Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22](OS(C(F)(F)F)(=O)=O)[C:23]4[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1.Cl>CS(C)=O>[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:23]4[CH2:29][NH:28][CH2:27][CH2:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: Cl
Solvent: CS(C)=O
Product: c1ccc(Nc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CNCC3)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
Aniline (0.017 mL, 0.18 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.1 g, 0.18 mmol, Example 1b) in DMSO (4 mL). The solution was heated in a microwave reactor at 80° C. for 1 h. HCl (2M aq, 1.5 mL) was added and the reaction was stirred in an open vessel at 76° C. for 30 min. The reaction was allowed to cool and DMSO was added to the solution. The product was purified by preparative HPLC to give N2-(4-(oxazol-5-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.017 g, 24%).
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:20][OH:21])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.CC(O)C>CC(C)=O.O>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:20]([OH:24])=[O:21])([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: CC(C)=O
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1CO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of diallyl 2-(hydroxymethyl)-6-methylbenzyl phosphate (1.22 g, 4.02 mmol) obtained from Example 22-(4) in acetone (25 ml) was cooled to 0° C., and Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 6 ml, ca. 16 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and then 2-propanol (1 ml) was added thereto to stop the reaction. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give an oily residue. The residue was dried using a vaccum pump, and then subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:dichloromethane=1:1) to afford the title compound (905.3 mg, 71% yield) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].Cl.[N:11]([O-])=[O:12].[Na+]>O>[N:11]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:12]
Reactant: O=C(O)C1COCCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCOCC1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 142.6 %

Procedure:
To a solution of morpholine-3-carboxylic acid (6.96 g, 52 mmol) in water (20 ml), at 0° C. under nitrogen, was added concentrated hydrochloric acid (4 ml), followed by sodium nitrite (5.0 g, 72 mmol) in small portions. The mixture was stirred at 0° C. for 1 hr, and then concentrated under vacuum at 30 to 35° C. The residue was stirred with 200 ml of acetone and filtered. The filtrate was evaporated and the residue treated with 50 ml of THF and concentrated. The process was repeated with 2×50 ml of THF to give 11.87 g of light yellow foam; MS (ESI) m/z 159.2 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3-fluorophenol: 1H-NMR (CDCl3) δ 7.91 (1H, d, J=2.8 Hz), 7.46 (1H, dd, J=8.7, 2.8 Hz), 7.31–7.06 (1H, m), 6.99 (1H, d, J=8.7 Hz), 6.83–6.61 (3H, m), 3.81 (3H, s).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:6]=1)([CH3:3])[CH3:2].CO.[OH-].[Na+]>O1CCCC1>[CH:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(OC)c(OC(C)C)cc1NCc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2cc(OC(C)C)c(OC)cc2C(=O)O)cc1
Yield: 99.1 %

Procedure:
A mixture of methyl 4-isopropoxy-5-methoxy-2-(4-methoxybenzyl)aminobenzoate (18.9 g), methanol (50 ml), tetrahydrofuran (150 ml) and a 1N aqueous sodium hydroxide solution (80 ml) was stirred at room temperature for 1 night, heated under reflux for 12 hours. The solvent was distilled off under reduced pressure, the reaction mixture was adjusted to about pH 6 by adding 1N hydrochloric acid and 5% citric acid. The precipitated solid was collected by filtration, washed and dried to obtain the target compound (18.0 g).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=C1)[CH2:7]3.[C:11]([O-:14])([O-])=O.C([O-])([O-])=[O:16].OO.OO.OO.[Na+].[Na+].[Na+].[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:7]1[CH:6]2[CH:10]3[O:16][CH:9]3[CH:8]1[CH:4]1[CH:5]2[CH:1]2[O:14][CH:11]2[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C1C2OC2C2C1C1CC2C2OC12
Temperature: 60 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
Dicyclopentadiene (1.32 g, 10 mmol) was dissolved in toluene (25 ml), and a composition containing sodium percarbonate (10.5 g, 66.7 mmol) and acetic anhydride (10.2 g, 100 mmol) was added thereto. The mixture was stirred at 60° C. After 12 hours, the reaction solution was washed with water to thereby completely remove acetic acid and sodium acetate, which were generated as by-products, and the remaining H2O2. Toluene was distilled off from the organic phase by distillation, and as a result, 1.62 g (99% yields) of dicyclopentadiene diepoxide with a GC purity of 100% was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]4=[CH:45][CH:46]=[CH:47][CH2:48][CH:43]4[NH:42][CH2:41]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]3[C:44]4=[CH:45][CH:46]=[CH:47][CH2:48][CH:43]4[NH:42][CH2:41]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-7-[4-(tetrahydrobenzimidazol-1-yl)-butyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[S:8].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:20]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[S:8])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1cc(-c2ccccc2)n(COCCO)c(=S)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(OCCOCn1c(-c2ccccc2)cc(=O)[nH]c1=S)c1ccccc1
Yield: 88.9 %

Procedure:
An amount of 294 mg (1 mmol) of 1-[(2-hydroxyethoxy)methyl]-6-phenylthiouracil was dissolved in 5 ml pyridine. To this solution 0.17 ml (1.5 mmol) of benzoyl chloride was added and the reaction mixture was allowed to react at room temperature for 2 hours. After the reaction, it was distributed between ethyl acetate and aqueous layers, and the said ethyl acetate layer then concentrated to dryness. The residue was crystallized from toluene to obtain 340 mg of 1-[(2-benzoyloxyethoxy)methyl]-6-phenylthiouracil (Yield: 85%). This was then suspended in 5 ml of toluene, and to this solution 449 mg (1.11 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4 diphosphetane-2,4-disulfide was added and the reaction mixture was allowed to react at 100° C. for 3 hours. After the reaction, the reaction mixture was distributed between ethyl acetate and aqueous layers, the ethyl actate layer concentrated to dryness. The residue was dissolved in 2 ml of tetrahydrofuran and 5 ml of ethanol. To this solution 2.25 ml of 1N sodium hydroxide aqueous solution was added and the reaction mixture was allowed to react at room temperature for 1 hour. It was then neutralized with hydrochloric acid, and concentrated to dryness. The residue was distributed between ethyl acetate and aqueous layers, and the said ethyl acetate layer was then concentrated to dryness. The resultant was dissolved in a small amount of chloroform, adsorbed on a silica gel column and eluted with 2.5% methanol/chloroform. The eluate was concentrated and dried to obtain a residue, which was crystallized from toluene to obtain 141 mg of the target compound (Yield: 53%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:12]#[C:11][CH2:10][CH2:9][OH:13])[CH:5]=[CH:4][N:3]=1
Reactant: C#CCCO
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,4-Dicloropyrimidine (4.47 g, 0.03M) was dissolved in triethylamine (250 ml) under argon. (Ph3P)2PdCl2 (420 mg, 0.006M, CuI (28 mg, 0.00015M) and 3-butyn-1-ol (2.36 ml, 0.03M) were added and the mixture was stirred at ambient temperature for 18 hrs. After evaporation to dryness, water (250 ml), was added and extracted with dichloromethane. The combined organic phases were dried and evaporated to dryness. The residual oil was chromatographed, eluting with iso-hexane/ethyl acetate 1:1 to yield 4-(2 chloro-4-pyrimidyl)-3-butyn-1-ol as an oil (3.3 g) NMR (CDCl3) d, 8.5, (d, 1H); 7.3, (d, 1H); 3.9, (t, 2H); 2.8, (m, 2H); 1.6, (s, 1H). Mass Spec found MH+ 183. This material was hydrogenated as described above, but in the presence of 1 equivalent of triethylamine, to give the required saturated alcohol which was oxidised using the previously described Swem oxidation to give the required 4-(4-pyrimidyl)-butan-1-al. NMR CDCl3 d, 9.8, (s, 1H); 9.1; (s, 1H); 8.5, (d, 1H); 7.1, (d, 1H); 2.8, (t, 2H); 2.5, (t, 2H); 2.1, (m, 2H). Mass spec found MH− 149. 3-(5-fluoropyrimidin-2-yl)propanal. To a stirred solution of (E)-1-ethoxy-3-(5-fluoropyrimidin-2-yl)prop-2-enyl ethyl ether and (Z)-1-ethoxy-3-(5-fluoropyrimidin-2-yl)prop-2-enyl ethyl ether (9.7 g, 43 mmol) in dry ethanol (100 ml) at room temperature under an atmosphere of argon, was added 10% palladium on activated charcoal (1.0 g). The reaction flask was then evacuated and filled with hydrogen gas. The mixture was then stirred for 18 hours at room temperature. The reaction was then filtered through a pad of celite and evaporated under reduced pressure to give a yellow oil (8.7 g, 89%). To a solution of this oil (15 g, 66 mmol) in THF (200 ml) at room temperature was added an aqueous solution of hydrochloric acid (36 ml of a 2M solution, 72 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was then diluted with ethyl acetate (100 ml) and the pH of the mixture brought to pH=9 by the addition of aqueous sodium hydrogen carbonate solution (saturated, 100 ml). The layers were then separated and the aqueous phase extracted with ethyl acetate (3×100 ml). The combined organic extracts were then dried (Na2SO4), filtered and evaporated under reduced pressure to give 3-(5-fluoropyrimidin-2-yl)propanal (16 g) which was used without further purification. 1H NMR (CDCl3): 9.90 (s, 1 H), 8.50 (s, 2 H), 3.33 (dd, 2 H, J=6.9, 6.9 Hz), 3.00 (dd, 2 H, J=6.9, 6.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10]([N:12]([CH2:24][CH3:25])[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH3:11]>[N+](C1C=CC=CC=1)([O-])=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:20]([C:19]3[CH:22]=[CH:23][C:16]([O:15][CH2:14][CH2:13][N:12]([CH2:24][CH3:25])[CH2:10][CH3:11])=[CH:17][CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)CCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
3.31 g 5-bromo-2,3-diaminopyridine and 3.90 g 4-(2-diethylamino-ethoxy)benzaldehyde in 120 ml nitrobenzene were heated to 140-150° C. for 24 hrs. The solvent was removed by vacuum distillation. The residue was dispersed in ethyl acetate and the crude product was isolated by filtration and washed thoroughly with more ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:2]([NH2:1])[CH:7]=1)[CH3:20]
Reactant: Nc1cc(CC(=O)[O-])ccc1-c1ccccc1
Reactant: CCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium 2-amino-4-biphenylacetate is dissolved in dimethylformamide and the solution treated with ethyliodide. The solution is stirred at room temperature for about 3 hours, the solution added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate, concentrated and crystallized to give ethyl-2-amino-4-biphenylacetate.
Reaction SMILES: [F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[CH2:13](O)[CH3:14].C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: CCO
Reactant: CC(C)CC(O)C(F)(F)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 84.9 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 20 g of ethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 20 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried, and concentrated, obtaining 24.5 g (yield 85%) of crude ethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(OCC)C.[OH:10][CH2:11][C:12]1[N:24]2[C:15]([C:16]3[CH:17]=[C:18]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]([C:25]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=4)=[N:20][C:21]=3[CH:22]=[CH:23]2)=[N:14][N:13]=1.B(F)(F)F.CCOCC>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:30][C:29]1([C:28]2[CH:31]=[CH:32][C:25]([C:19]3[C:18]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:17][C:16]4[C:15]5=[N:14][N:13]=[C:12]([CH2:11][OH:10])[N:24]5[CH:23]=[CH:22][C:21]=4[N:20]=3)=[CH:26][CH:27]=2)[CH2:2][CH2:1]1
Reactant: N#Cc1ccc(-c2nc3ccn4c(CO)nnc4c3cc2-c2ccccc2)cc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(c2ccc(-c3nc4ccn5c(CO)nnc5c4cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethylmagnesium bromide in diethyl ether (0.4 mL, 1.2 mMol, 3M) was added at −70° C. to a solution of 15-1 (0.1 g, 0.3 mmol) and titanium (IV) isopropoxide (0.17 g, 0.6 mMol) in anhydrous THF (7 mL). After 10 min, the cold bath was removed and the reaction was warmed to room temperature. After stirring for 1 hour, more ethylmagnesium bromide in diethyl ether (0.18 mL, 0.5 mMol, 3M) was added and the reaction was cooled to 0° C. in an ice bath and was treated with boron trifluoride etherate (0.18 g, 1.2 mMol). The reaction was stirred at 0° C. for 30 minutes then warmed to room temperature for 1 hour. The reaction was quenched with 1N HCl followed by stirring for 3 hours. The solution was basified with 1M NaOH, extracted with chloroform, dried with Na2SO4, filtered and concentrated in vacuo. Crude residue was taken up in methanol and purified using a C18 reverse phase HPLC to give 15-2 as a solid. LC/MS (M+1) calculated: 408.4; observed: 408.0
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]([CH2:20][O:21][CH3:22])[C:18]2[C:23]([CH:30]=O)=[C:24]([C:26]([O:28][CH3:29])=[O:27])[S:25][C:17]=2[C:16]=1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)C1C=CC=CC=1>CCOC(C)=O>[CH:32]1([C:16]2[C:17]3[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH3:30])[C:18]=3[N:19]([CH2:20][O:21][CH3:22])[C:15]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COCn1c(-c2ccccc2OCc2ccccc2)c(C2CCCCC2)c2sc(C(=O)OC)c(C=O)c21
Solvent: CCOC(C)=O
Product: COCn1c(-c2ccccc2O)c(C2CCCCC2)c2sc(C(=O)OC)c(C)c21
Reaction time: 48 h

Procedure:
Methyl 5-[2-(benzyloxy)phenyl]-6-cyclohexyl-3-formyl-4-(methoxymethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate was dissolved in EtOAc and the solution was degassed. Pd/C was added and after degassing again hydrogen atmosphere (60 psi) was applied. After hydrogenating for 2 days the catalyst was filtered off and all volatiles were evaporated i. vac. An off-white solid was obtained (89%). MS (ES+) m/z 414 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=2)[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH:21]=2)=[O:17])[CH2:7][CH2:6]1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Br:1][C:2]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=2)[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=2)=[O:17])[CH2:9][CH2:10]1
Reactant: COc1ccc(Br)c(CC2CCN(CCc3cccc(C(=O)NCc4cccc(CO[Si](C)(C)C(C)(C)C)c4)c3)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CC2CCN(CCc3cccc(C(=O)NCc4cccc(CO)c4)c3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
In tetra-n-butylammonium fluoride (a 1.0M THF solution, 5 mL, 5.0 mmol) was dissolved 3-{2-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]ethyl}-N-[3-(tert-butyldimethylsiloxymethyl)benzyl]benzamide (389 mg, 0.584 mmol), and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was purified by the use of a silica gel column (silica gel 30 mL; ethyl acetate˜ethyl acetate/triethylamine=10/1) to obtain the desired compound (235 mg, 73%) as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14](OC)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8]1>CCOCC>[N:7]1([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=[CH:8]1
Reactant: COC(=O)c1ccccc1-n1cccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccccc1-n1cccc1
Temperature: 25 °C

Procedure:
To a suspension of 117 g of lithium aluminum hydride in 2 L of anhydous ether (under an inert atmosphere) is added dropwise a solution of 428 g of methyl 2-(pyrrol-1-yl)-benzoate in 1.5 L of ether over a period of 4 hours. The reaction mixture is then heated at reflux temperature for an additional 4 hours and then allowed to cool to room temperature. After cooling in an ice-bath, the excess lithium aluminum hydride is destroyed by the dropwise addition of 117 ml of water over 1 hour, followed by dropwise addition of 117 ml of 15% sodium hydroxide and subsequent addition of 351 ml of water over a 30 minute period. The resultant granular solid is separated by filtration, the ether layer is then dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield 2-(pyrrol-1-yl)-benzyl alcohol which may be further purified by distillation in vacuo; b.p. 110°-114°/0.1 mm Hg.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (315 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (717 mg, yield: 91%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).