(#N)C>[CH:17]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:19])[CH3:18]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.4 %

Procedure:
To a solution of 5-hydroxyindole 23 (2.0 g, 0.015 mol) in 20 ml of acetonitrile, anhydrous potassium carbonate (4 grams, 0.028 mol) was added and stirred vigorously before isopropyl iodide (3 grams, 0.018 mol) was added. The reaction was stirred for 2 days at room temperature and the solid was washed with acetonitrile. The filtrate was concentrated and purified with flash-chromatography (80% n-hexane/20% ethyl acetate) to give the desired product 24 as a light-yellowish oil (1.72 g, 83%; M+1=176.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:19]=[C:18]([C:20]3[O:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:21]=3[O:29]CC3C=CC=CC=3)[O:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[N:19]=[C:18]([C:20]3[O:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:21]=3[OH:29])[O:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2noc(-c3oc4ccncc4c3OCc3ccccc3)n2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2noc(-c3oc4ccncc4c3O)n2)CC1

Procedure:
A solution of 4-[5-(3-benzyloxyfuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (Example 120, 200 mg, 500 μmol) and Pd (10% on C, 10 mg) in EtOH (10 mL) was stirred under a H2 atmosphere for 2.5 h. The mixture was diluted with CH2Cl2, to solubilise the product, before being filtered through celite. The filtrate was concentrated to furnish the title compound: RT=2.87 min; m/z (ES+)=401.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=4)[CH2:17][CH2:16]3)=[N:11][NH:10][C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=4)[CH2:19][CH2:20]3)=[N:11][N:10]([CH3:33])[C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=c1[nH]nc(CCN2CCN(c3cccc([N+](=O)[O-])c3)CC2)n1CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(CCN2CCN(c3cccc([N+](=O)[O-])c3)CC2)n(CC2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a mixture of 4-(cyclohexylmethyl)-5-{2-[4-(3-nitrophenyl)piperazin-1-yl]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (D9; 500 mg, 1.207 mmol) and NaH (60% in mineral oil, 97 mg, 2.412 mmol), DMF (20 mL) was added and the slurry was stirred at room temperature for 10 min. Methyl iodide (0.226 mL, 3.621 mmol) was added and the reaction mixture was stirred at room temperature for 2.5 hrs. The reaction was quenched with water (3 mL) and the solvents were removed in vacuo. The resulting yellow solid was triturated with 10% MeOH in AcOEt (250 mL) and the solid filtered. The filtrate was evaporated to afford 1.3 g crude yellow solid which was further purified by flash chromatography (Flash Master, Biotage Isolute SI, 5 g column, gradient AcOEt for 3 min, then 0-10% MeOH in AcOEt for 27 min and 10% MeOH in AcOEt for 15 min) to afford 490 mg (94%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.098 mmol) was dissolved in tetrahydrofuran (2 mL). Methanesulfonyl chloride (18 mg, 0.127 mmol) was added to the reaction mixture followed by triethylamine (136 uL, 0.977 mmol). The suspension was stirred at rt overnight. The compound was triturated with 1:1 ether-hexanes to yield desired product (14 mg, 29%). 1H NMR (300 MHz, dichloromethane-d2) δ 7.95 (1d, 1 H), 7.80 (1s, 1 H), 7.69-7.97.64 (m, 3 H), 7.27-7.25 (m, 4 H), 7.13 (d, 1 H), 6.54 (s, 1 H) 5.61 (bs, 2 H), 5.61 (bs, 2 H), 5.52 (s, 2H), 4.05-3.90 (m, 2H), 3.60-3.35 (m, 3 H), 2.75 (s, 3 H), 2.45 (m, 1 H), 2.20 (m, 1 H); ES-MS m/z 488.3 [M+H]+, HPLC RT (min) 2.72.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([CH2:16]O)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([CH2:16][N:41]3[C:37](=[O:47])[C:38]4[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:40]3=[O:42])=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(CO)[C@@H]2C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(CN3C(=O)c4ccccc4C3=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To alcohol 7 (1.13 g; 4.67 mmol), triphenyl phosphine (1.28 g; 4.88 mmol) and phthalimide (0.73 g; 4.96 mmol) in THF (75 mL) was added DIAD (0.98 mL; 4.94 mmol). The reaction mixture was stirred at room temperature overnight. The volatiles were evaporated and the residue chromatographed with 50% ethyl acetate/hexanes to yield phthalimide 8 as a white foam.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH2:12]O)([CH3:3])[CH3:2].[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1>C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>[CH:1]([N:4]1[C:5]2[C:6](=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[CH:12]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]1=[O:21])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cccc(NC(C)C)c1CO
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc2c(C)cccc2n(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.5 %

Procedure:
A mixture of 2-(isopropylamino)-6-methylbenzaldehyde (22.4 g, 127 mmol, step 2 in preparation 2), diethyl malonate (22.3 g, 139 mmol), piperidine (1.29 g, 15.2 mmol), and benzoic acid (572 mg, 4.7 mmol) in benzene (500 mL) was refluxed with stirring for 4 days. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:15˜1:2) to give 19.6 g (57%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:27][CH:26]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccccc3F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 25 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2-fluorobenzyl)-1-piperidinecarboxamide (0.50 g, 1.2 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.436 g, 1.08 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.21 g, 0.27 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C@@H:7]([NH:31][C:32](=[O:51])[NH:33][C@@H:34]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](ON1C(=O)CCC1=O)=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C@@H:54]([CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:77][C:78]1[N:79]([CH2:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH:80]=[CH:81][N:82]=1)[CH2:63][C:64]1[N:65]([CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH:66]=[CH:67][N:68]=1)[C:55]([OH:57])=[O:56].CCN(C(C)C)C(C)C>CN(C=O)C>[C:72]([O:71][C:70](=[O:76])[CH2:69][N:65]1[CH:66]=[CH:67][N:68]=[C:64]1[CH2:63][N:62]([CH2:77][C:78]1[N:79]([CH2:83][C:84](=[O:85])[O:86][C:87]([CH3:90])([CH3:89])[CH3:88])[CH:80]=[CH:81][N:82]=1)[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:54]([C:55]([OH:57])=[O:56])[NH:53][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:30])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:52])[NH:31][C:32](=[O:51])[NH:33][C@H:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:42][CH2:43][C:44](=[O:45])[O:46][C:47]([CH3:49])([CH3:50])[CH3:48])([CH3:73])([CH3:75])[CH3:74]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 22.8 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.291 g, 0.45 mmol), (S)-2-amino-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl) amino)hexanoic acid (0.22 g, 0.412 mmol) and DIPEA (1.0 mL) in DMF (4.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (7S,11S,26S)-26-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-2,2-dimethyl-4,9,17,24-tetraoxo-3-oxa-8,10,16,25-tetraazaheptacosan-27-oic acid (0.1089 g, 21%). MS (ESI), 581 (M/2+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.03 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which forms after scratching is filtered and air-dried, yield 7.0 g., m.p. 190°-213°C. Several recrystallizations from nitromethane, followed by a final recrystallization from acetonitrile, gives a light yellow solid with m.p. 223°-227°C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:19]=[CH:18][C:14]3[CH2:15][O:16][CH2:17][C:13]=3[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Pd]>[CH2:15]1[C:14]2[CH:18]=[CH:19][C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[CH:12][C:13]=2[CH2:17][O:16]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)COC3)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc3c(c2)COC3)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A solution of 5-[(4-nitrophenyl)oxy]-1,3-dihydro-2-benzofuran (Intermediate 74, 190 mg, 0.739 mmol), hydrazine hydrate (0.046 ml, 1.477 mmol) and Pd/C (157 mg, 0.148 mmol) in ethanol (6 ml) was stirred under argon at 90° C. After 4.5 hours 0.2 equivalents of Pd/C and 2 equivalents of hydrazine hydrate were added. After 1 more hour, the reaction mixture was cooled to room temperature and then filtered over celite and washed with methanol. The organic phase was concentrated and the residue was purified by SCX to afford the title compound (152 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20].C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:22]([NH:21][CH2:19][CH3:20])=[O:23])[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CCN=C=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, ethylisocyanate, and diisopropylethyl amine, are reacted to give the product. LC-MS: 333 (M++1). 1H NMR (DMSO-d6): 61.0 (t, 3H), 2.8–3.0 (m, 4H), 3.0–3.14 (q, 2H), 3.45–3.6 (m, 4H), 6.25 (s, 1H), 6.4–6.55 (s, 2H), 6.55–6.65 (m, 1H), 7.1–7.2 (m, 1H), 7.35–7.4 (m, 1H), 7.7–7.8 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[CH2:14][CH2:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH:25]1([CH2:31][NH:1][C:2]2[N:7]=[C:6]([C:8]3[NH:16][C:15]4[CH2:14][CH2:13][NH:12][C:11](=[O:17])[C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=CC1CCCCC1
Reactant: Nc1nccc(-c2cc3c([nH]2)CCNC3=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3ccnc(NCC4CCCCC4)n3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
2-(2-Amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (140 mg, 0.61 mmol), trifluoroacetic acid (565 μl, 7.33 mmol), and cyclohexanecarbaldehyde (151 μl, 1.25 mmol) were mixed in DMF (10 ml). Sodium triacetoxyborohydride (390 mg, 1.84 mmol) was added to the above solution and the reaction mixture stirred at room temperature under N2 for 20 h. Additional cyclohexanecarbaldehyde (151 μl, 1.25 mmol) and sodium triacetoxyborohydride (390 mg, 1.84 mmol) were added and the reaction mixture was stirred 20 hours longer. The reaction was quenched with 0.33N NaOH (50 ml), and the product was extracted with DCM (50 ml). The DCM extract was dried (MgSO4), and the solvent was evaporated. The residue was purified by flash chromatography (DCM-MeOH, 95:5) to give the product as a beige solid (80 mg, 40% yield).