Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].C[C:11](C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:12][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCC=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: C=CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Crude 7-octenal (30.5 g) (90.0% in gas chromatography simple area %, net: 27.5 g, 0.22 mol; cis-6-octenal: 4.7% in gas chromatography simple area %, and trans-6-octenal: 4.5% in gas chromatography simple area %) was dissolved in 95% by mass acetone aqueous solution (300.0 g). After adding Jones reagent (3M chromic acid-sulfuric acid aqueous solution) (100.0 mL) and stirring at room temperature for 2 hours, isopropanol (20.0 g) was added thereto. After the precipitate was filtered off and acetone was distilled off from the filtrate, the filtrate was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and saturated sodium chloride solution, the solvent was distilled off to obtain a crude product. Subsequently, this product was dissolved in methanol (300.0 g). After adding p-toluenesulfonic acid mono hydrate (3.0 g) thereto, the solution was heated at 60° C. for 2 hours. The solution was extracted with ethyl acetate, and the organic layer was washed with water and sodium carbonate aqueous solution. After that, the organic layer obtained by distilling off the solvent was distilled under a reduced pressure of 500 Pa. With this procedure, crude methyl 7-octenoate (34.3 g) (90.0% in gas chromatography simple area %, net: 30.9 g, net: 0.20 mol, yield: 91%; cis-6-octenonitrile: 4.7% in gas chromatography simple area %, and trans-6-octenonitrile: 4.5% in gas chromatography simple area %) was obtained as a distillate.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:25](Br)[CH:26]([CH3:28])[CH3:27]>O>[CH3:25][CH:26]([CH3:28])[CH2:27][C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(CC(C)C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium hydride (21 gram, 0.482 mole) was added to 200 ml dimethylformamide at 20° C. under nitrogen atmosphere. Then 80 grams (0.325 mole) of triethyl ethane-1,1,2-tricarboxylate (compound [3] made in example I) was added to the solution at a temperature of below 30° C. The reaction mixture was maintained at room temperature for 4 hours and 52 ml (0.482 mole) of isobutyl bromide (R2-X) was added drop wise after which the reaction mixture was stirred for another 20 hours at room temperature. When the reaction was complete 1 liter of cold water was added and the organic materials were extracted with dichloromethane (500 ml). The organic extracts were dried over sodium sulfate filtered and evaporated to give an oily substance, which was vacuum distilled to give 88 gram (89% of the theoretical maximum yield) triethyl 4-methylpentane-1,2,2-tricarboxylate, compound [4].
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>C(Cl)Cl.CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[O:21])=[CH:15][CH:14]=1
Reactant: OCCc1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of pyridinium chlorochromate (6.9 g, 21.4 mmol) in CH2Cl2 (100 ml) was added a solution of 2-(4-fluorophenyl)ethanol (3.0 g, 21.4 mmol) in CH2Cl2 (10 ml). The resulting suspension was stirred for 2 hours at room temperature and was then diluted with ether. The resulting suspension was filtered through a pad of Celite and washed with ether.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)=[O:22]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)c1
Reaction time: 5 h

Procedure:
A microwave vial was charged N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 650 mg, 2.02 mmol), 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 403 mg, 2.22 mmol) and DIPEA (1058 μl, 6.06 mmol) in dry DMSO (6.7 ml). The reaction was subjected to microwave irradiation at 120° C. for 2 hours and then at 140° C. for 5 hours. Upon cooling the mixture was partitioned between ethyl acetate and water, washing with water and brine, dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then further purified by column chromatography (basic silica 0-100% DCM/petrol) to afford the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[C:16]([CH2:18][C:19]([OH:21])=[O:20])#[N:17].N1C=CC=CC1=O>C1(C)C=CC=CC=1.O>[C:16]([C:18](=[CH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:19]([OH:21])=[O:20])#[N:17]
Reactant: COc1ccc(C=O)cc1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: O=c1cccc[nH]1
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(C#N)C(=O)O)cc1

Procedure:
A stirred mixture of p-anisaldehyde (60.7 ml), ammonium acetate (7.5 g), cyanoacetic acid (42.5 g), pyridone (70 ml) in toluene (390 ml) is refluxed using a Dean Stark trap until about 9 ml of water is collected. The reaction mixture is cooled and the solid precipitate filtered and stirred with 10% aqueous HCL. The solid is filtered and recrystallized from methanol yielding the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[N:5][N:6]=1.[C:14]([C:21](OCC)=[O:22])#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:8]([N:7]([CH2:11][CH2:12][CH3:13])[C:4]1[S:3][C:2]2=[N:1][C:21](=[O:22])[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:6]2[N:5]=1)[CH2:9][CH3:10]
Reactant: CCCN(CCC)c1nnc(N)s1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCCN(CCC)c1nn2c(C(=O)OCC)cc(=O)nc2s1

Procedure:
The procedure used was as in Example 5. However, there were reacted 10 g of 2-amino-5-[di-(n-propyl)amino]-1,3,4-thiadiazole and 8.5 g of diethyl acetylenedicarboxylate in the presence of 200 ml of ethanol to give 10.2 g (63% of the theoretical yield) of ethyl 2-[di-(n-propyl)amino]-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylate, melting at 95°-97° C.
Reaction SMILES: C1N(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:51](C(OC(C)(C)C)=O)[C@H:52]([C:57]([O:59]C(C)(C)C)=[O:58])[CH2:53][CH2:54][CH2:55][NH2:56]>C(Cl)Cl>[NH2:51][C@H:52]([C:57]([OH:59])=[O:58])[CH2:53][CH2:54][CH2:55][NH2:56]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCCC[C@H](N)C(=O)O
Reaction time: 1 h

Procedure:
DOTA (1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid) 0.5 mmol and 1.5 mmol of triethylamine were dissolved in 10 ml DCM. 0.6 mmol of DCC was dissolved in 5 ml DCM and added to the mixture. The reaction was carried out for 1 hour at room temperature. The white crystals that appeared in the mixture were filtered out. 0.5 mmol of solid BOC-Orn-OtBu was added to the reaction. The reaction was carried out for 20 hours at room temperature. The mixture was filtered and the DCM was evaporated. The product was washed several times with ethanol and air-dried. Cleavage of the protecting groups (BOC, OtBu) was carried out in 1 ml TFA+5% water for 3 hours. The acid was evaporated in a vacuum over a KOH pellet. The final product, L-Orn(DOTA), was washed several times with diethyl ether and dried. The product was dissolved in water and lyophilized.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[NH:10][C:11]([Br:17])=[C:12]([N+:14]([O-:16])=[O:15])[N:13]=1.Cl[CH2:19][O:20][CH3:21]>O>[Br:8][C:9]1[N:10]([CH2:19][O:20][CH3:21])[C:11]([Br:17])=[C:12]([N+:14]([O-:16])=[O:15])[N:13]=1
Reactant: COCCl
Reactant: O=[N+]([O-])c1nc(Br)[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1c(Br)nc([N+](=O)[O-])c1Br
Reaction time: 5 h
Yield: 84.3 %

Procedure:
Under an ice-cooling condition, sodium hydride (3.56 g) was added to a N,N-dimethylformamide (100 ml) solution of 2,5-dibromo-4-nitroimidazole (20.08 g). 10 minutes later, being added dropwise chloromethylmethyl ether (6.75 ml) thereto at 10 to 15° C., then the reaction mixture was turned back to a room temperature. After being stirred this reaction mixture for 5 hours, under an ice-cooling condition, sodium hydride (0.30 g) and chloromethylmethyl ether (0.56 ml) were added, further stirred at a room temperature for 1 hour. Then the reaction mixture was ice-cooled, water was added and extracted with ethyl acetate. The organic layer was washed with an aqueous solution being saturated with sodium chloride, dried over anhydrous sodium sulfate, then concentrated under a reduced pressure. Thus obtained crude crystals were washed with diisopropyl ether, and dried at 50° C. for 24 hours, there was obtained 2,5-dibromo-1-methoxymethyl-4-nitroimidazole (19.68 g, yield: 84.3%) as yellow powder product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([S:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(Cl)([Cl:28])=O.[CH3:30]O>>[ClH:28].[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][S:20][C:11]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([O:3][CH3:30])=[O:2])=[CH:5][CH:6]=2)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: CN(C)CCSc1nc2ccccc2cc1-c1ccc(C(=O)O)cc1
Reactant: CO
Product: COC(=O)c1ccc(-c2cc3ccccc3nc2SCCN(C)C)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(p-Carboxyphenyl)-2-(2-dimethylaminoethylthio)quinoline (0.7 g.) was added to a solution of thionyl chloride (1.5 ml.) in methanol (20 ml.) at 0°. The mixture was stirred at ambient temperature for 16 hr., and the solvent then evaporated. The solid residue was crystallised from methanol-ethyl acetate to give 2-(2-dimethylaminoethylthio)-3-(p-methoxycarbonylphenyl)quinoline hydrochloride, m.p. 224-5°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C:9]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)([C:11]1[CH:12]=[N:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)[CH3:10].C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:8][C:9]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)([C:11]1[CH:12]=[N:13][NH:14][CH:15]=1)[CH3:10]
Reactant: COC(=O)c1ccc(C(C)(O)c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)(O)c2cn[nH]c2)cc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
TFA (0.1 mL) in DCM (2 mL) were added dropwise to a mixture of methyl 4-[1-hydroxy-1-(1-trityl-1H-pyrazol-4-yl)ethyl]benzoate (0.2 g, 0.8 mmol), triethylsilane (0.2 mL) in DCM (5 mL) cooled to −40° C. Then the mixture was stirred at −40° C. for 2 hours. The mixture was adjusted to pH 7 by adding aqueous sodium bicarbonate solution at −40° C. After the reaction warmed to room temperature, the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by preparative thin layer chromatography to afford methyl 4-[1-hydroxy-1-(1H-pyrazol-4-yl)ethyl]benzoate. MS ESI calc'd. for C13H15N2O3 [M+H]+ 247. found 247. 1H NMR (400 MHz, CD3OD): δ 7.98 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (s, 2H), 3.90 (s, 3H), 1.89 (s, 3H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:11][CH:12]([Cl:16])[CH2:13][CH2:14][CH3:15]>C(O)C>[Cl:16][CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2]
Reactant: CCCC(Cl)CBr
Reactant: Sc1ccccc1Br
Agent: [Na]
Solvent: CCO
Product: CCCC(Cl)CSc1ccccc1Br
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 23.0 g of sodium metal is 500 ml of absolute ethanol is added, in about 0.5 hour, a solution of 173.0 g of o-bromothiophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hour, cooled to 0°, and treated, dropwise, with 185.5 g of 1-bromo-2-chloropentane. The addition requires about 1 hour. The mixture is stirred for about 2 hours at 0°, warmed slowly to reflux, and then heated under reflux for 2 hours. The mixture is filtered and the filtrate concentrated in vacuo at 40° to give about 255.7 g of o-bromophenyl 2-chloro-1-pentyl sulfide as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)C(OC)=O)[CH2:10]2)=[CH:4][CH:3]=1.[CH3:33][Li].C([O:37][CH2:38][CH3:39])C>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:38]([CH3:39])([OH:37])[CH3:33])[CH2:10]2)=[CH:31][CH:30]=1
Reactant: CCOCC
Reactant: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: [Li]C
Product: CC(C)(O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.15 g (2.43 mmol) of methyl {1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate (Preparation 5) in 10 mL of dry ethyl ether was cooled to −78° C. under nitrogen. Dropwise, 3.1 mL of a 1M solution of methyllithium in ether was added. After 30 minutes, another 3.1 mL of the 1M solution of methyllithium in ether was added dropwise and the solution was stirred at −78° C. for 30 min. The reaction was quenched by addition of water and the mixture was partitioned between ether and water. The aqueous extract was washed with ether and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography on a Waters RCM column (5 micron silica gel, 20 mm×10 cm) using a 2:1 mixture of hexane and 5:4:1 hexane-methyl tert-butyl ether-acetonitrile. Homogenous fractions were pooled and concentrated to afford the title compound; 1NMR (CDCl3) δ 1.35 (s, 3H), 3.49 (m, 2H), 4.09 (m, 2H), 4.46 (s, 1H), 6.68 (m, 1H), 6.70 (m, 1H), 7.26 (m, 4H), 7.34 (m, 4H); Mass Spectrum: m/e=474 (M+1 35Cl, 35Cl) and 476 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[O-:27][C:28]#[N:29].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(Cl)Cl>[CH2:8]([NH:29][C:28]([O:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][OH:7])=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: N#C[O-]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(CO)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)OC
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A suspension of 2.12 g (20 mmol) of 2-methoxy-1,3-propanediol 7.99 g (24 mmol) of octadecyl bromide, 2.43 g (30 mmol) of potassium cyanate and 1.29 g (4 mmol) of tetrabutyl ammonium bromide in 100 ml of dry acetonitrile was refluxed with stirring, at 100° C. for 24 hours. The resultant mixture was then diluted with hot methylene chloride, filtered and the filtrate concentrated in vacuo. The crude product was then purified by flash silica gel chromatography employing a mixture of petroleum ether and ethyl acetate in a 4:1 ratio as the eluent to yield the title compound as a solid, m.p. 56°-58° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]([OH:8])=O.[NH2:18][C:19]1[C:24](O)=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.C[Si](OP(=O)=O)(C)C.C([O-])(O)=O.[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][C:24]3[CH:23]=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=3[N:18]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2nc3cc(C)ccc3o2)ccc1-c1ccccn1

Procedure:
3-Methoxy-4-pyridin-2-yl benzoic acid (490 mg, 2.1 mmol), 2-amino-p-cresol (527 mg, 4.28 mmol) and trimethylsilyl polyphosphate (2 mL) was refluxed overnight under argon. Added water (100 mL) to the cooled reaction mixture and basified to pH 8 (solid NaHCO3). Extracted with EtOAc (3×60 mL), dried (Na2SO4) and concentrated in vacuo. The resulting yellow residue was purified by flash chromatography using a gradient elution of 1:9 EtOAc:hexanes to 1:4 EtOAc:hexanes to give the desired compound, 2-(3-methoxy-4-pyridin-2-ylphenyl)-5-methyl-1,3-benzoxazole, as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.74 (m, 1H), 7.98–7.16 (m, 10H), 4.03 (s, 3H), 2.51 (s, 3H). (ESI) 317 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1(S(N2C3N=CN=C([Cl:37])C=3C(I)=C2)(=O)=O)C=CC=CC=1.ClC1C=CC(B(O)O)=CC=1.[NH2:49][C:50]1[CH:51]=[C:52]([C:56]#[CH:57])[CH:53]=[CH:54][CH:55]=1>>[Cl:37][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:49][C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([C:56]#[CH:57])[CH:51]=4)=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(Cl)ncnc21
Reactant: COc1ccc(-c2c[nH]c3ncnc(Cl)c23)cc1
Reactant: C#Cc1cccc(N)c1
Agent: OB(O)c1ccc(Cl)cc1
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(-c4ccc(Cl)cc4)c23)c1
Yield: 33 %

Procedure:
Following the procedure described in Example 26, 4-chloro-[5-(4-methoxy-phenyl)]-7H-pyrrolo[2,3-d] pyrimidine, the intermediate, was made in 74% yield from 7-benzenesulfonyl-4-chloro-5iodo-7H-pyrrolo[2,3-d]pyrimidine and 4-chloro benzene boronic acid: TS-MS: 260 (MH+). The title compound was synthesized by coupling the intermediate with m-aminophenyl acetylene in 33% yield: MP: 225-227° C.; TSMS: 398 (MH+); anal. RP18-HPLC RT=6.45 minutes.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:13][C:14]3[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=3[O:22][CH3:23])[C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[O:24]1CCCOB1[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[C:19]([O-:20])(=[O:24])[CH3:14].[CH3:23][O:22][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[CH2:13][N:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:3][CH:4]=2)[N:9]=[C:8]1[NH3+:12]
Reactant: COc1cccc(OC)c1CN1Cc2ccc(Br)cc2N=C1N
Reactant: c1cncc(B2OCCCO2)c1
Product: CC(=O)[O-]
Product: COc1cccc(OC)c1CN1Cc2ccc(-c3cccnc3)cc2N=C1[NH3+]

Procedure:
Synthesis was performed according to EXAMPLE 82 from 7-bromo-3-(2,6-dimethoxybenzyl)-3,4-dihydroquinazolin-2-amine and 3-[1.3.2]-dioxaborinan-2-ylpyridine in a CEM microwave at 100° C. (120 watt) for 120 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:37])[CH:14]([CH2:18][S:19]([N:22]1[CH2:34][CH2:33][C:32]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:35][CH3:36])[CH:30]=3)[NH:25][C:24]=2[CH2:23]1)(=[O:21])=[O:20])[CH:15]([CH3:17])[CH3:16])(C)(C)C.ClCCl.CO>ClCCl>[CH3:36][O:35][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]1[CH2:23][N:22]([S:19]([CH2:18][CH:14]([CH:15]([CH3:17])[CH3:16])[C:13]([OH:37])=[O:12])(=[O:21])=[O:20])[CH2:34][CH2:33][C:32]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)OC(C)(C)C)C(C)C)C3
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)O)C(C)C)C3
Reaction time: 2 h
Yield: 62 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 2-(6-methoxy-1,3,4,9-tetrahydro-β-carboline-2-sulfonylmethyl)-3-methyl-butyric acid tert-butyl ester (237 mg) in dichloromethane (10 ml) at room temperature under nitrogen. The mixture was stirred for 2 h before being evaporated under reduced pressure. The residue was partitioned between 1M aqueous sodium hydroxide (15 ml) and diethyl ether (15 ml). The organics were extracted with 1M aqueous sodium hydroxide (15 ml). The combined aqueous portions were acidified to pH=5 with 10% citric acid and extracted with ethyl acetate (4×20 ml). The combined organics were washed with water (2×10 ml) and brine (10 ml), then dried (MgSO4), filtered and the solvent removed under reduced pressure to give, after chromatography (SiO2, 20:1 dichloromethane-methanol), the title compound (128 mg, 62%) as a white foam.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)#[N:30].CC(O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O>[C:29]([CH:31]1[CH2:36][CH2:35][N:34]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:33][CH2:32]1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.09 g (27.3 mmol) of NaBH(OAc)3 were added batchwise to a suspension, cooled to 0° C., of 5.44 g (27.3 mmol) tert.butyl 4-oxo-piperidin-1-carboxylate, 3.00 g (27.2 mmol) 4-cyanopiperidine and 1.6 mL (28.0 mmol) AcOH in 400 mL DCM and the reaction mixture was stirred overnight, while warming up to RT. 400 mL water were added and the mixture was acidified with citric acid. The organic phase was separated off, the aqueous phase was made alkaline with saturated NaHCO3 solution and extracted exhaustively with DCM. The combined organic phases were concentrated by evaporation i. vac. and the residue was crystallised with a little DIPE.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:24][C:25]([OH:30])([CH2:27][C:28]#[CH:29])[CH3:26]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:29]#[C:28][CH2:27][C:25]([CH3:26])([OH:30])[CH3:24])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: C#CCC(C)(C)O
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#CCC(C)(C)O)c3c(Cl)nc(N)nc32)c1C

Procedure:
Sonogashira coupling of 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidin-2-amine with 2-methylpent-4-yn-2-ol (H. Zhang et al., Tetrahedron Lett. 1999, 40, 7851) according to the general procedure A gave the title compound, as a solid. Mp=163-165° C. HPLC Rt=4.98 min.