Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH:21]([C:24]1([OH:28])[CH2:27][NH:26][CH2:25]1)([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:26]3[CH2:27][C:24]([CH:21]([CH3:23])[CH3:22])([OH:28])[CH2:25]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CC(C)C1(O)CNC1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C1(O)CN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (69 mg, 0.23 mmol) in DCE (5 mL) was added 3-isopropyl-azetidin-3-ol (27 mg, 0.23 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (99 mg, 0.47 mmol) was added and the resulting mixture stirred for a further 2 days. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) to give the title compound as a pale yellow oil (30 mg, 33%). LCMS (Method H): RT=2.65 min, [M+H]+ 395.5
Reaction SMILES: [C:1](#[N:3])[CH3:2].CC([O-])(CC)C.[K+].[CH3:11][C:12]1([C:18](OC)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.Cl>C1COCC1>[CH3:11][C:12]1([C:18]2[CH:2]=[C:1]([NH2:3])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:31])=[CH:24][CH:25]=3)[N:30]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(NN)cc1
Reactant: COC(=O)C1(C)CCCCC1
Reactant: CC#N
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C3(C)CCCCC3)cc2N)cc1
Temperature: 25 °C

Procedure:
To a mixture of acetonitrile (500 μL, 10.0 mmol) in THF (30 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in THF (1.7 M, 16.9 mL, 28.7 mmol), followed by methyl 1-methylcyclohexanecarboxylate (2.24 g, 14.4 mmol) and the reaction mixture maintained at RT for 17 hr and then concentrated to ˜20 mL in vacuo. The residue was diluted with EtOH (20 mL), treated with p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) and the resulting mixture acidified to pH1 by the addition of conc hydrochloric acid and then heated to 70° C. for 5 hr. The mixture was cooled to RT for 16 hr and concentrated to ˜20 mL in vacuo, diluted with water (30 mL) and was then basified to pH 12 by the addition of 2M aq NaOH. The resulting solution was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-20%, gradient elution) to afford the title compound, Intermediate A33, as a yellow oil, (˜50% purity, containing 3-(1-methylcyclohexyl)-3-oxopropanenitrile) (1.30 g, 25%); Rt 1.97 min (Method 2); m/z 270 (M+H)+ (ES+). The material was used in subsequent reactions without further purification.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:22])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][C:20]1[C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:35])([CH3:24])([CH3:25])[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccccc1Nc1ncccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1Nc1ncccc1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.05 mL, 7.53 mmol) was added to a mixture of N2-o-tolylpyridine-2,3-diamine (500 mg, 2.51 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (520 mg, 2.76 mmol), HOAt (380 mg, 2.76 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (530 mg, 2.76 mmol) in anhydrous DCM (20 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min and then slowly warmed to RT. Stirring at RT was continued for 16 h. The resulting mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method J): RT 2.19 min [M+H]+ 371.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:16])[C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CC(C)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 1-benzyl-3-methyl-4-piperidone (2.0 g, 9.8 mmol) in THF at about −78° C. under argon, was added Lithium diisopropylamide (7.35 mL, 14.7 mmol, 2 M in heptane/THF/ethylbenzene). After stirring for about 1 hour at about −78° C., iodomethane (0.73 mL, 11.8 mmol) was added. The reaction mixture was stirred for about 1 hour at about −78° C., then warmed to room temperature. Stirring was continued overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel, eluting with EtOAc/hexane (3:10) to give a yellow oil of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22](/[N:23]=[CH:1]/[C:3]2[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(/C=N/c2ccc(F)cc2)cc1

Procedure:
tert-Butyl (4-formylphenoxy)acetate (93.7 g, 0.40 mol) was dissolved in dry toluene (200 mL), added 4-fluoroaniline (38.1 mL, 0.40 mol) and p-toluene sulfonic acid (cat, ˜1 g). The mixture was refluxed in a Dean-Stark apparatus for 2 hours, cooled at an icebath and a precipitate was formed. The precipitate was filtered, washed with cold heptane and dried to afford the title compound.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11](Br)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(B(O)O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1cc(Br)cc(C=C(c2ccccc2)c2ccccc2)c1
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: Cc1ccccc1
Product: Brc1cc(C=C(c2ccccc2)c2ccccc2)cc(-c2cccc3ccccc23)c1
Yield: 59.6 %

Procedure:
Under an atmosphere of argon, 1-(2,2-diphenylvinyl)-3,5-dibromo-benzene (8.3 g, 20 mmole), 1-naphthaleneboronic acid (3.4 g, 20 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.4 mmole, 2% Pd) were dissolved into toluene (50 ml). To the obtained solution, a 2 M aqueous solution of sodium carbonate (30 ml, 60 mmole, 3 eq) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloro-methane and hexane+10% dichloromethane, successively) and a white glass solid (5.5 g, 60%) was obtained.
Reaction SMILES: C(O)(=O)C.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].[Br:16]N1C(=O)CCC1=O>O>[Br:16][C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH3:5])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Yield: 93.1 %

Procedure:
Pouring 60 milliliter of acetic acid over 5.0 g (33 mmol) of N-methyl-2-nitroaniline and 5.9 g (33 mmol) of N-bromosuccinimide, the resultant solution was refluxed with heating for 7 hours. After completion of the reaction, the reacted solution was poured into 500 milliliter of water, and precipitated solids were separated with filtration. Dissolving the resultant solids into ethyl acetate, the resultant solution was dried with the use of magnesium sulfate. After filtration, the solvent was removed by distillation under reduced pressure, and after drying the solids under reduced pressure at room temperature, 7.1 g of 4-bromo-N-methyl-2-nitroaniline as orange solids were obtained (yield: 93%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li][CH2:7][CH2:8][CH2:9]C.C(OCC)(=[O:14])CC>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:7][C:8](=[O:14])[CH3:9]
Reactant: c1cscn1
Reactant: CCOC(=O)CC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1nccs1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of thiazole (10 g, 0.12 mol) in dry THF (100 mL) at -78° C. was added BuLi (50 mL, 2.47M in hexane). The resulting reaction mixture was stirred 30 min. then ethyl propionate (18.8 mL, 0.16 mol) in THF was added and the cooling bath was removed. After 30 min. an aqueous solution of NH4OAc (25%) was added and the THF evaporated. Ether was added and washed successively with H2O, brine, dried over MgSO4 and evaporated. The residue was distilled under vacuum to give 12.1 g (73%) of the title compound.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:6]=1[C:7]([OH:9])=[O:8]>C(Cl)(Cl)Cl.O1CCOCC1>[Br:1][C:13]1[C:5]([O:4][CH3:3])=[C:6]([C:10]([O:14][CH3:15])=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)c(OC)c1C(=O)O
Reaction time: 8 h

Procedure:
A solution of 15 ml of bromine (0.3 mol) in 50 ml of chloroform is added dropwise while stirring and cooling in ice to 54.9 g (0.3 mol) of 2,6-dimethoxybenzoic acid in 150 ml of dioxan. The solution is left at room temperature overnight. The solvent is evaporated and the residue recrystallized from aqueous ethanol. Yield: 59.3 g, m.p. 144°-45° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]2[N:5]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)=O.C(Cl)Cl>[ClH:1].[CH3:12][C:10]1[N:11]=[C:4]2[C:3]([CH2:2][NH:17][C:16]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:15]=3[CH3:14])=[CH:8][CH:7]=[CH:6][N:5]2[C:9]=1[CH3:13]
Reactant: Cc1cccc(C)c1N
Reactant: Cc1nc2c(CCl)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cccc(C)c1NCc1cccn2c(C)c(C)nc12
Product: Cl

Procedure:
8-chloromethyl-2,3-dimethylimidazo[1,2-a]pyridine (0.06 g, 0.31 mmol), 2,6-dimethylaniline (0.039 g, 0.32 mmol), sodium carbonate (0.15 g, 1.4 mmol) and sodium iodide (0.06 g, 0.4 mmol) in acetone (3 ml) was stirred for 20 h. at room temperature. Methylene chloride was added and the solids were isolated by filtration and the solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (2:1). The oily product was solved in methylene chloride and treated with HCl/diethyl ether to give the title compound, 0.02 g. (18%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-4′-cyano-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G40) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light red solid (185 mg).
Reaction SMILES: O.O.Cl[Sn]Cl.[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([N+:28]([O-])=O)[CH:21]=2)=[CH:18][CH3:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH3:7].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([NH2:28])[CH:21]=2)=[CH:18][CH3:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH3:7]
Reactant: CC=C(c1ccc(OC)c(OCC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC=C(c1ccc(OC)c(N)c1)c1ccc(OC)c(OCC)c1
Temperature: 70 °C
Yield: 72.8 %

Procedure:
SnCl2.2H2O (3.98 g, 17.6 mmol) was added to a stirred suspension of (E/Z) 4-[1-(3-ethoxy-4-methoxy-phenyl)-propenyl]-1-methoxy-2-nitro-benzene (1.10 g, 3.2 mmol) in ethanol (200 proof, 20 mL) and ethyl acetate (10 mL). The reaction mixture was heated at 70° C. for 1 h. The solution was cooled down to room temperature, poured into ice water (100 mL), and basified with 10 N NaOH (20 mL) to pH ˜12. The aqueous layer was extracted with ethyl acetate (5×35 mL). The combined organic layers were washed with water (60 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 5-[1-(3-ethoxy-4-methoxy-phenyl) -propenyl]-2-methoxy-phenylamine as a solid (0.73 g, 73% yield): mp, 108-110° C.; 1H NMR (CDCl3) δ 1.39-1.46 (m, 6H, 2CH3), 1.72-1.77 (m, 6H, 2CH3), 3.71-3.75 (bp, 4H, 2NH2), 3.83-3.90 (m, 12H, 4OCH3), 3.99-4.09 (m, 4H, 2CH2), 5.97-6.05 (m, 2H, 2CH), 6.54-6.61 (m, 12H, Ar); 13C NMR (CDCl3) δ 14.79, 15.67, 15.72, 55.45, 55.52, 55.90, 55.95, 64.21, 64.26, 109.90, 109.95, 110.97, 111.01, 112.13, 114.11, 114.80, 116.83, 117.51, 119.89, 120.35, 121.81, 121.98, 122.44, 132.86, 132.93, 135.52, 135.57, 136.28, 136.49, 141.93, 142.02, 146.25, 146.53, 147.75, 148.02, 148.34; Anal. Calcd for C19H23NO3: C, 73.82; H, 7.40; N, 4.47. Found: C, 72.57; H, 7.47; N, 4.40.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:9]2)=[O:23])=[CH:20][CH:19]=1
Reactant: CN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN1CCC(c2cn(C(=O)c3ccc(F)cc3)c3ccccc23)CC1

Procedure:
(27.2 mg, 81%); from 3-(1-methyl-4-piperidinyl)-1H-indole (Example 5d, 21.5 mg, 0.10 mmol) and 4-fluorobenzoyl chloride (23.8 mg, 0.15 mmol), HRMS-FAB+ for C21H21N2OF, calculated MH+ : 337.17163; found: 337.17162.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH:43]1([NH:46][CH3:47])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:46]([CH:43]1[CH2:45][CH2:44]1)[CH3:47])=[O:25]
Reactant: CNC1CC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)C1CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and cyclopropyl-methylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction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
Reactant: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O[C@H](COC(=O)CCCCCCCCCCCCCCC)COP(=O)([O-])OCC[N+](C)(C)C
Agent: N[C@H](C(=O)O)[C@H](O)c1ccc(O)c(O)c1
Agent: O=P([O-])([O-])[O-]
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Yield: 10 %

Procedure:
A sonicated POPC/DOPS dispersion in phosphate buffer plus 10% sucrose (mole ratio 7:3) is prepared as described previously. 3H --labeled raffinose is entrapped in the vesicle cavity and external [3H,]- raffinose is removed by gel filtration on Sephadex G-50 as described previously. The lipid dispersion consisting of SUV with entrapped raffinose was chromatographed on Sepharose 4B before and after spray-drying. Before spray-drying it was found that 95% of the raffinose eluted together with the vesicle peak. After spray-drying 85% of the raffinose was eluted together with SUV. This experiment thus demonstrates that raffinose remains essentially entrapped during spray-drying at least to 90%.
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4](=[O:37])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][NH:33]5)=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.CCN(C(C)C)C(C)C.[CH3:53][CH:54]([CH3:66])[C@H:55]([NH:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)[C:56](O)=[O:57].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[C:56](=[O:57])[C@H:55]([CH:54]([CH3:53])[CH3:66])[NH:59][C:60]5[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=5)=[N:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:37]
Reactant: CC(C)[C@H](Nc1cccnc1)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](Nc5cccnc5)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-13) (0.060 g, 0.103 mmol) in DMF (2 mL) was added iPr2NEt (0.18 mL, 1.02 mmol), (S)-3-methyl-2-(pyridin-3-ylamino)butanoic acid (Cap-88) (0.040 g, 0.206 mmol) and HATU (0.078 g, 0.205 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then it was directly purified by prep HPLC (Luna 5 u C18/MeCN—H2O—NH4OAc). The resulting solid was repurified by flash chromatography (SiO2/0-10% MeOH—CH2Cl2) and the obtained product was lyophilized from CH3CN—H2O to give the title compound (0.044 g, 56%) as a solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:30])=[C:8]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+].CO>>[C:15]([C:14]1[C:8]2[C:9](=[CH:10][N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:5])[C:7]=2[OH:30])[N:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)#[N:16]
Reactant: CCOC(=O)c1ncc2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(-c2ccc(F)cc2)n(-c2ccccc2)c2cnc(C(=O)NCC(=O)O)c(O)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 431 (M+H)+.
Reaction SMILES: [N:1]1([S:7]Cl)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:16][C:17]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:21]=[CH:20][C:18]=1[NH2:19]>C(OCC)C>[Cl:35][C:26]1[CH:27]=[C:28]([C:31]([F:32])([F:34])[F:33])[CH:29]=[CH:30][C:25]=1[O:24][C:22]1[CH:21]=[CH:20][C:18]([NH:19][S:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:17]([F:16])[CH:23]=1
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: ClSN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1NSN1CCOCC1
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
The compound prepared in Example 5 (3.4 g) was dissolved in diethyl ether (10 ml). The solutionwas added to a solution of triethylamine (2.2 g) and the compound prepared in Example 1 (6.1 g) in diethyl ether (50 ml) at 15°-20° C. The solution was stirred for 20 minutes, diethyl ether was added (20 ml), the solution was washed with water, and dried. The solvent was removed by evaporation. Column chromatogrpahy on silica using 50:50 (v/v) diethyl ether-dichloromethane as eluant yielded the title compound as a brown oil (5 g).