Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)[CH:13]=2)=[CH:8][CH:7]=1.[H-].[Na+].[CH2:32](Cl)[O:33][CH2:34][CH2:35][O:36][CH3:37].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:14]([C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)[CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(-c2ccc(/C=C/C(=O)OC)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid methyl ester (120 mg, 0.309 mmol) in 1 ml of anhydrous DMF, was dropped into a 1 ml suspension of NaH (14.8 mg, 0.371 mmol, 60% in mineral oil) in anhydrous DMF (0.3 ml) at 0° C. The resulting red solution was stirred at RT for 30 min, then MEM-Cl (46 mg, 0.371 mmol) was added. After stirring overnight at RT, iced water was added and the mixture was extracted several times with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under vacuo. The resulting crude product was purified on silica gel (acetone:hexane 15:85) to obtain (E)-3-[3′-adamantan-1-yl-4′-(2-methoxyethoxymethoxy)-biphenyl-4-yl]-acrylic acid methyl ester (123 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)O[C:6](=[O:7])[C:5]2=[CH:12][C:13]=1[I:14].C(O)(=O)C.C(N)=[NH:20]>>[OH:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:13]([I:14])[CH:12]=2)[N:10]=[CH:9][N:20]=1
Reactant: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Reactant: N=CN
Solvent: CC(=O)O
Product: Oc1ncnc2cc(F)c(I)cc12
Temperature: 110 °C
Yield: 91.2 %

Procedure:
Dimethylfornamide (0.5 litres), 4-fluoro-5-iodo-isatoic anhydride (45 grams, 147 mmoles), and formamidine acetate (45.92 grams, 441 mmoles), were combined in a one litre one-neck flask fitted with a magnetic stir bar. The mixture was placed under anhydrous nitrogen and heated at 110° C. for 6 hours. The mixture was allowed to cool, followed by concentrating the reaction mixture to one third its original volume on the rotary evaporator. The resulting mixture was poured onto 3 litres of ice water. The resulting precipitated solid was collected by suction filtration. The solid was washed with an additional one litre of distilled water. The resulting solid was dried under vacuum at 70° C. to yield 38.9 grams (91%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 12.43(s, 1H), 8.46(d, 1H), 8.12(s, 1H), 7.49(d, 1H). ESI-MS m/z 291 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH:2]1[C:5]([NH2:7])=O.[Cl:8][CH2:9][C:10](Cl)=[O:11]>>[Cl:8][CH2:9][C:10]([N:1]1[CH2:4][CH2:3][C@H:2]1[C:5]#[N:7])=[O:11]
Reactant: NC(=O)C1CCN1
Reactant: O=C(Cl)CCl
Product: N#C[C@@H]1CCN1C(=O)CCl
Yield: 43.9 %

Procedure:
In a similar procedure as employed in the Intermediate Example 1, the azetidine-2-carboxylic acid amide (161 mg) obtained above was reacted with chloroacetyl chloride (200 mg) and then subjected to dehydration reaction to give the title compound (112 mg, Y.:44%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][CH:15]=[C:14]([Br:31])[CH:13]=2.[Cl:32][CH2:33][C:34](Cl)=O>ClCCl>[Br:31][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:34]([CH2:33][Cl:32])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cc(Br)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
Triethylamine (26.7 g, 264 mmol) was added to a solution of tert-butyl 3-[(3-amino-7-bromoquinolin-4-yl)amino]propylcarbamate (52.17 g, 132.0 mmol) in dichloromethane (370 mL). Chloroacetyl chloride (15.65 g, 138.6 mmol) was added, and the reaction was stirred overnight at ambient temperature. The solvent was removed under reduced pressure, and the residue was stirred in ethanol (1 L) overnight at ambient temperature. The solvent was removed under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed twice with water, concentrated under reduced pressure, and dried under high vacuum to provide 41.63 g of tert-butyl 3-[7-bromo-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[C:21]([CH:27]=[O:28])=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26].[F:29][C:30]([Si](C)(C)C)([F:32])[F:31]>C1COCC1.C(OCC)(=O)C>[Br:19][C:20]1[C:21]([CH:27]([OH:28])[C:30]([F:32])([F:31])[F:29])=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: Cc1ccnc(C=O)c1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccnc(C(O)C(F)(F)F)c1Br
Temperature: -15 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Tetrabutylammonium fluoride (1.0 mol/L) in THF (1.2 mL, 1.20 mmol) was added dropwise to a solution of 3-bromo-4-methyl-pyridine-2-carbaldehyde (150 mg, 0.75 mmol), and (trifluoromethyl)trimethylsilane (2.0 mol/L) in THF (0.49 mL, 0.975 mmol) in THF (10 mL) cooled at −15° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-30% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (90 mg, 44%), which was used in the next step without further purification.
Reaction SMILES: C(OCC)(=O)C.[OH:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14].[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[C:20]1([NH:26][C:27]([O:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C(C)C(=O)Nc1cccc(O)c1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1cccc(OC(=O)Nc2ccccc2)c1
Temperature: 65 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate and 17.7 parts of 3'-hydroxy-2-methylacrylanilide and heated with stirring to about 65°C. Phenyl isocyanate, 12 parts, is added. No apparent reaction occurs until one part of triethylamine is added to the reaction mixture. After a slight exothermic increase in temperature, the reaction mixture is heated at reflux for one-half hour, cooled and filtered. The solids are washed with ethyl acetate and air dried to give 22.8 parts of 3'-(phenylcarbamoyloxy)-2-methylacrylanilide, m.p. 177°-178°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5]2.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:22]1([S:28]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH2:5][CH:6]([NH:12][S:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH2:7]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(NC1CNc2ccc(Br)cc2C1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(NC1Cc2cc(Br)ccc2N(S(=O)(=O)c2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of compound 87A (98 mg, 0.299 mmol) in pyridine (3 ml) was added benzenesulfonyl chloride (0.042 mL, 0.33 mmol). The mixture was stirred at RT overnight, then concentrated. The residue was chromatographed (10 g silica gel) eluting with EtOAc (0-60%) in hexane to give the title compound (140 mg, 93%) as a white foam. HPLC: 99% at 7.06 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A 90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 529 [M+Na]+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].N12CCCN=C1CCCCC2.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(#N)C>[Si:20]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: N[C@@H](CCO)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)N[C@@H](CCO)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-homoserine (1 g, 8.4 mmol) in acetonitrile (10 ml) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.32 ml, 8.8 mmol, 1.05 eq). tert-butyldimethylsilyl chloride (1.33 g, 8.8 mmol, 1.05 eq) was then added portionwise over 5 minutes and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. A white precipitate formed, which was filtered off and washed with acetonitrile before drying under reduced pressure. The title compound was isolated as a white solid (1.8 g, 92% yield). 1H NMR (500 MHz, DMSO-d6), δ: 7.5 (1H, br s), 3.7 (1H, m), 3.35 (4H, br m), 1.95 (1H, m), 1.70 (1H, m), 0.9 (9H, s), 0.1 (6H, s).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:17]1[O:19][C@@H:18]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:17]1[O:19][C@@H:18]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](O)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](OC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In pyridine (0.6 mL) was dissolved ethyl (2S,3S)-3-[[1-(S)-[α-(R)-hydroxybenzyl]-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (300 mg, 0.894 mmol.). To the resulting solution was added acetic anhydride (0.085 mL, 0.901 mol.) under chilling with ice. The mixture was stirred for 18 hours at room temperature, and extracted with ether (8 mL, 3 portions) after addition of water (10 mL). The organic portion was washed successively with water, 1N hydrochloric acid, and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1), to give the titled compound as a slightly brownish crystalline product (267 mg, yield: 79%).
Reaction SMILES: [CH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.C([C:9]1[C:15](=O)[C:14](Cl)=[C:13](Cl)[C:11](=[O:12])[C:10]=1C#N)#N>>[C:1]1([CH:10]2[CH2:9][CH2:15][CH2:14][CH2:13][C:11]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: C1=CCC=CC1
Product: O=C1CCCCC1c1ccccc1
Yield: 56 %

Procedure:
Rh2 (S-DOSP)4-catalyzed decomposition of the cyclic vinyldiazoacetate 58 in the presence of 1,3-cyclohexadiene 40 resulted in the formation of the 1,4-cyclohexadiene 59 in 73% yield and 97% ee. The absolute configuration of compound 59 was determined by DDQ oxidation and ozonolysis to afford the 2-phenylcyclohexanone in a 56% yield. Found [α]26D=−17 (c=1.66, PhH) Lit. value: [α]24D=−113.5 (c=0.60, PhH), S-isomer. (Berti et al., J. Chem. Soc., pp. 3371–3377 (1971), which is hereby incorporated by reference.) Similarly, decomposition of the dienyldiazoacetate 60 in the presence of 1,3-cyclohexadiene 40 resulted in the formation of 61 (60% yield and 99% ee), in which both diene components have moved out of conjugation.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C@H:9]([NH2:11])[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[NH2:13][C:14]([C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1)=[O:15]>CC(O)C>[NH2:13][C:14]([C:16]1[C:17]([NH:11][C@@H:9]2[CH2:8][C@H:7]3[N:3]([CH2:4][CH2:5][CH2:6]3)[C:2]([CH3:12])([CH3:1])[CH2:10]2)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1)=[O:15]
Reactant: CC1(C)C[C@H](N)C[C@@H]2CCCN21
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Cl)ncc2C(N)=O)C[C@@H]2CCCN21
Reaction time: 72 h
Yield: 54 %

Procedure:
A mixture of (7R,8aS)-octahydro-5,5-dimethylindolizin-7-amine (1.25 g) and 5-aminocarbonyl-2,4-dichloropyrimidine (2.14 g, 1.5 eq.) in iPrOH (50 mL) was stirred at −10° C. to rt for 3 d. The solid was filtered off and washed with methanol (3×10 mL). The filtrate was evaporated under vacuum and the residue was purified by CombiFlash chromatography on silica gel (2N NH3 in MeOH/CH2Cl2=0-30%) to give the desired product (1.3 g, 54% over 3 steps).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([I:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1cc(Cl)c(F)cc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(F)c(I)c1O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (23.8 g, 126 mmol) in acetic acid (100 mL) was treated with N-iodosuccinimide (34.1 g, 151 mmol) and stirred at 70° C. for 2 hours. The reaction mixture was concentrated, diluted with EtOAc and quenched with sat. NaHCO3 solution. The organic layer was separated, washed with water, dried over MgSO4 and concentrated under reduced pressure to give the desired product to be used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=[C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]1=[N:20]O)([OH:3])=[O:2].[CH:22](OC)=[O:23]>[Pt]=O.CO>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[NH:20][CH:22]=[O:23])([OH:3])=[O:2]
Reactant: COC=O
Reactant: CN1C(=O)C(=NO)C(=NCCCCCC(=O)O)N(C)C1=O
Agent: O=[Pt]
Solvent: CO
Product: Cn1c(NCCCCCC(=O)O)c(NC=O)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A mixture of 15.8 g (0.05 mol) of the oxime (III), 200 ml of methanol, and 100 mg of platinum oxide was shaken under 4 atmospheres H2 for 15 minutes at room temperature. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure (35° C.) to give a red oil. Methyl formate (200 ml) was added and the resulting mixture refluxed under argon for 20 hours. It was then cooled in an ice bath and the white solid collected by filtration. Recrystallization from methanol gave 9.82 g (63% yield) of the formamido uracil (IV) as white crystals, mp 152°-153° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[NH:40]1[CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:1][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[C@@H:21]3[CH2:30][CH2:29][C:28]4[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=4[CH2:22]3)=[CH:38][CH:39]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: C1CNC1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN3CCC3)cc2)c1
Yield: 20.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and azetidine (10 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.4 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8]Br)#[N:2].Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])#[N:2]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)c(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), sarcosine tert-butyl ester hydrochloride (BACHEM; F-1135; 1 527.73 mg; 8.41 mmol; 1.20 eq.) and potassium carbonate (2.91 g; 21.02 mmol; 3 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for one night. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over magnesium sulfate and concentration in vacuo gave the title compound as a slightly yellow oil (1.9 g; 97%). 1H NMR (CDCl3) δ 7.86 (dd, J=6.5, 2.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.13 (t, J=9.0 Hz, 1H), 3.78 (s, 2H), 3.23 (s, 2H), 2.38 (s, 3H), 1.49 (s, 9H). 19F NMR (CDCl3) δ-108.3. GC/MS: 278. LC/MS (Method B): 279.1 (M+H)+. HPLC (Method A) Rt 2.25 min (Purity: 91.4%).
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:24]([NH2:27])([CH3:26])[CH3:25]>CS(C)=O.O>[CH:24]([NH:27][C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])[CH3:25]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Reactant: CC(C)N
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1NC(C)C
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 27.8 mg, 0.090 mmol) and isopropylamine (0.023 mL, 0.269 mmol) in DMSO (0.8 mL) was heated under argon in a sealed flask at 60° C. for 1 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-2-(3-(isopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (19.6 mg, 0.056 mmol, 63% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (1H, br. s.), 7.90 (1H, d, J=7.2 Hz), 7.56 (1H, d, J=7.4 Hz), 7.31 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=1.8 Hz), 6.97 (1H, br. s.), 6.89 (1H, d, J=7.2 Hz), 4.35 (1H, dq, J=13.3, 6.4 Hz), 3.46 (1H, dt, J=10.0, 3.4 Hz), 3.05-3.19 (2H, m), 2.54 (3H, s), 1.36 (3H, d, J=6.5 Hz), 1.32 (3H, d, J=6.5 Hz), 1.29 (3H, d, J=6.3 Hz). m/z (ESI, +ve) 350.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26]Br)[CH2:20]1)=[O:18])[CH3:15].O>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][O:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1CCCN(CCBr)C1
Reactant: OCCCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCCN(CCOCCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Sodium hydride (1.5 g, 37 mmol, 60% oil dispersion) was added portionwise to a stirred solution of 3-phenyl-1-propanol (5.0 g, 37 mmol) in toluene (25 ml) placed under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature and then heated at reflux for 45 minutes. The reaction mixture was allowed to cool and another portion of sodium hydride (1.5 g, 37 mmol, 60% oil dispersion) was added followed by toluene (25 ml). The suspension was heated at reflux for 15 minutes and allowed to cool. Keeping the temperature below 40° C. 1-(2-bromoethyl)-3piperidinecarboxylic acid ethyl ester hydrobromide (12.6 g, 37 mmol, EP 374801) was added portionwise. The reaction mixture was stirred for 3 days and then left for 3 weeks. The mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml). The phases were separated and the organic phase was extracted with 5% citric acid solution (3×100 ml). The combined acidic phases were extracted with ethyl acetate (100 ml) which was discarded. 4N sodium hydroxide was added to the aqueous phase until pH 8 and then it was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution and dried (Na2SO4). The solvent was evaporated in vacuo to give 3.2 g of 1-(2-(3-phenyl-1-propyloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>C(N(CC)CC)C.[Pd].[Cu]I>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:2]2[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CCN(CC)CCOc1ccc(Br)cc1
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc(C#Cc2ccc(OC)cc2)cc1
Yield: 79.9 %

Procedure:
To a solution of 15 g (0.06 mole) of 1-(4-bromophenoxy)-2-diethylaminoethane and 8.2 g (0.062 mole) of 4-methoxyphenylacetylene in 150 ml of triethylamine are added, under nitrogen, 420 mg of the palladium complex PdCl2 [P(C6H5)2 ]2 and 228 mg of copper(I) iodide. The reaction mixture is subsequently refluxed for 24 hours, then concentrated, and the residue is taken up in water. After extraction with 200 ml of ether, the combined ethereal phases are washed 3 times with water, dried and evaporated to dryness. The crude product is chromatographed on silica gel, affording 15.5 g (80%) of 1-[4-(4-methoxyphenylethynyl)phenoxy]-2-diethylaminoethane with a melting point of 59°-60° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]2[OH:31])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[ClH:32].C(OCC)(=O)C>C(OCC)C>[ClH:32].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[OH:31])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1ccco1

Procedure:
The solution of 4-{1-[N-(furan-2-ylcarbonyl)amino]cyclohexane carbonyl}amino-1-tert-butoxycarbonyl-3-piperidinol (30 g) obtained in Step 3 in 100 ml of 3N-hydrochloride/ethyl acetate was stirred for about 2 hours at room temperature. 100 ml of diethyl ether was added to the reaction mixture, and then the resulting white solid was filtered and dried to give 3.6 g of the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[N:9]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:10]3=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:22][CH2:23][CH2:24]Br>>[CH2:22]([N:14]1[C:10]2=[N:11][C:12]3[C:7]([C:8](=[O:21])[N:9]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]1=2)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=3)[CH2:23][CH3:24]
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc2[nH]c3ccccc3n12
Reactant: CCCBr
Product: CCCn1c2ccccc2n2c(=O)c3ccc([N+](=O)[O-])cc3nc12

Procedure:
6-(n-Propyl)-3-nitrobenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 3-nitrobenzimidazo[2,1-b]quinazolin-12(6H)one and n-propyl bromide.