Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].ClC(OCC(C)C)=O.[OH-].[Na+].[NH2:20][C@H:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:2][C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:20][C@H:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]1[NH:27][CH:26]=[N:25][CH:24]=1)=[O:9])=[O:3]
Reactant: CC(=O)NCCC(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O

Procedure:
5.24 Grams of 3-acetylaminopropionic acid was dissolved in a mixed solvent of 25 ml of chloroform and 4.04 g of triethylamine. To the solution which was stirred keeping the temperature below -5° C., was added 6.83 g of isobutyl chloroformate. After stirring for additional 20 minutes at room temperature, the resultant solution and 20 ml of 2 N aqueous sodium hydroxide solution were simultaneously added dropwise to 45 ml of aqueous solution containing 3.10 g of histidine which has been adjusted to a pH of 10.50 while the reaction system was stirred and maintained to a temperature below 10° C. and a pH between 10.30 and 10.50. After stirring for additional 30 minutes at room temperature, the reaction solution was settled and the lower layer (chloroform layer) was separated out. The aqueous layer was treated by a similar manner as in Example 4 to obtain 3.65 g of N-acetyl-L-carnosine crystals. The specific rotation power [α]D20 was 26.5 (C=3, H2O). Also, the infrared spectrum (IR) and high resolution nuclear magnetic resonance (NMR) were identical with those of an authentic sample.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:7]=1>CO.C(#N)C>[Cl:5][C:6]1[N:11]=[C:10]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:9]=[C:8]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:7]=1
Reactant: NC1CC1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CO
Product: FC(F)(F)COCc1cc(NC2CC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A solution of cyclopropanamine (68 mg, 1.20 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (104 mg, 0.40 mmol) in acetonitrile (2 mL). The mixture was stirred at rt overnight. The mixture was purified by preparative HPLC yielding to give the title compound (64 mg, 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:46][CH:43]3[CH2:45][CH2:44]3)=[O:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NC3CC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and cyclopropylamine (8.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-cyclopropylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (31.6 mg).
Reaction SMILES: [C:1]([CH:3]([CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH3:7])=[O:5])#[N:2].O1CCOCC1.[ClH:29]>>[Cl:29][C:1]1[NH:2][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C#N)CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(C3CCCCC3)cc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14% Hydrogen chloride—1,4-dioxane solution (50 mL) was added to methyl 2-cyano-4-(4-cyclohexylphenyl)-4-oxobutanoate (12.1 g) and the mixture was stirred at room temperature for 8 hr and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether and collected by filtration to give a nearly 1:1 mixture (3.41 g) of the title compound and methyl 2-amino-5-(4-cyclohexylphenyl)-3-furoate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2) to give the title compound as crystals (yield 0.64 g, 5%).
Reaction SMILES: COC1C([N+]([O-])=O)=CC=CC=1C=O.C1OCCOCCOCCOCCOCCOC1.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:61][O:62][C:63]1[C:68]([N+:69]([O-:71])=[O:70])=[CH:67][CH:66]=[CH:65][C:64]=1/[CH:72]=[CH:73]/[O:74]C.COC1C([N+]([O-])=O)=CC=CC=1/C=C\OC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.Cl>[CH3:61][O:62][C:63]1[C:68]([N+:69]([O-:71])=[O:70])=[CH:67][CH:66]=[CH:65][C:64]=1[CH2:72][CH:73]=[O:74]
Reactant: CO/C=C/c1cccc([N+](=O)[O-])c1OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CO/C=C\c1cccc([N+](=O)[O-])c1OC
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1c(CC=O)cccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 54 %

Procedure:
To a stirred solution of 2-(methoxy)-3-nitrobenzaldehyde in THF were added 18-Crown-6 (0.2 eq), (methoxymethyl)triphenylphosphonium chloride (2 eq) and potassium carbonate (6.5 eq). The resulting suspension was warmed to 60° C. for 2 hours then cooled to room temperature and filtered. The filtrate was concentrated under vacuum and purified by chromatography on a silica cartridge (eluent cyclohexane-ethyl acetate, 9:1) to give a mixture of 2-(methoxy)-1-[(E)-2-(methoxy)ethenyl]-3-nitrobenzene and 2-(methyloxy)-1-[(Z)-2-(methyloxy)ethenyl]-3-nitrobenzene. The alkene mixture was dissolved in THF and 6N hydrochloric acid (1:1), and stirred for 1 hour. The solution was made basic with aqueous sodium carbonate solution and extracted with DCM. The organic layer was washed (water, brine), dried (sodium sulfate) and concentrated under vacuum to give the title compound (54% overall yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:34]=[C:35]=[O:36])[CH2:32][CH3:33]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:34]([CH2:31][CH2:32][CH3:33])[C:35]2=[O:36])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: CCCN=C=O
Agent: [I-]
Agent: [Na+]
Product: CCCN1C(=O)N(S(=O)(=O)c2ccccc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and propyl isocyanate to give the title compound as a colorless solid. MS: 485.2 ([M+H]+)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[K+].Cl>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCCC(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O
Temperature: 0 °C
Yield: 70 %

Procedure:
6.11 g (19 mmole) of 4-cyanobiphenyl-4'-oxy-hexanoate, 11 g potassium hydroxide and 100 ml absolute ethanol were stirred at room temperature for 3 hours, after which time the mixture was poured into 300 ml ice water. The resultant solution was neutralized with hydrochloric acid. The solids were filtered out, washed with water, and dried in a vacuum desiccator for 48 hours. After recrystallization from absolute ethanol, the resultant product (70% yield) had a melting point of 165° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([CH3:8])[C:5]([OH:7])=[O:6].[CH3:9]O>OS(O)(=O)=O>[CH3:9][O:6][C:5](=[O:7])[CH:4]([CH3:8])[CH2:3][CH2:2][Br:1]
Reactant: CC(CCBr)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)CCBr

Procedure:
4-Bromo-2-methyl-butyric acid (2.16 g, 1 eq, prepared according to the procedure described in J. Am. Chem. Soc. 1990, 112, 2755) was dissolved in MeOH (10 mL) and a few drops of conc. H2SO4 were added. The reaction was stirred at reflux for 16 hours. After reaction completion, as monitored by LC-MS, MeOH was removed under reduced pressure, the oily residue was diluted with water, the pH adjusted to 9 with 10% NaOH, and the product was extracted with Et2O (2×20 mL) and dried over Na2SO4. The title compound was obtained as a colourless oil (1.29 g, 55% yield) after solvent removal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:9])[CH3:10])=[CH:4][C:3]=1[NH2:11]
Reactant: [H][H]
Reactant: CN(C)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(F)c(N)c1
Yield: 99.8 %

Procedure:
3.23 g (17.54 mmol) of (4-fluoro-3-nitrophenyl)-dimethylamine are added, at a temperature in the region of 20° C., to a suspension of 0.6 g (5.63 mmol) of 10% palladium-on-charcoal in 100 cm3 of methanol. After hydrogenation for 30 minutes in an autoclave under 5 bar of hydrogen, at a temperature in the, region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with 3 times 10 cm3 of methanol, and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa), to give 2.7 g of 4-fluoro-N1,N1-dimethylbenzene-1,3-diamine, in the form of a brown oil;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[CH2:12][OH:13].[CH3:14][N:15](CCN(C)C)C.CCOC(C)=O>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:13][CH2:12][CH:7]1[C:6]2[C:11](=[C:2]([C:14]#[N:15])[CH:3]=[CH:4][CH:5]=2)[O:10][CH2:9][CH2:8]1
Reactant: CN(C)CCN(C)C
Reactant: OCC1CCOc2c(Br)cccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc2c1OCCC2CO
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of (8-bromo-3,4-dihydro-2H-chromen-4-yl)methanol (1 g, 4.12 mmol) in 3 mL of DMF was added Zn(CN)2 (481 mg, 4.12 mmol), Pd2(dba)3 (67 mg, 0.04 mmol), TMEDA (191 mg, 1.6 mmol), Xantphose (48 mg, 0.08 mmol), and the mixture was stirred under microwave irradiation for 5 min at 100° C. The mixture was added with 10 mL of EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 4-(hydroxymethyl)-3,4-dihydro-2H-chromene-8-carbonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2Br)[O:9][N:8]=1.O.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[C:22]#[N:23])[O:9][N:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccc(C#N)c(-c2nc(-c3ccccn3)no2)c1
Temperature: 80 °C
Yield: 4 %

Procedure:
In a similar fashion, a mixture of 3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole (33.2 mg, 0.1 mmol), zinc cyanide (17.6 mg, 0.15 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in N,N-dimethylformamide (1 mL) was heated under an argon atmosphere at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography using 50% ethyl acetate in hexane afforded 1.1 mg (4%) of 3-(2-pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4-oxadiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[C:7]([O:14][CH:15]([CH3:17])[CH3:16])[CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[C:5](=[O:18])[CH2:4][CH2:3]1.[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C(N(CC)CC)C.O1CCCC1>CCCCCC.[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.C(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:13]#[C:12][C:9]2[CH:8]=[C:7]([O:14][CH:15]([CH3:16])[CH3:17])[C:6]3[C:5](=[O:18])[CH2:4][CH2:3][C:2]([CH3:1])([CH3:19])[C:11]=3[CH:10]=2)=[CH:28][CH:29]=1
Reactant: C#Cc1cc(OC(C)C)c2c(c1)C(C)(C)CCC2=O
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(OC(C)C)c3c(c2)C(C)(C)CCC3=O)cc1

Procedure:
Following General Procedure B and using 4,4-dimethyl-6-ethynyl-8-(2-propoxy)-3,4-dihydro-2H-naphthalen-1-one (Intermediate 127, 0.075 g, 0.29 mmol), 4-iodo phenyl acetic acid methyl ester (0.081 g, 0.29 mmol), triethyl amine (8 mL), tetrahydrofuran (3 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5–15% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (0.07 g, 64%).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCCOc1cccc(C#CC2(O)CCCCCC2)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NCCOc1cccc(C#CC2(O)CCCCCC2)c1
Temperature: 50 °C

Procedure:
To a solution of 2,2,2-trifluoro-N-(2-(3-((1-hydroxycycloheptyl)ethynyl)phenoxy)ethyl)acetamide (1.07 g, 2.9 mmol) in MeOH (20 mL) was added saturated aqueous K2CO3 (ca. 10 mL). The reaction mixture was stirred vigorously and heated at 50° C. for 2 h. After removal of the volatiles by concentration under reduced pressure, the mixture was partitioned into EtOAc and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (10% 7M NH3 in MeOH-EtOAc) gave 1-((3-(2-aminoethoxy)phenyl)ethynyl)cycloheptanol as a pale yellow solid. (Yield 0.70 g, 88%): 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J=8.0 Hz, 1H), 7.01 (dt, J=8.0, 0.8 Hz, 1H), 6.95 (dd, J=2.8, 1.6 Hz, 1H), 6.85 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 3.97 (t, J=4.8 Hz, 2H), 3.07 (br s, 2H), 2.08-2.13 (m, 2H), 1.87-1.94 (m, 2H), 1.59-1.74 (m, 11H).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22].C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[C:21]([C:24]1[CH:29]=[C:28]([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCCO
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (7.38 g, 19 mmol), 3-acetylphenyl boronic acid (4.67 g, 28.5 mmol), 1,3-propanediol (6.8 ml, 95 mmol), potassium carbonate (13.1 g, 95 mmol) and bis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in a mixture of dimethoxyethane (60 ml) and water (30 ml) was stirred at reflux in a nitrogen atmosphere for 1 hour. The cooled reaction mixture was filtered through a pad of Celite and the filter was rinsed with ethyl acetate. The organic layer was collected, dried over magnesium sulphate and concentrated under reduced pressure. The title product precipitated upon addition of diethyl ether to the concentrate (6.17 g, 85%) m/z, 381.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1ccc2c(c1)CCN2
Product: O=[N+]([O-])c1ccccc1N1CCc2ccccc21
Temperature: 120 °C

Procedure:
11.0 g (0.10 mole) of indoline and 28.2 g of 1-fluoro-2-nitrobenzene are combined and the resultant solution is stirred and heated to 120° C. and kept at that temperature 18 hours. The reaction mixture is then cooled to room temperature and partitioned between chloroform and water. The chloroform layer is separated, washed with water, dried and concentrated in vacuum. The residue is dissolved in isopropylether from which 1-(2-nitrophenyl)indoline, m.p. 62°-64° C., precipitates on standing.
Reaction SMILES: CC1C=CC(C([O:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([CH:20]([N:26]([CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[NH:10]2)=O)=CC=1.O1CCCC1.[OH-].[Li+].Cl>O>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9](=[O:8])[NH:10][C:11]([CH:20]([N:26]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:44])[CH3:45])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)OC2NC(C(C(=O)N(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)c3ccc(C)cc3)=Nc3cc(Cl)ccc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[1-[{3-[(tert-butoxycarbonyl)amino]propyl}(4-methylbenzoyl)amino]-2-(dimethylamino)-2-oxoethyl]-7-chloro-3,4-dihydroquinazolin-4-yl 4-methylbenzoate in a 1:1 mixture of tetrahydrofuran and water (20 ml), was added lithium hydroxide (284 mg, 2 eq.) at room temperature. The mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with 1M of aqueous hydrogen chloride to pH 6-7 and later extracted into methylene chloride. The organic layer was washed with more water, dried over magnesium sulfate, filtered and concentrated. The product was purified by flash chromatography to give tert-butyl 3-[[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]-propylcarbamate (257 mg) as a yellow solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O>[C:17]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(NCCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Sodium bicarbonate (12.6 g) was dissolved in distilled water (250 ml) and tyramine (20.6 g) added. The resulting suspension was heated to boiling to dissolve the tyramine, then cooled to room temperature. Benzyl chloroformate (25.6 g) was added while stirring and with occasional vigorous shaking. After stirring and shaking for an additional 1.5 hours, the precipitate was filtered off and washed with distilled water. The solid was dissolved in ether (250 ml) and washed with distilled water. The organic layer was dried over MgSO4 and evaporated in vacuo to give a residue which solidified upon cooling. Recrystallization from ether/hexane gave the desired product as colourless crystals, m.p. 96°-98° C.
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:15](O)(=[O:17])C.C([O-])(=O)C.[Na+].C=O>O>[OH:17][CH2:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1nc2ccccn2c1CO
Temperature: 90 °C
Yield: 49 %

Procedure:
A mixture of 570 mg (3.0 mmol) ethyl imidazolo[1,2-a]pyridine-2-carboxylate, glacial acetic acid (0.8 mL) and 1 g (12 mmol) sodium acetate is treated with 6 mL 37% formaldehyde in water. The mixture is heated in a sealed tube at 90° C. for 6 hr and the acetic acid removed in vacuo. The residue is made basic by addition of 2M sodium hydroxide and extracted into 3×10 mL dichloromethane containing 1% methanol. The organic extract is dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude residue. The residue is flash chromatographed with initially 10% methanol in dichloromethane to afford 325 mg (49%) ethyl 3-(hydroxymethyl)-imidazolo[1,2-a]pyridine-2-carboxylate.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH2:6]2)[CH2:2]1.C(N(CC)CC)C.[CH3:28][Si:29]([CH3:44])([CH3:43])[CH2:30][CH2:31][O:32][C:33](ON1C(=O)CCC1=O)=[O:34]>C(Cl)Cl.O>[N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:33]([O:32][CH2:31][CH2:30][Si:29]([CH3:44])([CH3:43])[CH3:28])=[O:34])[CH2:6]2)[CH2:2]1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccccc32)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccccc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 105.7 %

Procedure:
t-Butyl spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (10.0 g, 36.4 mmol) was dissolved in methylene chloride (73 mL). Thereafter, triethylamine (15.2 mL, 109 mmol) and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (14.2 g, 54.8 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 22 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (16.1 g, quant.) in the form of a light yellow oily product.