Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2ccc3cccnc3c2)ncn1

Procedure:
This compound could be prepared from 4,6-dichloro-pyrimidine and 7-aminoquinoline in the presence of K2CO3 and DMF.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(O)cccc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCC3=O)nc1
Yield: 30.3 %

Procedure:
Using a method similar to Intermediate 1, using 4-hydroxy-1-indanone (2.44 g, 16.5 mmol), 6-chloronicotinamide (2.34 g, 15.0 mmol) and K2CO3 (3.11 g, 22.5 mmol) gives the title compound (1.22 g) as a yellow solid. Mass spectrum (ion spray): m/z=269 (M+1); 1HNMR (DMSO-d6): 8.57 (s, 1H), 8.29 (d, 1H), 8.03 (s, 1H), 7.55-7.46 (M, 4H), 7.19 (d, 1H), 2.81 (t, 2H), 2.61 (t, 2H).
Reaction SMILES: [Cu][C:2]#[N:3].N(OC(C)(C)C)=O.[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:13]=1N>CS(C)=O>[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([Cl:22])[C:13]=1[C:2]#[N:3]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Product: N#Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
A solution of copper(I) cyanide (2.6 g, 29.0 mmol, Eq: 2) in DMSO (5 mL) was heated at 60° for 1 hr. Tert-butyl nitrite (5.98 g, 6.9 ml, 58.0 mmol, Eq: 4.00) and a solution 2,6-dichloro-4-nitroaniline (3 g, 14.5 mmol, Eq: 1.00) in DMSO (5 mL) was added and the reaction was stirred for 3 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate 3×. The organic extract was washed with brine and dried over sodium sulfate. Chromatography (200 g Analogix, 100% hex to 5% EtOAc/hex) gave 515 mg (16%) of desired product as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2([CH2:23][CH2:22][C:21](=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]2)[S:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30](I)[CH3:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([O:18][CH2:30][CH3:31])=[O:17])[C:10]2([CH2:19][CH2:20][C:21](=[CH:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:23]2)[S:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCI
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN1C(=O)C(CC(=O)OC(C)(C)C)SC12CCC(=CCC(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 7 ml of N,N-dimethylformamide was added 0.70 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. After adding 0.14 ml of ethyl iodide and 0.25 g of anhydrous potassium carbonate at 0-5° C., the resulting mixture was stirred at ambient temperature for 3 hours. The resulting mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.70 g of ethyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate was obtained as a light yellow oily product.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:11][C:12]1[N:17]=[C:16](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[CH:22]=[O:23])[CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C(OCC)C>[Br:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[CH:22]([OH:23])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:17]=1
Reactant: O=C/C=C/C=C/c1cccc(Br)n1
Reactant: CCCCCCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCC(O)/C=C/C=C/c1cccc(Br)n1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 196.3 %

Procedure:
A solution of octylmagnesium bromide (produced from 150 mg of magnesium in 5 ml of diethyl ether and 1.14 g of octyl bromide in 2.5 ml of diethyl ether) is instilled in a solution of 1.17 g of 5-(6-bromo-2-pyridyl)-(E,E)-2,4-pentadienaldehyde in 25 ml of diethyl ether with stirring and under argon atmosphere at -20° C. After 1.5 hours at -20° C., the reaction mixture is mixed with 15 ml of saturated ammonium chloride solution, shaken out with diethyl ether, dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate=95/5. 477 mg of 2-bromo-6-[(1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-pyridine is obtained as crude product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[CH:16](O)=O>>[CH3:10][O:9][C:6]1[C:7]2[N:8]=[CH:16][NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: O=CO
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Product: COc1ccc(CCN(C)C)c2[nH]cnc12

Procedure:
0.30 g of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated under reflux for 3 hours with 10 ml of formic acid. The solution is filtered and concentrated, thus obtaining 0.23 g of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]benzimidazole, formate, as a vitreous mass.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.[CH3:14][O-:15].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: Nc1nc2cc(Cl)ccc2nc1Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc2ccc(Cl)cc2nc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
To 3-amino-2,6-dichloroquinoxaline (1.30 g, 6.07 mmol) dissolved in tetrahydrofuran (60 ml), 25 wt % sodium methoxide (13.1 g, 60.7 mmol) in methanol was added at room temperature and stirred further at room temperature for 90 minutes. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.22 g of the titled compound (yield, 96%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[C:16](#[N:18])[CH3:17]>>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:18]3[CH:11]=[CH:10][CH:9]=[CH:14][CH:17]=[CH:16]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: CC#N
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Product: O=C(CN1C=CC=CC=C1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm 3 of acetonitrile and 0.69 cm3 of hexamethyleneimine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and the residue is taken up in 10 cm3 of diisopropyl ether, filtered off and dried under reduced pressure (90 Pa; 45° C.) to give 670 mg of N-(6-chloro-1H-indazol-3-yl)-1H-azepine-1-acetamide in the form of a yellow foam.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:26])=[O:4].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl.C(=O)(O)[O-]>[F:28][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][O:25][S:37]([CH3:36])(=[O:39])=[O:38])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:27])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-5-[4-(6-hydroxymethyl-pyridin-3-yl)-phenyl]-2,2-dimethyl-oxazolidin-3-yl}-ethanone (1.1 g, 2.792 mmol) in CH2Cl2 (50 mL) is added triethyl amine (0.564 g, 5.584 mmol) followed by methanesulphonyl chloride (0.365 g, 3.071 mmol) at 0° C. then stirred for 30 minutes at 0° C. Reaction mixture is diluted with saturated aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 30% ethyl acetate in hexane as an eluent to afford the title compound (0.875 g). 1H-NMR (400 MHz, DMSO) δ: 1.53 (s, 3H), 1.60 (S, 3H), 3.30 (s, 3H), 4.54-4.58 (m, 0.5H), 4.60-4.70 (m, 1H), 4.82-4.83 (m, 0.5H), 4.90-4.94 (m, 1H), 5.28 (d, J=3.68 Hz, 1H), 5.36 (s, 2H), 6.64 (t, J=52.4 Hz, 1H), 7.61-7.64 (m, 3H), 7.82 (d, J=8.08 Hz, 2H), 8.19-8.21 (dd, J1=2.4 Hz, J2=8.16 Hz, 1H), 8.94 (d, 2.2 Hz, 1H). LC-MS (m/z): [M+H]=473.2.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[CH3:13]I>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: CI
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)OC2=O
Reaction time: 48 h
Yield: 46.8 %

Procedure:
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (195 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (4 ml) under nitrogen was added minutes and then methyl iodide (0.37 ml, 6.0 mmol) was added. The reaction was stirred for 48 h. and then quenched with saturated ammonium chloride. The mixture was concentrated in vacuo, diluted in ethyl acetate (20 ml) and the organic phase washed with 1N hydrochloric acid (5 ml) and brine (3×5 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. To the crude solid was added methanol causing a precipitate to form. The flask was cooled in an ice bath for 2 h. and the solid filtered off, washed with methanol and dried in vacuo which afforded 0.1 g (47%) of 4-methoxy-isobenzofuran-1,3-dione as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](/[N:8]=[CH:9]/[N:10](C)C)=O)=[CH:4][CH:3]=1.O.[NH2:16]N>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[N:8]=[CH:9][NH:10][N:16]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(-c2nc[nH]n2)cc1
Temperature: 120 °C

Procedure:
To a stirred solution of (E)-4-chloro-N-((dimethylamino)methylene)benzamide (9.4 g, 44.6 mmol) in acetic Acid (13.5 ml) was added hydrazine hydrate (1.524 ml, 49.1 mmol). The reaction mixture immediately solidified and was heated to 120° C. for 2 hours. Whereupon was cooled to room temperature and azeotroped with toluene. The crystalline residue was stirred with water for a while. The precipitate was filtered off, washed with water and dried under vacuum. (Yield: 7.27 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([O:9][CH2:8][C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(COC(C)=O)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (Intermediate 35B, 342 mg, 0.750 mmol) was dissolved in DCM (4.0 ml). The reaction mixture was charged with DIEA (0.197 ml, 1.125 mmol) followed by acetyl chloride (0.064 ml, 0.900 mmol) and allowed to stir at rt for 15 minutes. The reaction was concentrated in vacuo to provide (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (41B). The products were carried forward without purification. MS: [M+H]+ m/z 498.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:37]=[CH:36][C:19]([C:20]([NH:22][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21])=[CH:18][C:17]=2[NH:38][C:39]2[C:40]3[CH:48]=[CH:47][C:46]([CH:49]([CH3:51])[CH3:50])=[N:45][C:41]=3[N:42]=[CH:43][N:44]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:37]=[CH:36][C:19]([C:20]([NH:22][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21])=[CH:18][C:17]=2[NH:38][C:39]2[C:40]3[CH:48]=[CH:47][C:46]([CH:49]([CH3:50])[CH3:51])=[N:45][C:41]=3[N:42]=[CH:43][N:44]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)(NC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(NC(=O)c1ccc(Sc2ccc(N)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
The product of Example 444A (93 mg.) was reacted with trifluoroacetic acid [TFA] (0.60 mL) in dichloromethane (0.60 mL) added dropwise at room temperature then stirred at room temperature for 1 hour. The reaction mixture was concentrated and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed on a C-18 HPLC column with a gradient elution of acetonitrile in 0.1% TFA water (0-100%). The desired fractions were combined, concentrated, dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 then brine, dried over MgSO4 and concentrated to give a pale yellow amorphous solid (67 mg, 84%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.07 (t, J=6.99 Hz, 3 H) 1.34 (d, J=6.62 Hz, 6 H) 1.84 (s, 3 H) 3.15-3.29 (m, 1 H) 4.03 (q, J=7.35 Hz, 2 H) 5.59 (s, 2 H) 6.62 (d, J=8.46 Hz, 2 H) 6.84 (d, J=8.46 Hz, 1 H) 7.12 (d, J=8.46 Hz, 2 H) 7.24-7.41 (m, 4 H) 7.52 (d, J=7.35 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.73 (dd, J=8.46, 1.84 Hz, 1 H) 7.90 (d, J=1.84 Hz, 1 H) 8.57 (s, 1 H) 8.83 (s, 1 H) 8.86 (d, J=8.46 Hz, 2 H) 10.13 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][C:19]#[CH:20])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Cl-].[Cl:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:22][CH:23]=[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:9]([CH2:18][C:19]#[CH:20])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: C#CCC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: C#CCC(C(=CCl)c1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-4-pentyn-1-one and chloromethyltriphenylphosphonium chloride there is obtained 3-[α-chloromethylene-2,4-dichloro-β-(2-propynyl)-phenethyl]-pyridine as an isomer-pure compound in the form of white crystals, m.p. 87-88° C.;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][CH3:25])[CH:18]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][CH3:25])[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: COc1cc(F)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC)c2c1C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (15.0 g), 4-fluoro-2-methoxyaniline (9.5 g), 4M hydrochloric acid in dioxane (4.5 ml) and dioxane (100.0 ml) were stirred at 100° C. overnight. Then the mixture was filtrated and the solid was dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:28][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:24]([F:25])([F:26])[F:27])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (84.1 mg, 0.187 mmol) and triethylamine (33.8 μL, 0.242 mmol) in tetrahydrofuran (1.0 mL) was added acetyl chloride (15.9 μL, 0.224 mmol) at 0° C. After 1 h, triethylamine (18.2 μL, 0.131 mmol) and acetyl chloride (8.0 μL, 0.112 mmol) was added. After 1 hr the reaction mixture was quenched with water, concentrated in vacuo, and purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (93.2 mg, 0.187 mmol, 100%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [C:1]([C@:3]1([OH:23])[C@H:8]([CH3:9])[CH2:7][C@H:6]2[C@H:10]3[C:19](=[CH:20][CH2:21][C@:4]12[CH3:5])[C:18]1[CH2:17][CH2:16][C:15](=[O:22])[CH2:14][C:13]=1[CH2:12][CH2:11]3)#[CH:2].C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[C:1]([C@:3]1([OH:23])[C@H:8]([CH3:9])[CH2:7][C@H:6]2[C@H:10]3[C:19]([CH:20]=[CH:21][C@:4]12[CH3:5])=[C:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)#[CH:2]
Reactant: C#C[C@]1(O)[C@H](C)C[C@H]2[C@@H]3CCC4=C(CCC(=O)C4)C3=CC[C@@]21C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Solvent: ClCCl
Product: C#C[C@]1(O)[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@@]21C
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
1.9 g of 17α-ethynyl-17β-hydroxy-16α-methyl-5(10),9(11)-estradien-3-one is dissolved in 60 ml of benzene and 20 ml of methylene chloride and combined at room temperature dropwise with a solution of 3.5 g of dichlorodicyano-p-benzoquinone. The mixture is agitated for 5 hours at room temperature and worked up as described in Example A. Crystallization of ether yields 1.65 g of 17α-ethynyl-17β-hydroxy-16α-methyl-4,9,11-estratrien-3-one, m.p. 176°-179° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:12]1COCC1>>[CH3:1][C:2]1[O:6][C:5]2[CH2:7][CH2:8][C:9](=[CH2:12])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(o1)CCCC2=O
Reactant: C1CCOC1
Product: C=C1CCc2oc(C)cc2C1=O

Procedure:
To a solution of the furanone of Step A (164.5 g/1.10 mole) in about 400 ml THF was added, in four separate portions, N-methylanilium trifluoroacetate (TAMA) (243 g) and trioxymethylene (99 g) over 31/2 hours, and the mixture refluxed for 20 hours. The mixture was cooled and partitioned between Et2O and water, the layers separated and the aqueous layer was extracted twice with Et2O. The combined Et2O layers were washed exhaustively with water, with NaHCO3 and then with brine, dried over MgSO4 and conc. in vacuo to yield an amber oil. This oil was flash chromatographed on silica gel using CH2Cl2 as solvent in several runs of 10-20 g per run. Fractions containing the fast moving material were combined, concentrated in vacuo to obtain the desired product as a yellow oil.
Reaction SMILES: [NH3:1].[OH:2][CH:3]1[O:7][CH:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([N:17]4[CH2:21][CH:20]([CH2:22][O:23][CH3:24])[O:19][C:18]4=[O:25])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:5][CH2:4]1>>[OH:7][C@H:6]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([N:17]3[CH2:21][C@H:20]([CH2:22][O:23][CH3:24])[O:19][C:18]3=[O:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)[CH2:5][CH2:4][C:3](=[O:2])[NH2:1]
Reactant: N
Reactant: COCC1CN(c2ccc3nc(C4CCC(O)O4)sc3c2)C(=O)O1
Product: COC[C@H]1CN(c2ccc3nc([C@@H](O)CCC(N)=O)sc3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
50 ml of liquid ammonia was put in a sealed tube at -78° C. and 2.9 g of 3-[2-(5-hydroxytetrahydrofuran-2-yl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone was added thereto. After sealing followed by stirring at room temperature for 3 h, ammonia was slowly evaporated. Acetone was added to the residue and the precipitated crystals were separated by filtration and dried to give 2.6 g of the titled compound.
Reaction SMILES: N[C:2]1[C:11]2[N:12]=[C:13]([CH2:25][CH2:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH2:25]([C:13]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:5][C:4]=3[N:3]=[CH:2][C:11]=2[N:12]=1)[CH2:26][CH2:27][CH3:28]
Reactant: OB(O)c1cccnc1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNC(=O)OC(C)(C)C
Product: CCCCc1nc2cnc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)OC(C)(C)C
Yield: 83.2 %

Procedure:
tert-Butyl [2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.09 g, 30.5 mmol) and 3-pyridylboronic acid (4.31 g, 35.0 mmol) were coupled according to the method described in Part G of Example 386. The reaction was heated for 2.5 hours. The crude product was triturated with toluene (15 mL/g) at 123° C. and isolated by filtration to provide 11.31 g of tert-butyl {2-[2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[NH4+].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CC=CC1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CCCC1

Procedure:
A solution of α-[2-(t-butoxycarbonylaminomethyl)-1,4-cyclohexadienyl]-acetic acid (1.33 g., 5 mmoles) in 3% ammonium hydroxide (10 ml.) was hydrogenated at 40 psi with palladium on charcoal (10%, 0.2 g.). A theoretical amount of hydrogen was taken up in 3 hours. The catalyst was removed and the filtrate was acidified to pH 2 with dil. HCl and extracted with ethyl acetate (2×50 ml.). The combined extracts were washed with water (20 ml.), dried with Na2SO4 and evaporated under reduced pressure to afford an oil (1.34 g.) which solidified on standing for several days. Recrystallization from n-hexane - ethyl acetate gave 1.2 g. title product as colorless prisms melting at 118°-119° C.