Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.8 g, 2.5 mmol) in dimethylformamide (10 mL). Add sodium hydride (0.13 g, 60% in oil, 3.25 mmol) portionwise. After about 30 minutes, when the gas evolution ceases, add pentyl bromide (0.34 mL, 2.74 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture and dilute with dichloromethane (150 mL) and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-pentyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.87 (silica gel, 5% methanol/dichloromethane/0.05% concentrated aqueous ammonia). Combine 1-t-butoxycarbonyl-4-(1-pentyl-1H-benzimidazol-2-yl)[1,4]diazepane (0.7 g, 1.8 mmol) and ethanol (5 mL). Add aqueous hydriodic acid (5 mL, 57%). Heat to reflux. After 1 hour, cool to ambient temperature and dilute with diethyl ether (250 mL) and stir to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][S:7]([OH:10])(=O)=[O:8])=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:13]>>[CH2:1]([O:3][C:4]([CH2:6][S:7]([Cl:13])(=[O:10])=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CS(=O)(=O)Cl
Temperature: 125 °C
Yield: 80 %

Procedure:
A mixture of (ethoxycarbonyl)methanesulfonic acid (10 g, 60 mmol.) and POCl3 (45 mL) was heated at 125° C. for 5 h. The mixture was cooled and filtered, and excess POCl3 was removed to give crude (ethoxycarbonyl)methanesulfonyl chloride (8.1 g, 80%) used directly without purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]3[CH:19]=2)=[CH:2]1.[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(#N)C.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>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:26]4[CH:27]=[C:22]([CH2:21][OH:20])[CH:23]=[CH:24][CH:25]=4)=[CH:14][N:13]3[CH:19]=2)=[CH:2]1
Reactant: Brc1ccc2nc(-c3coc4ccccc34)cn2c1
Reactant: OCc1cccc(B(O)O)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
Solvent: CC#N
Product: OCc1cccc(-c2ccc3nc(-c4coc5ccccc45)cn3c2)c1
Yield: 40.5 %

Procedure:
100 mg of 2-(benzofuran-3-yl)-6-bromoimidazo[1,2-a]pyridine, 73 mg of 3-(hydroxymethyl)phenylboronic acid and 11 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube. 2 ml of acetonitrile, 2 ml of toluene and 1.5 ml of a 2M solution of sodium carbonate are added thereto. The tube is placed in a microwave device and irradiated at 150° C. for 15 min. The organic phase is separated, dried, and then concentrated under reduced pressure. The oily residue is taken up with 3 ml of dichloromethane and triturated for 1 hour. The precipitate is recovered by filtration, washed with diisopropyl ether and dried in a desiccator under reduced pressure. 44 mg of compound are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CN(C)C=O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:2][C:3]([NH:5][C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])=[O:4])=[CH:18][CH:17]=1
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(Cl)cc1)Nc1ccccc1C(=O)O
Temperature: 0 °C
Yield: 144.4 %

Procedure:
N(chloroacetyl)anthranilic acid 3.2 g (0.02 mol) and p-chloroaniline 3.95 g (0.005 mol) were dissolved in 4 ml of dimethylformamide and heated at 80° to 90° C. for 4 hours. The reaction solution was poured into ice water and deposited crystals were collected by filtration. These crystals were washed with ether and recrystallized from ethanol to obtain N-[(4-chlorophenylamino)acetyl]anthranilic acid 2.2 g (yield: 72.2%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCn1cc(Br)cn1
Reactant: Fc1c(Cl)ccc2cc[nH]c12
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCn1cc(-n2ccc3ccc(Cl)c(F)c32)cn1
Temperature: 140 °C
Yield: 36 %

Procedure:
To a stirred solution of 6-chloro-7-fluoro-1H-indole 8 (400 mg, 2.36 mmol) in toluene (10 mL) were added 4-bromo-1-ethyl-1H-pyrazole 4 (Step 3 above; 414 mg, 2.36 mmol), potassium phosphate (1.25 g, 5.91 mmol), N,N′-dimethylethylenediamine (84 mg, 0.95 mmol) and Cu(I)I (45 mg, 0.24 mmol) at RT under inert atmosphere. The resulted solution was purged with argon and sealed the tube. The reaction mixture was then heated to 140° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT, diluted with hexane (10 mL) and filtered through a short pad of celite. The filtrate was washed with water (2×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 8-10% EtOAc/Hexanes) to afford compound 9 (224 mg, 36%) as a light brown thick liquid. 1H NMR (500 MHz, CDCl3): δ 7.64 (s, 1H), 7.61 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.12-7.07 (m, 2H), 6.60-6.59 (m, 1H), 4.22 (q, J=7.5 Hz, 2H), 1.55 (t, J=7.5 Hz, 3H); LC-MS (ESI): 94.7%; m/z 264.1 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 3.87 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:10][NH:9][CH2:8][CH:7]1[CH2:6]C[CH2:4]2.C([OH:13])C>[Pd]>[NH2:1][CH2:2][C:3]12[CH2:10][NH:9][CH2:8][CH:7]1[CH2:6][O:13][CH2:4]2
Reactant: CCO
Reactant: NCC12CCCC1CNC2
Agent: [Pd]
Product: NCC12CNCC1COC2

Procedure:
2.8 g (12.1 mmol) of 1-aminomethyl-7-azabicyclo-[3.3.0]octane are dissolved in 50 ml of ethanol and hydrogenated on 0.3 g of palladium-active charcoal at 100° C. and 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated and distilled.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O1CCOCC1>[CH2:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[CH:19][CH:20]=2)[CH2:25][CH2:26]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(N3CCNc4ccccc43)cc2)CC1
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
8.9 g of 4-[4-(4-(benzyloxycarbonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in 220 ml of dichloromethane. 55 ml of a 4N solution of hydrochloric acid in dioxane are slowly added at 0° C. The mixture is stirred for 5 minutes under cold conditions and then it is allowed to return to ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h and is then diluted with dichloromethane. A saturated aqueous sodium carbonate solution is added and then the addition is continued with solid sodium carbonate until a pH=7-8 is reached. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulphate, filtered through a sintered glass filter and concentrated under vacuum. 7.2 g of 4-[4-(3,4-dihydro-2H-quinoxalin-1-yl)phenyl]piperazine-1-carboxylic acid benzyl ester are obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])[C:6]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[O:21])=[CH:5]2.C(N(CC)CC)C.[CH3:37][C:38]([CH3:44])([CH3:43])[CH2:39][C:40](Cl)=[O:41]>ClCCl>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:40](=[O:41])[CH2:39][C:38]([CH3:44])([CH3:43])[CH3:37])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[O:21]
Reactant: Cc1cccc(NC(=O)c2cc3cc(N)ccc3n2Cc2c(F)cccc2F)c1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2cc3cc(NC(=O)CC(C)(C)C)ccc3n2Cc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
59 mg (0.150 mmol) of the compound from Example XIV and 0.04 ml (0.30 mmol) of triethylamine are initially-charged in 5 ml of dichloromethane. At 0° C., a solution of 26 mg of 3,3-dimethylbutyryl chloride (0.195 mmol) in 1 ml of dichloromethane is added dropwise, and the mixture is stirred at RT for 30 min. The reaction solution is concentrated and the residue is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane→cyclohexane:ethyl acetate 2.5:1). The resulting product is taken up in a little ethyl acetate, precipitated by addition of n-pentane, filtered off with suction and dried. This gives 35 mg (45% of theory) of a light-beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH2:16]([OH:19])[CH2:17]O.[C:20]1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:20])=[O:13])[O:19][CH2:16][CH2:17][O:15]2)=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: OCCO
Reactant: O=C([O-])CCCC(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)CCCC1(c2ccc(F)cc2)OCCO1
Yield: 91 %

Procedure:
To a solution of 5-(4-fluorophenyl)-5-oxopentanoate (2.26 g, 10 mmol) in toluene (60 ml) was added ethylene glycol (1.95 ml, 35 mmol) and p-toluenesulfonic acid monohydrate (60 mg, 0.32 mmol) and the mixture refluxed in a Dean-Stark apparatus under nitrogen for 17 h. The toluene was removed by rotary evaporator and the residue treated with sodium bicarbonate solution (5%, 50 ml) and extracted with ether (2×50 ml). The ether extract was washed with brine (1×50 ml), dried (Na2SO4) and evaporated to give methyl 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]butanoate (9) as a pale yellow oil (2.47 g, 91%). 1H nmr (CDCl3, 300 MHz) 1.6-1.7, m, H3; 1.9, m, H4; 2.30, t (7.5 Hz), H2; 3.64, s, OMe; 3.7-3.8, m, CH2O; 3.95-4.05, m, CH2O; 7.01, m, H3′,5′; 7.41, m, H2′,6′. ESI (+ve) MS m/z 269 (M+H, 45%).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.[C:17]1([CH2:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:23]([NH:24][CH2:1][C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CNCc2ccccc2)COC1(C)C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A mixture of tert-butyl (4S)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.0 g, 4.36 mmol), phenylmethanamine (491 mg, 4.58 mmol) and toluene (8 mL) was heated under reflux with stirring for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in 1,2-dichloroethane (10 mL), to which sodium bis(acetyloxy)boranuidyl acetate (2.31 g, 10.91 mmol) was added. The mixture was stirred at room temperature for two days, then diluted with water (25 mL), extracted with dichloromethane (25 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to afford 849 mg of the product.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][CH:3]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CCN(CC)CC>C1COCC1.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:10]1[C:5]2[N:6]([C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:3][N:4]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#C[Si](C)(C)C)cnc12
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
A mixture of 3-iodo-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20 step 3) (4.02 g, 10 mmol ), trimethylsilylacetylene (2.8 mL, 20 mmol), Et3N (2.1 mL, 15 mmol), PdCl2(PPh3)2 (70 mg, 1 mol %) and PPh3 (26 mg, 1 mol %) in THF (20 mL) was stirred for 10 min at 23° C. while being purged with Argon. Then CuI (19 mg, 1 mol %) was added. Stirring was continued for 16 h at 80° C. The reaction mixture was purified by column chromatography (heptane/AcOEt) to give the title compound as a yellow foam (3.15 g, 85%). MS (ISP) 373.2 [(M+H)+].
Reaction SMILES: BrCCC1C([Cl:10])=CC(Cl)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1CCBr.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(Cl)(Cl)Cl>[ClH:10].[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:20])[CH:16]=1)[O:12][CH2:5][CH2:6][NH:27][CH:24]([CH3:26])[CH3:25]
Reactant: Clc1cc(Cl)c(CCBr)c(Oc2cc(Cl)cc(Cl)c2CCBr)c1
Reactant: CC(C)N
Solvent: ClC(Cl)Cl
Product: CC(C)NCCOc1cc(Cl)cc(Cl)c1
Product: Cl

Procedure:
Following the procedure of Preparation 1, 2-bromoethyl-3,5-dichlorophenyl ether and isopropyl amine were reacted in refluxing chloroform overnight) to yield an oil, the free base of the title compound. Thereafter, a portion of the oil was reacted with ethereal hydrogen chloride to form the hydrochloride salt in 43.4% yield, m.p. 195°-197° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:10]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:25]=O>CO>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][N:17]([CH2:25][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:24]
Reactant: C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCOC(=O)CCNCc1ccccc1
Solvent: CO
Product: CCOC(=O)CCN(Cc1ccccc1)Cn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1H-benzo[d][1,2,3]triazole (5.46 g, 45.8 mmol) in MeOH (32 mL) at 0° C. were added ethyl 3-(benzylamino)propanoate (10 g, 45.8 mmol) and an aqueous solution of formaldehyde (36%, 4.56 mL, 59.6 mmol). The reaction mixture was warmed to room temperature and stirred for 12 hours. The solvent was evaporated and the residue was purified by flash-chromatography over 330 g flash pack using gradient EtOAc/Heptane 5-50% over 40 minutes. The title compound was obtained as colorless oil (12.62 g, 81%).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[C:4](=[O:8])/[CH:5]=[CH:6]/[CH3:7])[CH3:2].C(O)C.[H][H]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][CH2:6][CH3:7])[CH3:2].[CH2:1]([N:3]([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][CH:6]=[CH2:7])[CH3:2]
Reactant: [H][H]
Reactant: C/C=C/C(=O)N(CC)CC
Solvent: CCO
Solvent: c1ccncc1
Product: C=CCC(=O)N(CC)CC
Product: CCCC(=O)N(CC)CC

Procedure:
56.5 g of crotonic acid diethylamide 36.9 g of ethanol, 1.27 g of pyridine and 2.74 g of Co2 (CO)8 are reacted analogously to Example 1 for 1.5 hours at 170° C. under a carbon monoxide pressure of 150 bar (+approx. 2% by volume of hydrogen). Analysis showed that 99.6 mol % of the crotonic acid diethylamide had reacted. Relative to this, C5 -dicarboxylic acid derivatives containing mixed derivative groups had been formed at a selectivity of conversion of 97.4 mol %; 2-methylsuccinic acid 1-ethylester-4-diethylamide was 93.6% of this. In addition, butyric acid diethylamide and but-3-enoic acid diethylamide had been formed at selectivities of conversion of 1.2 mol % and 0.4 mol %, respectively.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([NH2:17])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([NH:17][C:24]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][N:18]=4)=[O:25])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1cccc2ccc(-c3ccccc3)nc12
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
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2ccc(-c3ccccc3)nc12)c1cnccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.3 %

Procedure:
2-Phenylquinolin-8-amine (60 mg, 0.27 mmol) was taken up in 2 mL of DMF along with pyrazine-2-carboxylic acid (34 mg, 0.27 mmol), HATU (207 mg, 0.54 mmol) and DIEA (95 μL, 0.54 mmol). The reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (using aqueous CH3CN that has been buffered with 0.1% TFA) to afford 10 mg of the product. MS (ESI) calcd for C20H14N4O (m/z): 326.12. found: 327 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][CH2:11][CH2:12][OH:13].N[C:15](N)=[O:16]>O>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[N:10]([CH2:11][CH2:12][OH:13])[C:15](=[O:16])[NH:1][C:2]=2[CH:7]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)c(Cl)cc1NCCO
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCO
Temperature: 190 °C
Yield: 99 %

Procedure:
A mixture of 50 parts of 2-[(2-amino-4,5-dichlorophenyl)-amino]ethanol and 46 parts of urea is stirred and heated for 2 hours in an oil-bath at about 190° C. The reaction mixture is cooled and water is added. The water is decanted and the residue is boiled in 2-propanol. Upon stirring, the mixture is cooled to room temperature. The product is filtered off and dried, yielding 55 parts (99%) of 5,6-dichloro-1,3-dihydro-1-(2-hydroxyethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15](O)[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.O>C(#N)C>[Br:27][C:28]1[CH:29]=[C:30]([S:34]([N:11]2[C:10](=[O:13])[N:9](/[CH:14]=[CH:15]/[C:16]([F:19])([F:18])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1n(S(=O)(=O)c2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1/C=C/C(F)(F)F

Procedure:
500 mg (1.63 mmol) of the compound from Example 5A were dissolved in 10 ml of acetonitrile, and 449 mg (3.25 mmol) of potassium carbonate and 415 mg (1.63 mmol) of 3-bromobenzenesulfonyl chloride were added. The mixture was heated under reflux for 2 h. For work-up, 10 ml of water were added and the mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→5:1→1:1). This gave 285 mg (34% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The 4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester (1.00 g, 3.11 mmol) was taken up in anhydrous THF under argon and cooled to 0° C. BH3 THF (1.0 M, 6.22 mmol, 6.22 mL) was added to the solution dropwise over 10 min. The reaction mixture was then allowed to stir at 0° C. for 30 min then warmed to room temp and stirred for an additional 30 min. The reaction was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (1:1 hexane-ethyl acetate) Yield 814 mg. 1H NMR (CDCl3, 300 MHz): δ 1.48 (s, 9H), 1.63-1.76 (m, 1H), 2.10-2.26 (m, 1H), 3.33 (m, 1H), 3.50-3.60 (m, 1H), 3.63-3.75 (m, 2H), 4.05-4.19 (m, 2H), 4.49 (s, 2H), 7.23-7.39 (m, 5H).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20](=[O:22])[CH3:21])=[CH:18][CH:19]=3)[C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][C:3]([C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([F:23])=[CH:25][CH:26]=1)=[CH:2][CH:1]=3)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2c3ccc(C(C)=O)cc3c3cc(C(=O)c4ccc(F)cc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-carbazol-9-yl-phenyl)-ethanone (5.71 g) in CH2Cl2 (150 mL) is added p-fluorobenzoyl chloride (3.17 g) and AlCl3 (5.41 g) at 0° C. After stirring overnight at room temperature, acetyl chloride (1.73 g) and AlCl3 (2.93 g) are further added at 0° C. and the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water, and the crude product is extracted twice with CH2Cl2. The combined organic layer is washed with H2O and brine, dried over MgSO4, and concentrated to give the residue, which is purified by washing with hot TBME. The structure of the product, which is obtained as a white solid, is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 2.73 (s, 3H), 2.75 (s, 3H), 7.23 (t, 2H), 7.48 (d, 1H), 7.51 (d, 1H), 7.72 (d, 2H), 7.91 (dd, 2H), 7.99 (d, 1H), 8.14 (d, 1H), 8.28 (d, 2H), 8.66 (s, 1H), 8.80 (s, 1H).