Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]2[N:5]([C:9]([C:12]3[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64](O)(=[O:67])[C:65]#[CH:66]>C(Cl)Cl>[CH:19]([O:18][C:16]1[CH:17]=[C:12]([C:9]2[N:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:64](=[O:67])[C:65]#[CH:66])[C:4]3=[N:11][CH:10]=2)[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[O:24])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: C#CC(=O)O
Reactant: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(CN)cccn23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)NCc1cccn2c(-c3cc(NC(=O)NCC(F)(F)F)cc(OC(C)C)c3)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of 1-(3-(8-(aminomethyl)imidazo[1,2-a]pyridin-3-yl)-5-isopropoxyphenyl)-3-(2,2,2-trifluoroethyl)urea (26 mg, 0.062 mmol) in DCM (3 ml) was added DIEA (0.075 ml, 0.432 mmol) and HATU (35.2 mg, 0.093 mmol) and finally propiolic acid (4.95 μl, 0.080 mmol). Reaction was stirred for 30 minutes at room temperature. Reaction was loaded directly onto silica column and purified by flash chromatography (0-10% CH2Cl2/MeOH) to give the title compound (19 mg, 0.040 mmol, 65.0% yield) as an off white solid. MS (ES+) C23H22F3N5O3 requires: 473. Found: 474 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.92 (s, 1H), 8.47 (d, J=6.8 Hz, 1H), 7.74 (s, 1H), 7.17 (d, J=1.9 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 4.69-4.58 (m, 2H), 3.93 (dd, J=9.7, 6.4 Hz, 2H), 2.72-2.64 (m, 1H), 1.30-1.19 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH:19]([F:21])[F:20])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]=[C:10]([O:16]C)[CH:9]=2)[CH:7]=1.Br.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH:19]([F:21])[F:20])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][NH:11][C:10](=[O:16])[CH:9]=2)[CH:7]=1
Reactant: COc1cc(-c2cc(Cl)ccc2OC(F)F)c(OC)cn1
Agent: Br
Agent: c1cc[nH+]cc1
Product: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
170 mg (purity 90%, 0.49 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-2,5-dimethoxypyridine and pyridinium hydrobromide were reacted according to General Method 3A. Yield: 127 mg (87% of theory)
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[CH:15][CH:14]=1.FC(F)(F)[C:33](O)=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH:33]([C:30]1[CH:29]=[C:16]([CH:15]=[CH:14][C:13]=1[O:12][CH3:11])[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[O:34]
Reactant: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18 g of hexamethylene tetramine was added little by little to a mixture of 31 g N-(4-methoxybenzyl)phthalimide and 100 ml trifluoroacetic acid, stirred at room temperature for 1 hr, and then heated under reflux for 4 hr. The reaction solution was cooled to 0° C., and water was added thereto. Potassium carbonate was added thereto and the resulting crystals were collected by filtration. The crystals were dried to give 20 g of N-(3-formyl-4-methoxybenzyl)phthalimide.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([O:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:12])([CH3:11])[CH3:10].CI>C1COCC1>[C:9]([O:13][C:14](=[O:20])[CH:15]([CH3:2])[CH2:16][C:17]([OH:19])=[O:18])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(CC(=O)O)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of LDA (6.3 mmol, 2M in hexane) in THF (5 mL) at −78° C. is added a solution of succinic acid mono-tert-butyl ester (523 mg, 3 mmol) in THF (2 mL) dropwise. After the addition, the mixture is warmed to −20° C. slowly and stirred at −20° C. for 30 minutes. The solution is re-cooled to −78° C. and MeI (511 mg, 3.6 mmol) is added dropwise. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure to give 2-methyl-succinic acid 1-tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][NH:12]2.Cl.CN(C)CCCN=C=NCC.[N:29]1([C:35]2[N:36]=[C:37]([CH2:42][C:43]([O-])=[O:44])[NH:38][C:39](=[O:41])[CH:40]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][N:12]2[C:43](=[O:44])[CH2:42][C:37]1[NH:38][C:39](=[O:41])[CH:40]=[C:35]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:36]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1ccccc1-c1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccccc3F)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
115 mg of 4-(2-fluorophenyl)-2,3-dihydro-1H-indole (diluted in 3 ml of pyridine) and 125 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 211 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 3 ml of pyridine. The reaction mixture is stirred at ambient temperature for 3 days. The reaction medium is diluted in ethyl acetate (100 ml) and then successively washed with an aqueous 1N hydrochloric acid solution, an aqueous 1N sodium hydroxide solution and a saturated aqueous sodium chloride solution. The organic phase is then dried over magnesium sulfate, filtered through sintered glass, and concentrated under reduced pressure. 187 mg of 2-{2-[4-(2-fluorophenyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=O.Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].N1C=CC=CC=1>C(O)C>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][N:23]=[C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=2)[CH3:1])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(C)=O)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(C)=NOCc2ccc([N+](=O)[O-])cc2)cc1F
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A solution of 3-fluoro-4-methoxyacetophenone (0.064 g, 0.380 mmol), O-(4-nitrobenzyl)hydroxylamine hydrochloride (0.111 g, 0.552 mmol) and pyridine (0.14 ml, 1.73 mmol) in ethanol (7 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a yellow oil which was diluted with water/dichloromethane. The suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a yellow oil. The crude product was purified by column chromatography (SiO2), eluting with 9:1 petrol/ethyl acetate, to give a yellow oil which was triturated with petrol, and the resultant off white solid was further washed with petrol to give 3′-fluoro-4′-methoxyacetophenone-O-4-nitrobenzyloxime (CP9-123) as a white solid (0.079 g, 65%), m.p. 67-68°.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][B:5]([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[O:4][C:3]1([CH3:13])[CH3:12].[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>O1CCCC1>[CH3:12][C:3]1([CH3:13])[C:2]([CH3:14])([CH3:1])[O:6][B:5]([C:7]2[CH:8]=[N:9][N:10]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:11]=2)[O:4]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.82 g, 30.0 mmol) in tetrahydrofuran (80 mL). This was followed by the addition of NaH (70%) (2.05 g, 85.4 mmol) in portions at 0° C. To this was added SEMCl (6.4 mL, 36.1 mmol) dropwise. The reaction mixture was stirred overnight at room temperature, then quenched with 50 mL of NH4Cl (sat). The aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 7 g (72%) of the title compound as colorless oil.
Reaction SMILES: C[Si](Br)(C)C.[F:6][CH:7]([P:17]([OH:20])(=[O:19])[OH:18])[CH2:8][CH:9]([O:15]C)[C:10]1[N:14]=[CH:13][NH:12][N:11]=1>ClCCl.CCOCC>[F:6][CH:7]([P:17]([OH:20])(=[O:18])[OH:19])[CH2:8][CH:9]([OH:15])[C:10]1[N:14]=[CH:13][NH:12][N:11]=1
Reactant: COC(CC(F)P(=O)(O)O)c1nc[nH]n1
Agent: C[Si](C)(C)Br
Solvent: CCOCC
Solvent: ClCCl
Product: O=P(O)(O)C(F)CC(O)c1nc[nH]n1

Procedure:
A solution of this material in dichloromethane was treated with trimethylsilyl bromide as described in Example 24 to give, after ion-exchange chromatography, 1-fluoro-3-methoxy-3(1,2,4-triazol-3-yl) propane phosphonic acid (Compound No. 46 in Table 1) also as a mixture of diastereoisomers in a ratio of 3:1 or 1:3. NMR(D2O): δ 2.15-2.4(2H,m); 3.25(3H,s); 4.4-4.8(1H,m); 4.85(1H,t); 8.9(1H,2 xs). FAB M/S: MH+ 240. More vigorous deprotection, for example in the presence of iodide ion, will result in ether cleavage to give 1-fluoro-3-hydroxy-3(1,2,4-triazol-3-yl)propane phosphonic acid (Compound No. 45 in Table 1), also as a mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])=[O:10])[CH2:2][CH2:3][CH3:4].[CH2:18]([OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:25][C:12]([CH2:13][CH2:14][C:15]([NH:11][C:9](=[O:10])[O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:16])=[O:17]
Reactant: OCCCCCCO
Reactant: CCCCOCCOC(=O)N1C(=O)CCC1=O
Product: CCCCOCCOC(=O)NC(=O)CCC(=O)OCCCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-butoxyethyloxycarbonylsuccinimide with 1,6-hexanediol under conditions shown in Table 20, butoxyethyl N-{3-(6-hydroxyhexyloxycarbonyl)propionyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 17.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:6][CH:5]=1.Cl.[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:27]2[CH2:28][CH2:29][N:30]([C:3]([C:4]3[CH:9]=[CH:8][C:7]([N:10]4[CH2:14][CH2:13][O:12][C:11]4=[O:15])=[N:6][CH:5]=3)=[O:16])[CH2:31][CH2:32]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1
Reactant: COC(=O)c1ccc(N2CCOC2=O)nc1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)nc1C
Yield: 21.4 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using 6-(2-oxooxazolidin-3-yl)nicotinic acid methyl ester (250 mg) described in Preparation Example 138 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (328 mg) described in Preparation Example 52 after neutralization and conversion to a free form, the title compound (95 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.5 %

Procedure:
Under hydrogen gas atmosphere, a mixture of ethyl N-(2,6-dinitrophenyl)-beta-alaninate (Reference Example 24; 1.39 g, 4.92 mmol), 10% palladium on carbon (50% wet, 280 mg) and tetrahydrofuran (50 mL) was stirred at room temperature for 6 hr. The reaction mixture was filtered and concentrated in vacuo to give the title compound as an oil (1.00 g, 4.50 mmol, 91%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCCN1CCCC1

Procedure:
5-Chloro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide to give the title compound. MS+ve APCI 413 [M++1].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Br[CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=1>C1COCC1>[N:7]1([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: Cc1cc(CBr)ccc1C#N
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(Cn2ccnc2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To the suspension of potassium carbonate (2.16 g, 15.7 mmol) in THF at room temperature was added imidazole (4.27 g, 62.8 mmol). The mixture was stirred at room temperature for 10 minutes then 4-(bromomethyl)-2-methylbenzonitrile (CAS 1001055-64-6) (6.6 g, 31.4 mmol) was added and refluxed for 24 hours. The mixture was then cooled to room temperature. Potassium carbonate was filtered off. The filtrate was concentrated and residue was redissolved in dichloromethane. The dichloromethane phase was washed with water (three times) and then HCl (three times). To the combined HCl phase was added sodium carbonate (solid) and extracted with ethyl acetate. Ethyl acetate phase was washed with water and brine, dried over sodium sulfate and concentrated. Column chromatography (10% methanol/ethyl acetate) gave 4-((1H-imidazol-1-yl)methyl)-2-methylbenzonitrile (3.59 g, 58%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)=[C:15](Cl)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C1COCC1.[CH3:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)=[C:15]([C:39]4[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc3c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc3c2-c2ccc(C)cc2)cc1
Temperature: 70 °C
Yield: 61.2 %

Procedure:
To a stirring solution of 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (41.7 mg, 0.10 mmol) in a 1:1 mixture of THF and methanol (4 mL) at room temperature under argon was added 4-methylphenylboronic acid (40.8 g, 0.30 mmol), PXPd (16.2 g, 0.03 mmol), and K2CO3 (41 mg, 0.3 mmol). The resulting suspension was heated at 70° C. under argon for 10 min. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, water (25 mL) and EtOAc (25 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to obtain 29 mg of the title compound as a white lyophilate. HPLC/MS: retention time=4.36 min, [M+H]+=474. 1H NMR (CDCl3): δ 7.78 (d, J=7.5 Hz, 1H), 7.59 (d, J=7.1 Hz, 2H), 7.50 (d, J=7.1 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 7.09-7.00 (m, 6H), 6.65 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[C:25]([OH:30])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[CH2:52][CH2:53]O>C1COCC1>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[C:25]([O:30][CH2:53][CH2:52][C:46]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=2[Cl:44])[CH:24]=1
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.6 g of triphenylphosphine and 1 g of 4-Bromo-3-hydroxy-benzoic acid methyl ester were dissolved in 15 ml of anhydrous THF. The solution was cooled to 0° C. to 10° C. and a solution of 0.88 ml DEAD in 5 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 0.69 ml 2-(2,4-Dichlorophenyl)-ethanol in 2 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 3 h, then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate/1:1. The filtrate was dried under reduced pressure. The product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/1:1. Yield 2 g.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:41][O:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>ClCCl>[CH3:41][O:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:27]([C:24]2[N:16]3[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]4[CH:9]=[CH:8][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:31][CH:30]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17]3)=[CH:26][CH:25]=2)=[O:28])=[CH:45][CH:44]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (1.0 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.31 g) and 4-methoxy aniline (0.35 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® and the eluate evaporated to dryness to provide the desired title compound (1.0 g) as an off-white amorphous solid.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)OC1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2.C(O)(=O)C>CO>[CH:18]1[C:19]2[C:14](=[C:13]([NH:12][CH:4]3[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]3)[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][N:17]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC(Nc2cccc3cnccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
1,4-Cyclohexanedione monoethylene ketal (6.2 g), 5-amino-isoquinoline (4.3 g), and acetic acid (0.5 ml) were dissolved in methanol (50 ml), and a borane-pyridine complex (4.0 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr, was then cooled to room temperature, and was concentrated. The residue was dissolved in acetic acid-water (1:1, 50 ml), and the mixture was then stirred at 80° C. for 3 hr. The reaction mixture was concentrated to remove a major part of acetic acid. A saturated aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (5.8 g).
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]2([CH2:10][C@@H:9]3[C@@H:5]([CH2:6][C:7](=[O:16])[CH:8]3C(OCC)=O)[CH2:4]2)[O:2]1.[OH-].[Na+].Cl>O.C(O)C>[CH2:18]1[CH2:1][O:2][C:3]2([CH2:4][C@@H:5]3[C@@H:9]([CH2:8][C:7](=[O:16])[CH2:6]3)[CH2:10]2)[O:17]1
Reactant: CCOC(=O)C1C(=O)C[C@H]2CC3(C[C@@H]12)OCCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A solution of 294 mg of (1S,5R,6R,7S)-3,3-ethylenedioxy-7-hydroxy-6-ethoxycarbonylbicyclo [3.3.0]octane (III)' in methylene chloride (2 ml) as prepared in Example 1 was added to a solution of a chromic anhydride-pyridine complex in methylene chloride [prepared from chromic anhydride (688 mg), pyridine (1088 mg) and methylene chloride (18 ml)], and the mixture was stirred at room temperature for 10 minutes. The supernatant was separated, the residue was washed with ether, and the combined organic layer was extracted with 5% aqueous sodium hydroxide solution. The aqueous layer was neutralized with dilute hydrochloric acid and extracted with ether. The organic layer was successively washed with saturated aqueous copper sulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, and concentrated to obtain 92 mg of (1R,5S)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo[3.3.0]octan-3-one. To the thus obtained (1R,5S)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo [3,3,0]octan-3-one were added 20 mg of sodium hydroxide and 0.9 ml of water-ethanol mixed solution (4:1), and the mixture was stirred at 90° C. for 4 hours. After cooling, the reaction mixture was neutralized with dilute hydrochloric acid and extracted with ether. The organic layer was then washed with saturated brine, dried over sodium sulfate, and concentrated to give 42 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[C:9]([C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1occc1Br
Reactant: C#CCCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCC#Cc1ccoc1C=O
Yield: 39 %

Procedure:
Reaction of 3-bromofuran-2-carboxaldehyde (3.86 g, 21.5 mmole, from Example 5) with 1-tridecyne (6.7 g) as described in Example 1 afforded 2.28 g (39% of the title compound after chromatography with dichloromethane on silica. Recrystallisation from petroleum ether [bp 40°-60° C.] afforded material of mp 56°-57° C., νmax 3170, 3120, 2230, 1660, 1420, 1355, 1280 cm-1 ; δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.11-1.67 (18H, m, alkylene chain), 2.40 (2H, t, J 6.3 Hz, CH2C≡C), 6.47 (1H, d, J ca 2 Hz, C-4H), 7.51 (1H, d, J ca 2 Hz, C-5H), 9.71 (1H, s CHO).