Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH2:18][CH2:19][C@@H:20]1[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21]1=[O:27]>CCOCC.O1CCCC1>[CH2:19]([C@@H:20]1[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21]1=[O:27])[CH2:18][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: CC1(C)OC(=O)[C@H](CCO)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC[C@@H]1OC(C)(C)OC1=O
Temperature: -10 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a flame-dried 500 mL three-necked round bottom flask under nitrogen containing a suspension of 4.85 g (25.48 mmol) of cuprous iodide in 200 mL of anhydrous ether and held at -30° C. was added dropwise 31.85 mL of 1.6M n-BuLi (50.96 mmol) in hexanes. The dark red-brown solution was stirred at -30° C. to -40° C. for 2 hours and cooled to -78° C. (S)-5-(2-hydroxyethyl)-2,2-dimethyl-l,3-dioxolan-4-one p-toluenesulfonate (4.0 g, 12.74 mmol), dissolved in 30 mL of anhydrous ether and 10 mL of anhydrous tetrahydrofuran, was added dropwise while maintaining the temperature below -70° C. The reaction mixture was stirred for 18 hours at -78° C. Following completion (TLC monitoring), the reaction was warmed to -10° C. and quenched by the addition of 125 mL of precooled saturated ammonium chloride solution. Ether (100 mL) was added and the mixture filtered over Celite. The aqueous phase was extracted with 3×175 mL ether. The combined ether extract was washed with 2×125 mL of saturated ammonium chloride solution, 1×75 mL of water and 2×100 mL of brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified (silica gel) using ethyl acetate:hexanes (1:5) as eluant to give 2.44 g (95%) of the title compound as a colorless oil: [α]D25 0.6°(c=1.9, CH3OH); IR (Kbr, cm-1) 2958, 2933, 2861, 1797; 1H NMR (CDCl3) δ 4.39 (dd, J=4.4, 7.1 Hz, 1H), 1.95-1.81 (m, 1H), 1.81-1.62 (m, 1H), 1.61 (s, 3H), 1.54 (s, 3H), 1.49-1.38 (m, 2H), 1.35-1.29 (m, 6H), 0.89 (t, J=6.6 13C NMR (CDCl3) δ 173.3, 110.2, 74.2, 31.7, 31.6, 28.8, 25.8, 24.8, 22.5, 13.9; HRMS calculated for C11H20O3 (M+), 200.1412, found 200.1422.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:19](O)=[O:20])=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O.C1C=CC=CC=1>CN(C)C=O>[C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:19]([Cl:25])=[O:20])=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2c(=O)c(C(=O)O)coc2c1OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc2c(=O)c(C(=O)Cl)coc2c1OC(C)=O

Procedure:
A mixture of 7,8-diacetoxychromone-3-carboxylic acid (9.5 g, 31 mmol), thionyl chloride (2.6 ml), dimethylformamide (0.1 ml) and benzene (300 ml) was refluxed for 1.5 hours. After the addition of thionyl chloride (2.6 ml) was dimethylformamide (0.1 ml), the mixture was refluxed for a further one hour and evaporated to dryness. The residue was triturated with n-hexane to give the desired compound (9.3 g).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]=[S:15]>CC(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]([NH:13][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[S:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)N=C=S
Solvent: CC(C)=O
Product: CCOC(=O)NC(=S)N1CCN(c2ccccc2)CC1
Yield: 71.5 %

Procedure:
1-Phenylpiperazine (10 g, 62 mmol) was added to a solution of ethyl isothiocyanatoformate (8.1 g, 62 mmol) in acetone (30 mL) and the mixture was refluxed under heating for 1 h. The reaction mixture was concentrated and the crude crystals were recrystallized from ethyl acetate to give the title compound (13 g, yield 73%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:16]1([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:23]1([N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([N:22]([C:23]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH:26]=[CH:25][CH:24]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:9][CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccc3c(c2)Cc2cc(N(c4ccccc4)c4cccc5ccccc45)ccc2-3)c2cccc3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a 2-liter three-neck round bottom flask was added anhydrous toluene (1000 mL) by cannula. 2,7-dibromofluorene (50.0 g) was added to this flask, then stirred until all dissolved. N-phenyl-1-naphthylamine (81.14 g) was then added. The reaction vessel was purged with a strong nitrogen flow for 30 minutes, followed by the addition of sodium tert-butoxide (44.5 g) by funnel. Tris(dibenzylideneacetone)dipalladium(0) (5.65 g) was added to the reaction. Tri-tert-butyl phosphine (3.75 g) in anhydrous toluene (20 mL) was added via syringe. The reaction was heated to reflux for 2 hours and reaction completion was confirmed by thin-layer chromatography. The vessel was removed from heat and allowed to cool to room temperature. The reaction solution was filtered through a celite/silica gel plug and solvent was then removed by rotary evaporation. The crude material was initially purified by flash chromatography, followed by sublimation to yield NMR pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[NH:11][N:10]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[NH:11][N:10]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3c(Cl)cccc3Cl)n[nH]2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)n[nH]2)c1
Temperature: 75 °C
Yield: 52 %

Procedure:
The 3-(2,6-dichlorophenyl)-5-(3-nitrophenyl) pyrazole prepared in Step 2 (57 mg) was dissolved in 50% aqueous ethanol and treated with iron powder (57 mg, 6 molar equivalents), and ammonium chloride (18.2 mg, 2 molar equivalents). The mixture was heated at 70-80° C. for 4 h. The reaction mixture was cooled to room temperature then filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-(2,6-dichlorophenyl)-5-(3-aminophenyl)pyrazole as a white solid (27 mg). NMR (300 MHz, CDCl3): 7.40 (d, 2H), 7.25 (t, 1H), 7.20 (m, 1H), 7.11 (m, 2H), 6.68 ppm (m, 2H). LC-MS tr=5.66 min (Method Z) MH+=303-307
Reaction SMILES: [Na:1].[NH2:2][C:3]1[C:4]([F:13])=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[CH2:8][C:9]#[N:10].C([O:19][N:20]=O)CC(C)C>C(O)C>[Na:1].[NH2:2][C:3]1[C:4]([F:13])=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8](=[N:20][OH:19])[C:9]#[N:10]
Reactant: N#CCc1cc(N)c(F)cc1Cl
Reactant: CC(C)CCON=O
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1cc(N)c(F)cc1Cl

Procedure:
0.3 g of sodium in 20 ml of absolute ethanol is introduced, with stirring, into a three-necked flask. There are then added slowly dropwise at room temperature, with stirring, firstly 1.8 g of 5-amino-2-chloro-4-fluorobenzyl cyanide and subsequently 1.5 ml of isopentylnitrite. The reaction solution is stirred at room temperature for a further 15 hours, and afterwards concentrated by evaporation. The residue is is taken up in glacial acetic acid, stirred up and filtered to thus obtain 2.2 g of the sodium salt of 5-amino-2-chloro-4-fluorobenzoyl cyanide which melts at 263°-264° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH:12]=O)[C:5]2=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH:12]=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]2=[O:14]
Reactant: O=Cc1coc2ccc(Br)cc2c1=O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=c1c(C=Nc2ccccc2)coc2ccc(Br)cc12
Yield: 98.1 %

Procedure:
A suspension of 6-bromo-3-formylchromone (150 mg; 0.59 mmol) in toluene (10 ml) was heated at 50°-55° C. until the solute had completely dissolved. Aniline (55 μl; 0.59 mmol) was added and the temperature was maintained for 15 minutes. On cooling, a yellow precipitate formed which was filtered off and dried under reduced pressure to give 6-bromo-3-(phenyliminomethyl)chromone (190 mg; 98%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]2[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1.[CH3:31][CH2:32][O-:33].[Na+]>C(O)C>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]3[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=3[N:3]=[C:2]2[O:33][CH2:32][CH3:31])=[CH:9][CH:10]=1)#[N:21]
Reactant: CCOC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 36.2 %

Procedure:
To a solution of ethyl 2-chloro-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (1.0 g) in ethanol (30 ml) was added NaOEt (0.17 g) and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated to dryness. The resultant residue was dissolved in ethyl acetate and the solution was washed with water, and then dried. After evaporation of the solvent, the residue was purified by column chromatography on silica gel to give the title compound as colorless crystals (0.37 g, 70%). 1H-NMR and IR spectra indicate that the product according to this working Example is completely identical with that obtained in Working Example 4.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1>CS(C)=O.C(OCC)(=O)C>[NH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:29]2[CH2:30][CH2:31][N:26]([CH2:12][CH:13]3[O:25][C:17]4=[C:18]5[C:22](=[CH:23][CH:24]=[C:16]4[O:15][CH2:14]3)[NH:21][CH:20]=[CH:19]5)[CH2:27][CH:28]=2)=[CH:33]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]ccc4c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4[nH]ccc4c3O2)C1

Procedure:
A solution of 0.65 g (1.8 mmole) of (2R)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl 4-methylbenzenesulfonate and 0.71 g (3.6 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl )-1H-indole in 30 mL of DMSO was heated at 65° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2-4% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with methylene chloride/hexane (1:1) to give 0.39 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 126° C., which retains one equivalent of DMSO.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]1[N:22]2CN3CN(C2)C[N:18]1C3.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N:18]1[C:13]2[C:14]3[C:5]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]=2[NH:22][CH:17]=1)=[CH:4][CH:3]=[CH:2][CH:1]=3
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: c1ccc2c(c1)c1ccccc1c1[nH]cnc21

Procedure:
Phenanthrene-9,10-quinone or an appropriately substituted analog is reacted with hexamethylenetetramine (hexamine) and ammonium acetate in glacial acetic acid to produce the corresponding phenanthro[9,10-d]imidazole. The reaction is carried out with refluxing of the acetic acid. ##STR8## [Edgar A. Stock and A. R. Day, J. Am. Chem. Soc., 65, 452 (1943)].
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH3:9][N:10]1C(=O)O[C:13](=[O:14])[C:12]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:11]12.CS(C)=O>O>[CH3:9][N:10]1[C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13](=[O:14])[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 12.3 g. of L-proline, 17.7 g. of N-methyl isatoic anhydride and 100 ml. of dimethyl sulfoxide is heated on a steam bath for 6 hours, cooled and then diluted with 250 ml. of water. The reaction mixture is extracted three times with benzene. The combined benzene layers are washed twice with water and concentrated to remove the solvent. The residue is recrystallized from ethyl acetate yielding the pure dextrorotatory isomer.
Reaction SMILES: [OH-:1].[Na+].N[CH2:4][C:5]([OH:7])=O>>[O:1]=[CH:4][C@@H:5]([C@H:4]([C@@H:5]([C@@H:4]([CH2:5][OH:7])[OH:1])[OH:7])[OH:1])[OH:7]
Reactant: [OH-]
Reactant: NCC(=O)O
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 28 °C
Reaction time: 24 h

Procedure:
The BIBB 10 medium was adjusted to pH 7.0 with 10% sodium hydroxide solution before sterilization. The culture medium was shaken on a rotary shaker at 260 rpm for 24 hours at 28° C., then 3 ml of same were inoculated into 100 ml of fresh BIBB 10 medium supplemented with 0.5% of glycine before inoculation. These cultures were cultivated for 18 hours under the above cultural environment, and after checking the cells were collected by centrifugation (3500 rpm, 10 min.). The mycelium derived from 100 ml of the culture broth was suspended in 4 ml of PH mixture (pH 7.0) containing the following components:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[N:4]1[C:15](=[O:16])[C:14]2[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=2[C:12]1=[O:17]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F
Yield: 77.5 %

Procedure:
2-Fluoro-5-nitroaniline (IV) (50 g) and 3,4,5,6-tetrahydrophthalic anhydride (49 g) were dissolved in acetic acid (200 ml), and the resultant solution was heated under reflux for 4 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 72 g of N-(2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide (VII). M.P., 154.9° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:23][CH2:24]2)=[O:18])[C:13]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[CH2:48][CH2:47][N:46]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Product: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3ccc(CC)c(CC)c3)NC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 34 from (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:12][CH2:13][C:14]([NH2:16])=[O:15])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Br)cc1NCC(N)=O
Temperature: 120 °C
Yield: 100.3 %

Procedure:
9.1 g (45.5 mmol) 4-bromo-2-fluorobenzonitrile, 10.0 g (91.0 mmol) glycinamide hydrochloride and 15.7 g (114 mmol) K2CO3 were suspended in 80 ml DMSO and heated at 120° C. for 5.5 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 11.6 g (100%) 2-(5-bromo-2-cyano-phenylamino)acetamide was obtained. ESI-MS [m/z]: 254, 256 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=2[CH3:17])[CH:5]=[CH:4][C:3]1=[O:18].[Br:19]Br>C(O)(=O)C>[Br:19][C:4]1[C:3](=[O:18])[N:2]([CH3:1])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=2[CH3:17])[CH:5]=1
Reactant: Cc1c(-c2ccc(=O)n(C)c2)cccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(-c2cc(Br)c(=O)n(C)c2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
A 10-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 1-methyl-5-(2-methyl-3-nitrophenyl)pyridin-2-one (10) (0.60 mg, 2.46 mmol) and glacial acetic acid (5 mL). To the resulting solution bromine (0.59 g, 3.70 mmol) was added. The reaction was stirred for 18 h at room temperature. After this time the reaction was partitioned between water (25 mL) and ethyl acetate (75 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL), brine (50 mL) and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated to a constant weight under reduced pressure to afford 0.075 g (93%) of 3-bromo-1-methyl-5-(2-methyl-3-nitrophenyl)pyridin-2-one (11) as a yellow oil: 1H NMR (300 MHz, CDCl3) 7.83 (dd, 1H, J=7.2, 2.1 Hz), 7.75 (d, 1H, J=2.4 Hz), 7.42 (dd, 1H, J=7.8, 2.4 Hz), 7.38 (t, 1H, J=7.5 Hz), 7.29 (d, 1H, J=2.4 Hz), 3.70 (s, 3H), 2.40 (s, 3H); MS (ESI+) m/z 323 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[S:27](N)([NH2:30])(=[O:29])=[O:28]>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: NS(N)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(N)(=O)=O)CC2)nc1N

Procedure:
[4-Amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (308 mg, 0.848 mmol, Example 107) in dioxane (3 mL) and sulfamide (814 mg, 8.48 mmol, Aldrich) refluxed overnight. The mixture was diluted with water and sodium bicarbonate and extracted with dichloromethane. The organic solution was washed with water, dried (MgSO4), filtered and evaporated. Chromatography on silica gel (methanol/triethylamine/ethyl acetate 5:2:95) gave, after crystallization from ethanol/ethyl ether, 255 mg of colorless solid, MP 217-218° C. MS(ES) MH+443
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12](I)[N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:10]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)CCC.CC(O)=O>CN(C=O)C.[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>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:10]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(I)n1-c1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2ccccn2)n1-c1ccc(OC)cc1
Temperature: 140 °C
Yield: 84.7 %

Procedure:
To a solution of ethyl 3,4-bis(benzyloxy)-5-iodo-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (28) (300 mg, 0.51 mmol) in DMF (5 mL) was added 2-(tributylstannyl)pyridine (280 μL, 0.87 mmol), copper(I) iodide (19.6 mg, 0.10 mmol) and dichlorobis(triphenylphosphine)palladium(II) (36.1 mg, 0.05 mmol). The mixture was heated in a microwave at 140° C. for 30 min, AcOH (2 mL) was added and the crude product was loaded onto a column of SCX (5 g). The column was washed with MeOH and then the product was eluted with 1% NH3 in MeOH. The resultant mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (12 g, 20-100% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(pyridin-2-yl)-1H-pyrrole-2-carboxylate (UL1-082) (231 mg, 83%) as a pale yellow oil: m/z 535 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1H NMR (400 MHz, DMSO-d6) δ: 8.47-8.40 (m, 1H), 7.71-7.63 (m, 1H), 7.54-7.47 (m, 2H), 7.45-7.16 (m, 10H), 7.12-7.03 (m, 2H), 6.83-6.76 (m, 2H), 5.18 (s, 2H), 4.96 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 1.03 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42][NH2:43])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42][NH:43][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(O)c1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-benzoic acid (Example 41 before reverse phase chromatography, 0.08 g, 0.185 mmol), (2-aminoethyl)-carbamic acid tert-butyl ester (0.036 g, 0.2 mmol), N—N-Diisopropylethylamine (0.08 mL, 0.46 mmol) and HBTU (0.076 g, 0.2 mmol) are mixed in 10 mL of DMF and stirred at RT for 8 h under nitrogen. The crude mixture is diluted with EtOAc (30 mL) and extracted with saturated NaHCO3. The organic phase is separated and washed with saturated brine, dried (Na2SO4), filtered, evaporated to a solid mass. The crude product is purified by MPLC on silica gel (80% EtOAc/Hexanes, 1% MeOH) to yield the title compound, 0.059 g (56%), as white solid.