Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[CH3:25])[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1.FC(F)(F)C(O)=O.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[CH3:25])[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2nc(O)c3c(c2=O)Cc2ccc(Cl)cc2N3)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
7-Chloro-4-hydroxy-2-(4-methoxy-2-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (5.0 mL, 13.1 mmol) was suspended in tetrahydrofuran (170 mL) under nitrogen cooled to 0° C. and treated with trifluoroacetic acid (18 mL, 235 mmol). Over a 10 minute period, the reaction mixture was then treated with NaBH4 (1.973 g, 52.2 mmol). The reaction mixture was stirred at 0° C. for 6 hours and then was stored in a freezer overnight. The reaction mixture was then treated with additional NaBH4 (approximately 1.0 g) and stirred at 0° C. for 2 hours. The reaction mixture was poured onto water (500 mL) and extracted with ethyl acetate (2×200 mL). The ethyl acetate extracts were combined and then concentrated in vacuo. The residue was poured onto ether (400 mL) and the solid which formed was collected by filtration to afford crude product. The crude was recrystallized from methanol to afford 1.91 g of the title compound as an off-white solid, mp 264-266° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCn1ccc2cc(C(=O)O)ccc21
Reaction time: 12 h

Procedure:
Sodium hydride (50% in oil, 1.4 g) was added to methyl 1H-indole-5-carboxylate (5.0 g) in DMF (100 ml) and, bromobutane (3.9 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:6). The resulting ester was dissolved in methanol (10 ml) and boiled under reflux with sodium hydroxide (0.6 g ) in water (10 ml) for 12 hours. The mixture was diluted with water and acidified with hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 217.27 (C13H15NO2); MS (ESI): 218 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[CH2:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([C:18]([O:20]C)=O)[CH2:7][C:6]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4]>O>[CH2:7]1[C:6]2[NH:22][C:23]3[C:24]([C:3](=[O:4])[C:5]=2[CH2:10][C:9]2[NH:11][C:12]4[C:13]([C:18](=[O:20])[C:8]1=2)=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3
Reactant: COC(=O)C1=C(Nc2ccccc2)CC(C(=O)OC)=C(Nc2ccccc2)C1
Solvent: O
Product: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Temperature: 80 °C
Yield: 95.6 %

Procedure:
To 120.0 g of polyphosphoric acid (118%) was added with stirring 20.0 g (52.9 mmol) of 2,5-bis(phenylamino)-1,4-cyclohexadiene-1,4-dicarboxylic acid dimethyl ester. The stirred mixture was irradiated in the microwave oven for 1.5 minutes. After the reaction mixture was cooled to 80° C., water was added with stirring. The resultant slurry was stirred for 5 minutes, after which the solid component was collected by filtration and washed with 3.0 liters of water. The presscake was dried overnight in an oven at 60° C. to give 15.9 g of 6,13-dihydroquinacridone (95.7% yield, 97.0% spectroscopic purity).
Reaction SMILES: [CH3:1][C:2]1OC(=O)[CH:6]([C:10]([CH3:12])=O)[C:4](=[O:5])[CH:3]=1.[NH3:13]>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[CH:6]=[C:10]([CH3:12])[N:13]=1
Reactant: N
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Product: Cc1cc(O)cc(C)n1

Procedure:
Five separate batches of dehydroacetic acid (1.5 g, 8.92 mmol) are each suspended in conc. ammonia (4 mL) and irradiated at 120° C. for 20 minutes (150 W, Discover® System microwave reactor by CEM Corporation, Matthews, N.C., USA) in the microwave. Once cooled, the solutions are combined and evaporated to dryness to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=O)[C:5]=1[O:23][CH3:24]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:12]([C:14]3[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=3)[NH:11][C:6]=2[C:5]=1[O:23][CH3:24])=[O:25]
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2cc([N+](=O)[O-])cn2C)c1OC
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(-c3cc([N+](=O)[O-])cn3C)[nH]c2c1OC
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
The aforementioned mixture of amides 14a/14b (500 mg, 1.43 mmol) was suspended in glacial acetic acid (8 mL) and heated to 90° C. for 7 h. Most of the solvent was evaporated, and the yellow residue was suspended in Et2O. After being vigorously stirred for 20 min, the precipitate was filtered and washed with Et2O. Drying under hv gave 404 mg (85%) of 15 as a beige solid. Data of 15: Rf 0.80 (hexane/EtOAc 1:5). 1H NMR (300 MHz, DMSOd6): δ 3.76 (s, 3H), 4.14 (s, 3H), 4.34 (s, 3H), 7.14-7.17 (m, 1H), 7.48-7.55 (m, 3H), 8.25 (s, 1H). MS (ESI): m/z (rel intensity) 331 (98).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](I)=[CH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[CH2:16])[CH:18]=[CH2:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(I)c1ccc(OCc2ccccc2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=CC(=C)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-benzyloxy-4-(1-iodo-vinyl)-benzene (12.0 g, 0.035 mol), vinyl tributyl tin (16.0 mL, 0.056 mol) and PdCl2(CH3CN)2 (150 mg, 0.0579 mmol) were dissolved in DMF (300 mL). The reaction mixture was stirred at 25° C. for 16 h, then partitioned between ethyl acetate (800 mL) and H2O (400 mL). The organic layer was washed by brine, concentrated and purified on SiO2 (15% ethyl acetate/Hexane) to yield 1-benzyloxy-4-(1-methylene-allyl)-benzene.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=1[S:40]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])(=[O:41])=[O:42]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-chloro-6-methylbenzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Agent: Br
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one (601 mg, 2.93 mmol) in acetic acid (880 μL) is added hydrobromic acid (48% in H2O) (8.8 mL). The resulting solution is heated to reflux (105°-110° C.), stirred 2 hrs, then cooled to room temp and concentrated under reduced pressure. The residue is dissolved in EtOAc and the organic layer washed with water, brine, dried over MgSO4 and concentrated. The residue is purified by triturating with a small volume of ether to give 495 mg of title compound as an off white solid. MS (ESI) 192 (M+H)+.
Reaction SMILES: C([NH:19]CC(O)CN1CCN(CC(O)CNCCCCCCCCC=CCCCCCCCC)CC1)CCCCCCCC=CCCCCCCCC.BrCCC[N:57]1[C:61](=[O:62])[C:60]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:59]2[C:58]1=[O:67].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)(Cl)Cl>[C:58]([NH2:19])(=[O:67])[C:59]1[C:60](=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:61]([NH2:57])=[O:62]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCCCCCCCC=CCCCCCCCCNCC(O)CN1CCN(CC(O)CNCCCCCCCCC=CCCCCCCCC)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccccc1C(N)=O
Temperature: 100 °C

Procedure:
Compound 3 (2.5 g) was treated with N-(3-bromopropyl)phthalimide (2.19 g) and diisopropylethylamine (2 ml) in DMF (10 ml). The reaction mixture was heated at 100° C. for 3 hours and then diluted with chloroform (300 ml) and extracted with water (4×300 ml). The chloroform was removed on a rotary evaporator and the residue subjected to flash chromatography using chloroform and methanol/chloroform as eluants to obtain the desired phthlamide adduct (Compound 4). Hydrazine hydrate (0.75 ml) was added to a solution of the phthalimide compound 4 (1.7 g) in 100% reagent alcohol (100 ml). The reaction mix was refluxed overnight and cooled to room temperature for about 1 hr. The reaction mix was then cooled at 4° C. overnight and the precipitate obtained by filtration. The solid was washed with ethanol chilled to −20° C. (2×20 ml) and dried in vacuo. The residue was dissolved in chloroform (300 ml), filtered and extracted twice with water (200 ml). The chloroform was removed on a rotary evaporator to give 1,4-Bis[(3-(3-aminopropyl)-oleoylamino)-2-hydroxypropyl]piperazine (Compound 5) in a quantitative yield. This material was acidified with HCL in dioxane and purified on reverse phase (C-18) flash chromatography using aqueous methanol as eluant and characterized by TLC and mass spectrometry.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:23].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CBr
Reactant: Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Temperature: 25 °C
Reaction time: 19 h
Yield: 94.8 %

Procedure:
A mixture of 1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthol (356 mg, 0.931 mmol), prepared in step 1 of Example 3, methyl bromoacetate (106 μL, 1.12 mmol) and cesium carbonate (457 mg, 1.40 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 19 h. The reaction was concentrated under reduced pressure to remove the acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted multiple times with methylene chloride. The combined organic extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give methyl {[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetate (401 mg, 95%) as an off-white solid, mp 156-159° C. Elemental Analysis for C22H16BrNO3S Calc'd: C, 58.16; H, 3.55; N, 3.08. Found: C, 57.87; H, 3.43; N, 2.94.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([N:9]=[C:10]=[O:11])=[O:8])=[O:5])[CH3:2].[C:12]([CH:14]1[CH2:16][NH:15]1)#[N:13]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][C:7]([NH:9][C:10]([N:15]1[CH2:16][CH:14]1[C:12]#[N:13])=[O:11])=[O:8])=[O:5])[CH3:2]
Reactant: N#CC1CN1
Reactant: CCOC(=O)CC(=O)N=C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)NC(=O)N1CC1C#N
Reaction time: 0.08 h

Procedure:
4 g. Ethoxycarbonylacetyl isocyanate are dissolved in 40 ml. toluene and mixed, while stirring, at 20°-30° C. with a solution of 1.73 g. 2-cyanoaziridine in 20 ml. toluene. After about 5 minutes, an oily deposit separates out which, after trituration, gradually solidifies. The suspension thus obtained is further stirred for 1 hour at ambient temperature, then filtered off with suction and washed with toluene and the solid product triturated with anhydrous diethyl ether. There are thus obtained 3.7 g. 1-(N-ethoxycarbonylacetyl-carbamoyl)-2-cyanoaziridine; m.p. 121°-123° C. The product is practically insoluble in water but is soluble in dilute aqueous sodium hydroxide solution.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:22]=O)[C:8]([OH:21])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([OH:21])=[C:7]([CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2cccc(C(F)(F)F)c2)c1O

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 27, Step 2 5-(tert-butyl)-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine. HPLC/MS Rt=6.64 min, m/z 380.2 (M+H+).
Reaction SMILES: OO[S:3]([O-:5])=O.[K+].S1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([C:18]2[N:27]=[C:26]([NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:39])[CH:24]=3)[N:19]=2)[CH2:9][CH2:8]1>O.CO>[O:5]=[S:3]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][N:10]([C:18]2[N:27]=[C:26]([NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:39])[CH:24]=3)[N:19]=2)[CH2:9][CH2:8]1
Reactant: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Reaction time: 0.33 h
Yield: 128.7 %

Procedure:
To a solution of oxone (120 mg, 0.200 mmol) in water (0.7 mL) which was cooled below 0° C. in an ice bath, was added a solution of tert-butyl {2-[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-yl]aminoethyl}carbamate (155 mg, 0.333 mmol) in methanol (3 mL) dropwise. The mixture was stirred below 0° C. about 20 minutes. The formed precipitate was collected by filtration, washed with water and purified by flash column chromatography to afford 124 mg of the product as a white solid (yield was 77%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([OH:29])=[O:28]>COCCOC.CCO.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>[C:1]([O:5][C:6]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][C:27]([OH:29])=[O:28])[CH:36]=1)[CH3:9])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Reactant: O=C(O)Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: COCCOC
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(CC(=O)O)c1
Temperature: 160 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1951 μmol) in a mixture of DME/EtOH/2N Na2CO3: 1/1/1 (10 ml) were added 3-carboxymethylphenylboronic acid (1.5 eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 160° C. for 15 minutes. The reaction mixture was cooled to RT, filtered over celite and washed with EtOAc and MeOH. The solvents were removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:17]3=[N:18][CH:19]=2)[CH:9]=1)[C:5]([OH:7])=O)[CH3:3].[CH3:39][NH:40][CH3:41].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:3][N:2]([CH3:1])[CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:17]3=[N:18][CH:19]=2)[CH:9]=1)[C:5]([N:40]([CH3:41])[CH3:39])=[O:7]
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)O)N(C)C)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)N(C)C)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of dimethylamino-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (56 mg, 0.11 mmol), dimethylamine (2 N in THF, 0.08 mL, 0.16 mmol), and diisopropylethylamine (21 mg, 0.16 mmol) in THF (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 560 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].C1O[CH:7]([C:8]2[C:9](I)=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)OC1.C(N(CC)CC)C.Cl>CO>[NH:2]1[C:9]2=[N:10][C:11]3[C:16]([CH:17]=[C:8]2[CH:7]=[N:3]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: Ic1nc2ccccc2cc1C1OCCO1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: c1ccc2nc3[nH]ncc3cc2c1
Reaction time: 1 h

Procedure:
Hydrazine hydrate (10 g, 0.20 mol) is added dropwise to a suspension of 2-iodoquinoline-3-carboxaldehyde ethylene ketal (65.5 g, 0.20 mol), (O. Mech-Cohn, J. Chem. Soc., Perkin I, 2509 (1981), m.p. 104.5°-106.5° C. in methanol (250 mL) containing triethylamine 28 mL) at reflux. After refluxing overnight additional hdyrazine hydrate (10 g) is added and the mixture is stirred at reflux for another six and one-half hours. Concentrated hydrochloric acid (75 mL) is then added dropwise, while the mixture is refluxing and the reaction continued for one hour. The reaction mixture is cooled, poured onto ice and allowed to stand for two days. A red solid is removed by filtration and the filtrate is concentrated by rotary evaporation to remove methanol. The remaining solution is adjusted to pH 9 with concentrated ammonium hydroxide and the cream colored precipitate is filtered, washed with water and air dried. Recrystallization from ethanol gives an analytical sample, melting point 207°-208° C., calcd. for C10H7N3 :C, 70.99; H, 4.17; N, 24.84. Found: C, 70.82: H. 4.06; N, 24.18.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9]CC)=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>[OH-].[Na+]>[Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1

Procedure:
Ethyl 5-bromo-4-(p-chlorophenyl)pyrrole-3-carboxylate (15 g., 0.045 mmol) is added to 200 mL of 10% sodium hydroxide and the slurry heated to reflux. After everything appears to dissolve the mixture is refluxed an additional 40 minutes. The mixture is cooled, filtered and the filtrate acidified. The white precipitate (8.0 g,, 58%) is collected and dried. The solid has m.p. >205° C. and an NMR (d6 -DMSO) which showed a pyrrole proton at 7.52 (d). The mass spectrum is also consistent for a monobrominated compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OCC)(=O)C>ClCCl>[CH:8]([C:4]1[CH:3]=[C:2]([NH:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH:7]=[CH:6][CH:5]=1)=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C=O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.3 g (10.73 mmol) of 3-aminobenzenecarbaldehyde were initially charged in 30 ml of dichloromethane. 849 mg (10.73 mmol) of pyridine and 1.3 g (10.73 mmol) of methanesulfonyl chloride were added, and the mixture was then stirred at RT overnight. Ethyl acetate was added, and the reaction solution was washed in each case once with 1 N hydrochloric acid, water and saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel 60 (mobile phase: dichloromethane/methanol 100/0→50/1).
Reaction SMILES: [P:1]([O:8]CC)([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH3:11][O:12][C:13](=[O:37])[CH:14]([NH:34][CH:35]=[O:36])[CH:15]=[C:16]([CH2:32]Br)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH3:11][O:12][C:13](=[O:37])[CH:14]([NH:34][CH:35]=[O:36])[CH:15]=[C:16]([CH2:32][P:1]([O:2][CH2:3][CH3:4])([O:5][CH2:6][CH3:7])=[O:8])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: COC(=O)C(C=C(CBr)CCCCNC(=O)OCc1ccccc1)NC=O
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC(=CC(NC=O)C(=O)OC)CCCCNC(=O)OCc1ccccc1)OCC

Procedure:
5 ml of triethyl phosphite are added to 1.45 g (3.3 mmol) of 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester, and the mixture is heated at 75° for 8 hours with stirring. The excess triethyl phosphite is distilled off under reduced pressure to give an oily residue which is purified by chromatography on a silica gel column with first ethyl acetate and then ethyl acetate/methanol (9:1). 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.