Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16](C)[C:17](OC(C)(C)C)=O)[N:9]=[CH:8][N:7]=[C:6]2[O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:35])=[CH:29]2.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH3:17])[S:51]([CH3:50])(=[O:53])=[O:52])[N:9]=[CH:8][N:7]=[C:6]2[O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:35])=[CH:29]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN(C)S(C)(=O)=O
Reaction time: 1 h
Yield: 38.2 %

Procedure:
A suspension of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)quinazoline (148 mg, 0.31 mmol), (prepared as described in Example 149), in methylene chloride (4 ml) containing TFA (1 ml) was stirred for 1 hour. After removing the volatiles under vacuum, the residue was azeotroped with toluene. The residue was dissolved in methylene chloride (3 ml) and triethylamine (215 μl, 1.5 mmol) was added followed by methanesulphonyl chloride (48 μl, 0.62 mmol). After stirring for 1 hour at ambient temperature, the mixture was partitioned between methylene chloride and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/methanol (99/1 followed by 97/3). After evaporation of the solvent, the solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulphonylamino)ethoxy)quinazoline (54 mg, 38%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH:11]([CH:13]=O)=O.O.ICCI.O.NN.[OH-].[K+]>C(O)C.CN(C)C=O>[NH:4]1[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:13][CH2:11][NH:1][CH2:2][CH2:3]1
Reactant: NCCNCCNCCN
Reactant: O=CC=O
Agent: ICCI
Agent: NN
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: C1CNCCNCCNCCN1
Reaction time: 20 h

Procedure:
50 g of triethylenetetramine (0.342 mol) is dissolved in 1 l of ethanol and mixed at room temperature with 39 ml of 40% glyoxal in water (0.342 mol). After 20 hours of stirring, the solvent is distilled off in a vacuum, and an orange-colored oil is obtained, which is then taken up in 400 ml of dimethylformamide and is mixed with 82.6 ml (274.8 g=1.026 mol) of 1,2-diiodoethane. After 5 hours of stirring at 40° C., it is concentrated by evaporation in a vacuum, the residue is taken up in 400 ml of ethanol and acidified to pH=3-4 with 37% aqueous hydrochloric acid. 166 ml (171 g=3.42 mol) of hydrazine hydrate is added to this reaction solution at room temperature, and it is heated under reflux for 30 hours. The reaction solution is set at pH=13 with solid potassium hydroxide. The reaction solution is subsequently concentrated by evaporation in a vacuum, taken up once more in 100 ml of ethanol, and the solvent is removed again in a vacuum. The residue is mixed with 25 g of activated carbon and 150 ml of formaldehyde diethylacetal, and it is heated under reflux for some time before the hot solution is filtered through a membrane. After the solution is cooled, the product is isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH:21]=1)=[O:5].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:5]
Reactant: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc23)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc23)CC1
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 0.40 gm (1.04 mMol) 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 5.2 mL trifluoroacetic acid were added 0.208 mL (1.3 mMol) triethylsilane and the reaction mixture was stirred at ambient. After 2 hours, the reaction mixture was concentrated under reduced pressure. To the residue was added 2N sodium hydroxide and the aqueous was extracted with dichloromethane. The combined organic extracts were washed with 2N sodium hydroxide, dried over sodium sulfate and then concentrated under reduced pressure to give an orange foam. The foam was subjected to radial chromatography (2 mm silica), eluting with 100:10:1 dichloromethane:methanol:ammonium hydroxide. The residue was crystallized from ethyl acetate/hexanes to give 0.27 gm (67.3%) of the title compound as a burnt orange powder.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH2:18]([O:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][N:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:18]([O:25][C:26]1[C:31]([C:2]2[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([O:16][CH3:17])=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])=[CH:30][CH:29]=[CH:28][N:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OB(c2cccnc2OCc2ccccc2)OC1(C)C
Reactant: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1Br
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: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Yield: 100.7 %

Procedure:
step 2—A sealed tube containing 60 (70 mg), 2-benzoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (145 mg), Na2CO3 (62 g) and Pd(PPh3)4 (27 mg) in a mixture of MeOH (4 mL) and DCM (1 mL) was irradiated in a microwave synthesizer at 115° C. for 30 min. The organic volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 40% EtOAc/hexanes to afford 95 mg of 2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-N-methyl-benzamide (62) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[ClH:29]>CC(O)C.CC(OC)(C)C>[ClH:29].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Agent: Cl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Temperature: 40 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate in iPrOH (3 volumes) at 40° C. under nitrogen was added a solution of 5-6N HCl in isopropanol (2-2.4 molar equivalents). The mixture was stirred at 40° C. for 18 hours, cooled to room temp and diluted with TBME (4 volumes). Stirred at room temp for 2 hours, collected by filtration, washed with TBME and air dried to leave an off white powder. Yield: 97% of theoretical.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=O)(C)(C)C.[ClH:37]>C(Cl)Cl.CO.O1CCOCC1>[ClH:37].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([C@H:11]5[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]5[OH:36])[CH:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@H]3CCNC[C@H]3O)cc1OCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108 %

Procedure:
To a solution of racemic-cis-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (92 mg, 0.186 mmol) in DCM (0.5 mL) and methanol (0.3 mL) was added slowly a solution of hydrogen chloride in dioxane (4M, 0.8 mL). The mixture was stirred at room temperature for 2 h 20 min, then concentrated in vacuo. The resultant residue was triturated twice with ether and dried under vacuum to give racemic-cis-4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-ol hydrochloride (86 mg, 108%). LCMS RT=1.93, [M+H]+=395.
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:15]=1[C:16]([OH:18])=[O:17]>C(=O)(OC)OC.CCOC(C)=O.O>[CH3:24][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[C:15]=1[C:16]([O:18][CH3:2])=[O:17]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1cccc(OC)c1C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: COC(=O)OC
Product: COC(=O)c1c(OC)cccc1OC
Temperature: 90 °C

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), (836 mg, 5.49 mmol), was added to a mixture of 2,6-dimethoxybenzoic acid (1), (1.0 g, 5.49 mmol), in dimethyl carbonate (DMC) (10 mL) and the resulting mixture was heated to reflux at 90° C. for 4 hours. The reaction mixture was cooled to 25° C. and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and washed in sequence with 10 mL of water, 2 M HCl (2×30 mL), saturated aqueous NaHCO3 (2×30 mL) and water (2×25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl 2,6-dimethoxybenzoate (2) as a white solid. The yield of the 2,6-dimethoxybenzoate as determined by HPLC was 97-98% conversion.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([OH:27])=O)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])=[O:27])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and N1,N1-dimethyl-1,2-ethanediamine were coupled to give 109bp. 1H NMR (400 MHz, CDCl3) δ 8.28 (br s, 1 H), 7.67 (s, 1 H), 7.56 (m, 1 H), 7.25 (m, 1 H), 6.88 (m, 2 H), 6.78 (m, 1 H), 6.69 (s, 1 H), 5.07 (s, 2 H), 3.78 (m, 2 H), 3.31 (s, 3 H), 3.27 (m, 2 H), 2.84 (s, 6 H). LCMS (ESI) m/z: 472.2
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)C[C@@H](N)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC
Reaction time: 18 h
Yield: 86 %

Procedure:
To a suspension of D-aspartic acid dimethyl ester hydrochloride (36.0 g, 182 mmol) in THF (360 mL) was added 4-fluorobenzenesulfonyl chloride (39.0 g, 200 mmol, 1.1 equiv.). To the previous mixture at 0° C. was added dropwise triethylamine (60.8 g, 601 mmol, 3.3 equiv.). After a period of 18 h at room temperature, the reaction mixture was filtered and the solid washed with methyl tert-butyl ether (30 mL). The filtrate was evaporated followed by the addition of methyl tert-butyl ether (300 mL). To the resulting mixture was added 100 mL of HCl 1 M. The organic phase was separated and sequentially washed with water, half-saturated sodium bicarbonate, HCl 0.5 M and half-saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 50 g of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([C@H:36]([OH:38])[CH3:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:38][C@H:36]([CH3:37])[C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:23])[CH2:34][OH:35]
Reactant: C[C@@H](O)[C@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.226 mmol), (2R,3R)-2-aminobutane-1,3-diol (25 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by trituration with 1:1 heptane/dichloromethane to afford 115 mg (96%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide as a white solid. MS: [M+H]+=529.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].[C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([C:15](=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[C:3]=2[CH3:14])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1c(N=C(c2ccccc2)c2ccccc2)ccc(C#N)c1C(F)(F)F
Yield: 79.1 %

Procedure:
To a stirred solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (3.59 g, 17.9 mmol) in toluene (80 mL) was added benzophenone (3.59 g, 19.7 mmol) followed by PTSA monohydrate (0.035 g, 0.18 mmol). The reaction flask was fitted with a Dean-Stark trap and heated at reflux for 7 d. The reaction was concentrated and purified by SiO2 chromatography (5% EtOAc in hexanes) to afford 4-[(diphenylmethylidene)amino]-3-methyl-2-(trifluoromethyl)benzonitrile (5.16 g, 79%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 7.71-7.01 (m, 10H), 7.65 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[C:18]([C:23]2[C:24]([C:30]#[N:31])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:21]=1[F:22]>>[F:29][C:26]1[CH:25]=[C:24]([C:30]#[N:31])[C:23]([C:18]2[CH:17]=[CH:16][C:21]([F:22])=[C:20]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:19]=2)=[CH:28][CH:27]=1
Reactant: N#Cc1cc(F)ccc1-c1ccc(F)c(Br)c1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3cc(-c4ccc(F)cc4C#N)ccc3F)cnc2c1F
Yield: 6 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 3′-bromo-4,4′-difluorobiphenyl-2-carbonitrile (prepared in the same way as in Example 2) as described in Example 6 to give 4,4′-difluoro-3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile (trifluoroacetate salt) as an off-white solid (23 mg, 6%); m/z (ES+) 408 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6]/[C:7](=[C:14]2\[C:15](=[O:26])[NH:16][C:17]3[C:22]\2=[CH:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=3)/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:29]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6]/[C:7](=[C:14]2\[C:15](=[O:26])[NH:16][C:17]3[C:22]\2=[CH:21][CH:20]=[C:19]([C:23](=[O:24])[NH2:29])[CH:18]=3)/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:27][CH:28]=1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(Br)cc1)c1ccccc1
Reactant: N
Product: NC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Br)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-bromo-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and ammonia Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C22H16BrN2O3
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][S:9][CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:31][O:32][C:33](=[O:62])[C@H:34]([CH2:58][CH2:59][S:60][CH3:61])[NH:35][C:36](=[O:57])[CH2:37][N:38]([CH2:50][C@@H:51]([NH2:56])[CH:52]([CH3:55])[CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1.CCN(CC)CC>CN(C=O)C>[CH3:31][O:32][C:33](=[O:62])[C@H:34]([CH2:58][CH2:59][S:60][CH3:61])[NH:35][C:36](=[O:57])[CH2:37][N:38]([CH2:50][C@@H:51]([NH:56][C:11](=[O:13])[CH2:10][S:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[C@@H:52]([CH3:55])[CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CSCc1ccc([N+](=O)[O-])cc1
Reactant: CCC(C)[C@H](N)CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)CSCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(4-Nitrobenzylthio)acetic acid (68 mg, 300 μmol), dissolved in DMF (4 mL), was treated with HOBT (51 rag, 300 μmol), EDC (65 mg, 300 μmol), and N-[2(S)-amino-3-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (133 mg, 250 μmol). The pH was adjusted to 7.5 with Et3N (110 μL, 250 μmol) and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and the residue was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with H2O (2×50 mL), dried (MgSO4), filtered, and concentrated to give a crude product which was purified by chromatography (silica gel, eluting with 1:1 to 1:2 hexane: EtOAc) to provide the title compound. 1H NMR (CDCl3); δ0.89 (t, 3H, J=7.5 Hz), 0.91 (d, 3H, J=6.9 Hz), 1.02-1.19 (m, 1H), 1.37-1.6 (m, 2H), 1.67-1.79 (m, 1H), 1.85-1.98 (m, 1H), 1.95 (s, 3H), 2.0-2.1 (m, 3H), 2.74 (dd, 1H, J=3, 12 Hz), 2.86-3.01 (m, 3H), 3.21 (d, 1H, J=14 Hz), 3.29 (d, 1H, 14 Hz), 3.69 (s, 3H), 3.74 (d, 1H, J=12 Hz), 3.8 (d, 1H, J=12 Hz), 3.83-3.94 (m, 1H), 4.05 (d, 1H, J=9 Hz), 4.18 (d, 1H, J=9 Hz), 4.41-4.49 (m, 1H), 6.7 (d, 1H, J=8 Hz), 7.39-7.53 (m, 7H), 7.8-7.9 (m, 2H), 8.14-8.22 (m, 2H).
Reaction SMILES: OO.[CH:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1>>[CH:12]1[CH:13]=[C:14]2[C:15]([OH:17])=[C:16]3[C:7](=[C:8]([OH:18])[C:9]2=[CH:10][CH:11]=1)[CH:6]=[CH:5][CH:4]=[CH:3]3
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: OO
Product: Oc1c2ccccc2c(O)c2ccccc12

Procedure:
Hydrogen peroxide can be prepared, for example, by the anthraquinone process by means of which virtually the entire world production of hydrogen peroxide is prepared. This process is based on the catalytic hydrogenation of an anthraquinone compound to form the corresponding anthrahydroquinone compound, followed by reaction of this with oxygen to form hydrogen peroxide and subsequent extraction to separate off the hydrogen peroxide formed. The anthraquinone compound obtained back is hydrogenated again to close the catalysis cycle.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[N+:14]([C:3]1[CH:2]=[CH:1][C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)oc1ccccc12
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Combine dibenzofurane (20.0 g, 0.11 mol) and acetic acid (80 ml). Heat to 65° C. Add 98% nitric acid (20.0 g, 11.8 mol). After 3 hours, cool to room temperature to give a solid. Collect the solid by filtration, rinse with water, and dry to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:22]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:23]([C:39]([NH:41][C@H:42]([C:55](O)=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:22]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:23]([C:39]([NH:41][C@H:42]([C:55]([NH:1][C@H:2]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Yield: 63.1 %

Procedure:
compound SP306P. Same procedure as above with Trp-NHPh (99.6 mg, 0.356 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (214 mg, 0.356 mmol), EDC (75.3 mg, 0.392 mmol) and HOBt (53.7 mg, 0.397 mmol) in CH2Cl2/DMF (1.5 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (193.5 mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ 1.21-1.62 (m, 6H, 3 CH2 Lys), 1.3 (s, 9H, (CH3)3), 1.36 (s, 9H, (CH3)3), 2.64 (m, 1H, CH2 Tyr), 2.87 (m, 3H, CH2 Lys, CH2 Tyr), 3.05 (dd, J=14.7 Hz, J=7.7 Hz, 1H, CH2 Trp), 3.19 (dd, J=14.7 Hz, J=6.2 Hz, 1H, CH2 Trp), 4.11 (m, 1H, CHα), 4.31 (m, 1H, CHU), 4.71 (m, 1H, CHU), 5.02 (s, 2H, CH2 (Bn)), 6.71 (m, 1H), 6.87-7.42 (m, 17H), 7.58 (m, 3H), 7.9 (d, J=7.3 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H), 10 (s, 1H), 10.8 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 22.5, 29.2, 32 (3 CH2 Lys), 27.8 (CH2 Trp), 28.1, 28.2 (2 (CH3)3), 36.3 (CH2 Tyr), 39.8 (CH2 Lys), 52.4, 54.2, 55.8 (CHα Tyr, Lys, Trp), 69.1 (CH2 (Bn)), 77.3, 78.1 (2 C(CH3)3), 109.6, 111.2, 114.3, 118.2, 118.4, 119.4, 120.8, 123.3, 123.4, 127.3, 127.5, 127.7, 128.3, 128.6, 130.1, 130.2, 136, 137.2, 138.8 (25 aromatic C), 155.2, 155.5, 156.8 (Car-O, 2 CO carbamate), 170.1, 171.5, 171.6 (3 CO amide). Anal. Calcd. for C49H60N6O8, 1.5H2O: C, 66.27; H, 7.15; N, 9.46. Found: C, 66.42; H, 6.96; N, 9.34.