Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:22]=[CH:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32OCC[O:24]3)[CH2:6]1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[C:1]([O:4][C@H:5]1[CH:22]=[CH:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C=C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23OCCO3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)O[C@H]1C=C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
Ketal 5 (0.44 g) from Example 1 was dissolved in acetone-water (30 ml, 8:2), and treated with toluene-p-sulfonic acid monohydrate (0.1 g). After the mixture had been stirred at room temperature for 16 hr it was concentrated to half of its volume and diluted with a cold half saturated sodium bicarbonate solution. The solution was cooled, filtered to give white solid compound (0.38 g, 98%), which was further crystallized from methanol. M.p. 185-87° C., purity 99% (LC-MS).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4](=[O:21])[CH:5]2[CH2:20][C:8]3([C:19]=1[C:18]1[CH:17]=[CH:16][C:15]4[NH:14][N:13]=[CH:12][C:11]=4[C:10]=1[CH2:9]3)[CH2:7][CH2:6]2>C(O)C.CO>[F:22][C:2]([F:1])([F:23])[C:3]1[C:4](=[O:21])[C@H:5]2[CH2:20][C@@:8]3([C:19]=1[C:18]1[CH:17]=[CH:16][C:15]4[NH:14][N:13]=[CH:12][C:11]=4[C:10]=1[CH2:9]3)[CH2:7][CH2:6]2
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3CC23CCC1C3
Solvent: CO
Solvent: CCO
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3

Procedure:
Racemic (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one (260 mg) was dissolved in ˜4/1 ethanol/methanol and resolved by chiral HPLC on a 2.0×25 cm Daicel Chiralcel OJ column (elution with 25% EtOH:Heptane at 7.5 mL/min, fractions monitored at 340 nm). The fractions containing the first enantiomer to elute (enantiomer A) were combined and concentrated to a clear oil which had a positive rotation. The pure fractions containing the second enantiomer to elute (enantiomer B) were combined, concentrated, and lyophilized from benzene to give (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a -methanoazuleno[2,1-e]indazol-7(8H)-one as a white solid which had a negative rotation.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[O:15].[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](O)=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)Cl.CN1C(=O)CCC1.O>[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:5][CH2:6][CH2:7][CH2:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]4=[O:15])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1
Reactant: O=c1ccccn1CCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1ccccc1=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
Thionyl chloride (0.55 ml, 7.5 mmol) was added to a solution of 1-(3-hydroxypropyl)-1,2dihyro-2-pyridone (770 mg, 5 mmol) in trichloromethane (1 5 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then at ambient temperature for 2 hours. The volatiles were removed by evaporation, the residue azeotroped with toluene and dried under vacuum to give crude 1-(3-chloropropyl)-1,2-dihydro-2-pyridone (500 mg) which was used directly. Part of this product (206 mg, 1.2 mmol) was then added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (303 mg, 2.2 mmol) in NMP (20 ml) and the reaction mixture was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)quinazoline (194 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23]Br)[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.O.[NH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]([CH3:21])[C:11](=[O:12])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH2:23][N:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)=[CH:15][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: CN(C(=O)CC(CCBr)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)CC(CCN1CCC(=O)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 47 %

Procedure:
3,4-Dichloro-beta-(2-bromoethyl)-N-methyl-N-(4-chlorophenyl)benzene propanamide (4.6 g) in DMF (60 mL) was treated with 4-piperidone monohydrate hydrochloride (3.94 g) and K2CO3 (5.3 g). The mixture was stirred vigorously at ambient temperature for 120 hours. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 95:5 (CH2Cl2 :MeOH) gave the title compound (2.25 g). Mass spectrum (FAB): 467.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([N:10]2[C:18]([C:19]#[N:20])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[C:11]2=[O:21])=[C:4]([F:22])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:10]2[C:18]([C:19]#[N:20])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[C:11]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(-n2c(C#N)c3n(c2=O)CCCC3)c(F)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: N#Cc1c2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCCC2
Yield: 84 %

Procedure:
The product of Example 53, 2-(4-chloro-2-fluoro-5-methoxyphenyl)-2,3,5,6,7,8-hexahydro-3-oxoimidazo[1,5-a]pyridine-1-carbonitrile, (4 g, 0.012 mol) was dissolved in benzene and treated with 8.3 g (0.062 mol) of AlCl3 using conditions described in Example 32 to furnish 3.1 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,3,5,6,7,8-hexahydro-3-oxoimidazo[1,5-a]pyridine-1-carbonitrile (m.p. 204°-6° C.).
Reaction SMILES: [CH:1]1([N:7]([CH3:25])[C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>C1C=CC=CC=1>[CH:1]1([N:7]([CH3:25])[C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[S:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Solvent: c1ccccc1
Product: CN(C(=S)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Yield: 200.6 %

Procedure:
A solution of 13.7 g of 6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]carbostyril and 4.45 g of phosphorus pentasulfide in 200 ml of benzene was refluxed for 5 hours. The reaction mixture was allowed to cool. The insolubles were removed by filtration. The filtrate was subjected to distillation to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluant: 5% methanol/dichloromethane) to obtain 7.2 g of 6-[3-(N-cyclohexyl-N-methylaminothiocarbonyl)propoxy]carbostyril.
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=O)=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:24]([C:26]1[C:27](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[O:28][C:29]([CH3:33])([CH3:32])[C:30]=1[CH3:31])#[N:25].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:31][C:30]2[C:29]([CH3:32])([CH3:33])[O:28][C:27](=[C:34]([C:35]#[N:36])[C:37]#[N:38])[C:26]=2[C:24]#[N:25])=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=CC=CC=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 61.3 %

Procedure:
In 3 ml of ethanol and 1 ml of tetrahydrofuran were dissolved 146 mg (0.46 mmol) of 5-(4-dibutylamino-2-methoxyphenyl)-2,4-pentadienal and 101 mg (0.51 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 36 mg of ammonium acetate, and the mixture was stirred at room temperature for 19 hours. The precipitate was separated by filtration, washed with ethanol, and purified by silica gel column chromatography to give 140 mg of a dark greenish brown crystal (yield: 60.9%; mp: 156-160° C.)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[NH:39][C:38]3=[O:47])[CH2:33][CH2:32]2)=[O:30])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14](COCC[Si](C)(C)C)[N:15]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([NH:28][C:29]([N:31]2[CH2:32][CH2:33][CH:34]([N:37]3[CH2:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[NH:39][C:38]3=[O:47])[CH2:35][CH2:36]2)=[O:30])[CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(Br)n2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Temperature: 60 °C
Reaction time: 4 h
Yield: 60.8 %

Procedure:
To the solution of (±)-N-(1-(6-bromopyridin-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (197.4 mg, 0.274 mmol) in tetrahydrofuran (8 mL) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (0.55 mL, 0.549 mmol, 2 equiv). The mixture was stirred under nitrogen at 60° C. for 4 h. Another 0.5 mL of TBAF was added and the mixture was stirred overnight. Tetrahydrofuran was removed in vacuo and the residue was partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The solid residue was purified by flash column chromatography (10% methanol in methylene chloride) to afford the desired product (98 mg, 61%) as a white solid. MS (ESI) [M+H]+=588, 1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.32-6.78 (m, 9H), 6.69 (d, J=7.6 Hz, 1H), 5.79 (d, J=7.2 Hz, 1H), 5.17 (q, J=6.8 Hz, 1H), 4.60-4.48 (m, 1H), 4.25-4.00 (m, 4H), 3.27 (dd, J=13.2 and 6.4 Hz, 1H), 3.06 (dd, J=13.6 and 8.0 Hz, 1H), 2.85 (t, J=11.4 Hz, 2H), 2.45 (s, 3H), 1.80-1.50 (m, 5H). HPLC tR=1.62 min.
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)=O.N[C:16]1[C:20](C)=[CH:19][NH:18][N:17]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:19][C:20]1[CH:16]=[N:17][N:18]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=3)=[CH:4][CH:3]=[N:2][C:14]=12
Reactant: Cc1c[nH]nc1N
Reactant: Cc1cccc(C(=O)C=CN(C)C)n1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: Cc1cccc(-c2ccnc3c(C)cnn23)n1

Procedure:
As for example 53, a mixture of 3-dimethylamino-1-(6-methyl-2-pyridyl)-2-propen-1-one and 3-amino-4-methylpyrazole in glacial acetic is refluxed for 4 hours to give the product of the example.
Reaction SMILES: [C:1]([N:3]1[CH2:8][C:7]2[C:9]3[C:18]([OH:19])=[CH:17][C:16]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:10]=3[O:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH2:5][CH2:4]1)#[N:2].IC.[C:31](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([N:3]1[CH2:8][C:7]2[C:9]3[C:18]([O:19][CH3:31])=[CH:17][C:16]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:10]=3[O:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH2:5][CH2:4]1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Reaction time: 7 h
Yield: 77.3 %

Procedure:
A mixture of 2.3 g (0.006 mole) of 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 2.8 g (0.02 mole) of iodomethane and 10 g (0.0725 mole) of potassium carbonate in anhydrous acetone was heated at reflux, with stirring, for 7 hours. After cooling, the solid was removed by filtration and discarded, and the mother liquor was concentrated on a rotary evaporator. The residual material was taken up in diethyl ether (70 ml) and washed with water, 1N HCl, and again with water. The organic layer was dried over sodium sulfate, filtered and concentrated to give 1.84 g (78%) of 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-methoxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine as a yellow oil. The ir and nmr spectra confirmed the structure. The compound appeared pure by thin-layer chromatography (silica gel, chloroform solvent system).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.O.C([O-])(O)=O.[Na+].[CH3:23][CH2:24]O>CCOCC>[CH2:23]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([OH:11])[CH:4]=1)[CH3:24]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)c(O)c1

Procedure:
A solution of 4-fluoro-3-hydroxy-benzoic acid (32.0 mmol) in EtOH (120 mL) is treated with conc. sulfuric acid (25.7 mL) and heated to reflux for 16 h. Water (600 mL), NaHCO3 (100 g) and ether (300 mL) are added successively, the layers are separated and the aqueous layer is extracted twice with ether. The combined organic layers are washed twice with brine, dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (DMSO-d6): δ=7.75 (d, J=8.5 Hz, 1H); 7.58-7.63 (m, 1H); 7.12 (t, J=9.3 Hz, 1H); 6.21 (bs, 1H); 4.39 (q, J=7.0 Hz, 2H); 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9](N)=[O:10].[OH-:13].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9]([OH:13])=[O:10]
Reactant: CC1(C)CCC(C)(C)C1C(N)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCC(C)(C)C1C(=O)O
Temperature: 80 °C
Yield: 94 %

Procedure:
3.38 g of (2,2,5,5-tetramethylcyclopentane-1-yl) carboxamide was dissolved in 30 ml of methanol, and 15 ml of an aqueous 3N sodium hydroxide solution was added thereto. Then, the mixture was heated at 80° C. for 5 hours. After cooling, 40 ml of 2N hydrochloric acid was added thereto, and the mixture was extracted with 100 ml and 50 ml of ethyl acetate. The organic layers were combined, washed with 100 ml of water and 50 ml of aqueous saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure, whereby 3.20 g of 2,2,5,5-tetramethylcyclopentanecarboxylic acid was obtained. Yield 94%. (m.p. 113.6° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][C:16]([OH:19])=[N:15]2)=[CH:10][CH:9]=1.Cl[C:21]1[C:26]([C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=1.Cl>C(O)(C)(C)C.CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[CH:17][C:16]([O:19][C:21]3[C:26]([C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:15]2)=[CH:12][CH:13]=1
Reactant: COC(=O)C(=O)c1cccnc1Cl
Reactant: Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: COC(=O)C(=O)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 1 h
Yield: 40.4 %

Procedure:
At 60° C., 4.7 g (42 mmol) of potassium tert-butoxide were added a little at a time to a solution of 7.4 g (38.1 mmol) of 1-(4-chlorophenyl)-3-hydroxypyrazole in 15 ml of tert-butanol. The mixture was stirred at this temperature for 1 hour and the solvent was then removed under reduced pressure. The residue was dissolved in 25 ml of abs. dimethyl sulfoxide, and a solution of 8.0 g (38.1 mmol) of methyl (2-chloropyridin-3-yl)glyoxylate in 10 ml of abs. dimethyl sulfoxide was then added at such a rate that the temperature did not exceed 30° C. After 30 minutes at room temperature, 50 ml of 0.5 N HCl were added and the reaction mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with water and dried over sodium sulfate. The solvent was subsequently removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (10:1) as eluant. 5.5 g (40%) of the title compound were obtained as a clear oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:30])[CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[I:31].[Li+].[OH-]>C1COCC1.C(O)C>[I:31][C:7]1[CH:8]=[C:9]([N:12]([CH3:30])[CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1I
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CN(C)c1ccc(OCC(=O)O)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A solution of (2-iodo-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester (140 mg, 0.24 mmol) in THF (1.2 ml) and ethanol (1.2 ml) was treated at 0° C. with 1N LiOH (0.73 ml) and stirred for 3 h at RT. The reaction was extracted with aqueous 10% KHSO4/Et2O (3×). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. The product was crystallized from CH2Cl2 to give 79 mg of pure (2-iodo-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid, MS: 561.1 (M-H)−, MP: 172.5-173.0° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[F-].[K+]>CS(C)=O.CCOC(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 150 °C
Yield: 59.8 %

Procedure:
A solution of 4-fluorobenzonitrile (1.00 g, 8.26mmol) and morpholine (0.77 mL, 9.08 mmol) in dimethyl sulfoxide (40 mL) was treated with 37% KF on alumina, and the mixture was heated at 150° C. for 5 h. After cooling, the mixture was diluted with EtOAc and filtered through diatomaceous earth. The filtrate was washed with water (3×), brine (1×), and then dried with magnesium sulfate. The extract was concentrated and the residue was purified by chromatography (SiO2, 20 to 30% EtOAc in hexanes) yielding 930 mg (60%) of the title compound.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]1[F:23])(C)(C)C.Cl.C=O.N>C(O)C>[F:23][C:11]1[N:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:14]2=[C:13]([C:15]#[N:16])[C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCn1cc(C#N)c(-c2ccccc2)c1F
Agent: C=O
Agent: Cl
Agent: N
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)c(F)n2c1CNCC2
Temperature: 90 °C
Yield: 41 %

Procedure:
To a suspension of 2.50 g (7.59 mmol) of tert-butyl{2-[2-fluoro-4-cyano-3-phenyl-1H-pyrrol-1-yl]ethyl}carbamate in 5 ml of ethanol are added slowly 25 ml (100 mmol) of aqueous 4N hydrochloric acid solution and 0.25 g (2.8 mmol) of paraformaldehyde. The mixture is heated at 90° C. for a further 2 hours. After cooling, the reaction medium is basified slowly by adding aqueous ammonia and the product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The black oil obtained is purified by chromatography on a column of silica gel, eluting with a mixture of 2 to 5% methanol in dichloromethane, to give 0.75 g of 6-fluoro-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile in the form of a brown oil after drying.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=C.[O:13]=[O+][O-].N#N.[BH4-].[Na+].[NH4+].[Cl-]>N1C=CC=CC=1.C(Cl)Cl.CO>[OH:13][CH2:2][CH2:1][O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCOCC(C)(C)C(=O)OC
Reactant: O=[O+][O-]
Agent: N#N
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)COCCO
Temperature: -78 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A mixture of crude methyl 3-(allyloxy)-2,2-dimethylpropanoate (7.28 g, 1 eq.), MeOH (63 ml), DCM (63 ml) and pyridine (16 ml) was cooled to −78° C. O3 was passed through the reaction mixture until the colorless solution turned light blue. N2 was passed for 1 min. NaBH4 (4.00 g, 2.5 eq.) was added. The reaction mixture was stirred at 0° C. for 3 h. Saturated aqueous NH4Cl was carefully added. The resulting mixture was extracted with EtOAc, dried over MgSO4 and concentrated. Silica gel chromatography using 6-66% EtOAc-heptane yields the title compound as a colorless oil (7.45 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)=[O:9])=[N:6][CH:7]=1.[I-].[CH3:18][S+](C)(C)=O.CCCCCCCCCCCCCC[N+](C)(C)C.[OH-].[Na+]>O.ClC(Cl)(Cl)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH2:18][O:9]2)=[N:11][CH:12]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccc(Cl)cn1)c1ccc(Cl)cn1
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)(Cl)Cl
Product: Clc1ccc(C2(c3ccc(Cl)cn3)CO2)nc1

Procedure:
A mixture of bis-(5-chloropyrid-2-yl)ketone (0.8 g), trimethylsulphoxonium iodide (0.84 g), cetrimide (0.08 g) and sodium hydroxide (3 g) in water (16 ml) and 1,1,1-trichloroethane (30 ml) was stirred vigorously and heated at 70° to 75° C. for 2.5 hours. Further trimethylsulphoxonium iodide (0.86 g) was added and the mixture heated at 75° to 80° C. for a further 2 hours. The mixture was cooled, diluted with water (10 ml) and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried over magnesium sulfate and evaporated to yield the crude title compound as a brownish paste (0.8 g), which was used directly.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1>>[F:18][C:6]1[CH:5]=[C:4]([NH:19][C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:33])[N:22]=2)[CH:3]=[C:2]([F:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Product: Nc1nc(Nc2cc(F)c(Oc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
Analogously to example 25, the title compound is synthesized from 100 mg (0.36 mmol) of [3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XXXIV) and 87 mg (0.36 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX). Purification by preparative HPLC gives the product.