Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.Cl.C(OCC)(=O)C>CO>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][CH:16]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH2:17][CH2:18]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCCc3ccccc3NC(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCCc3ccccc3N)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.8 %

Procedure:
To a solution of tert-butyl [2-[3-[4-[N-(5-metylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]propyl]phenyl]carbamate (790 mg) in methanol (15 mL) was added a 4N hydrochloric acid/ethyl acetate solution (2.3 mL) at room temperature. The solution was stirred at room temperature for 16 hours. The solution was then concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue and the solution was extracted with chloroform. The extract was dried over over anhydrous sodium sulfate, and then, concentrated under reduced pressure to give the title compound (700 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])O.S(Cl)([Cl:22])=O>C(#N)C>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([CH:10]([Cl:22])[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Solvent: CC#N
Product: Fc1ccc(Br)cc1C(Cl)c1cc2ccccc2s1
Temperature: 15 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
Into an acetonitrile (10 ml) solution of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (1.0 g) was dropwise added thionyl chloride (706 mg) at a temperature of 5° C. or lower, followed by stirring at 5.0 to 25.0° C. for 3.5 hours. The reaction mixture was subjected to distillation under reduced pressure to distill off the solvent and the residue was subjected to vacuum drying to obtain 2-[(5-bromo-2-fluorophenyl)(chloro)methyl]-1-benzothiophene [1.05 g, yield: 100%, purity: 99% (HPLC)].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].CO>C1COCC1>[C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(Br)cc2F)c1C(=O)O
Yield: 100.6 %

Procedure:
In a fashion similar to that described for preparation 16 (120 mg), 4-ethoxycarbonyl-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (350 mg, 1.06 mmol), 5N NaOH (1 ml, 5 mmol), methanol (5 ml), and THF (1 ml) gave 4-carboxy-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (320 mg, 100%) that was used without purification.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.C[Sn](C)(C)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:6][N:5]=1
Reactant: CSc1nsc(Cl)n1
Reactant: C[Sn](C)(C)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1nsc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To 30 ml of toluene were added 500 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, 794 mg of trimethylphenyltin and 346 mg of tetrakistriphenylphosphine palladium, and the mixture was heated under reflux for 8 hours in a nitrogen atmosphere. Then, the reaction mixture was cooled to room temperature, and a 20% aqueous potassium fluoride solution was added to the reaction mixture, followed by stirring. This mixture was filtered through Celite, and the filtrate was concentrated. The resulting residue was subjected to silica gel column chromatography to obtain 455 mg of 3-methylthio-5-phenyl-1,2,4-thiadiazole.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18](O)=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24]C)C>>[C:1]([NH:9][CH:10]([CH2:18][N:23]([CH3:24])[CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: CCN(CC)CC
Product: CN(C)CC(Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 26.5 g of N-benzoyl phenylalanine (XIII) in 200 ml of T.H.F. are added 11 g of triethylamine, it is cooled to 0° C. and 11 g of ethyl chloroformiate are added. After 30 mn at 0° C., a solution of 4.5 g of diethyllamine in 50 ml of T.H.F. is added, then it is left for 2 hours at ambient temperature. Then the solvent is evaporated, the residue taken up in water, extracted with chloroform, dried on sodium sulfate, filtered and the filtrate evaporated. Thus, the expected product was obtained with a yield of 81%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>C(#N)C>[F:9][C:5]1[C:6]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:7][C:2]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:3][C:4]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Fc1c(Cl)nc(Cl)nc1C(F)(F)F
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: Fc1c(-n2ccnc2)nc(-n2ccnc2)nc1C(F)(F)F

Procedure:
2,4-Dichloro-5-fluoro-6-trifluoromethylpyrimidine (2.74 g) was dissolved in acetonitrile (30 ml) and imidazole (3.97 g) was added at room temperature with stirring. The mixture was stirred over night and then the solvent was removed under reduced pressure. The residue was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with carbon tetrachloride to give crude, 5-fluoro-2,4-diimidazol-1-yl-6-trifluoromethylpyrimidine. It was recrystallized from isopropanol as colorless crystalline solid, mp 142-150° C. (decomposed).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(O[C:13](=O)[NH:14][CH:15]1C[N:17]([CH:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:16]1)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[C:25]1([CH:22]2[CH2:23][CH2:24][CH:19]([NH:17][CH:16]3[CH2:13][NH:14][CH2:15]3)[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2CCC(NC3CNC3)CC2)cc1

Procedure:
The title compound was prepared as colorless oil from the TFA de-protection of [1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-carbamic acid tert-butyl ester (as prepared in the previous step) using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([O:29][CH2:30][CH3:31])=[C:8]([CH:28]=1)[C:9]([NH:11][C:12]1[C:13]([C:25]([NH2:27])=[O:26])=[N:14][N:15]([CH:19]2[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20]2)[C:16]=1[CH2:17][CH3:18])=O)(=[O:3])[CH3:2].[CH2:32](O)[CH2:33]CC>>[C:1]([C:4]1[CH:28]=[C:8]([C:9]2[NH:27][C:25](=[O:26])[C:13]3[C:12](=[C:16]([CH2:17][CH3:18])[N:15]([CH:19]4[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20]4)[N:14]=3)[N:11]=2)[C:7]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCCO
Reactant: CCOc1ncc(C(C)=O)cc1C(=O)Nc1c(C(N)=O)nn(C2CN(CC)C2)c1CC
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CN(CC)C3)nc2c(=O)[nH]1

Procedure:
To a stirred suspension of 5-Acetyl-N-[3-(aminocarbonyl)-5-ethyl-1-(1-ethyl-3-azetidinyl)-1H-pyrazol-4-yl]-2-ethoxynicotinamide, the title compound of Preparation 2(e), (1.07 g, 2.5 mMol) in n-butanol (10 mL) under nitrogen atmosphere at room temperature was added n-butyl acetate (7.5 mMol, 0.87 mL) followed by potassium carbonate (7.5 mMol, 1.04 mg) as a single solid portion. The reaction was left to stir at room temperature for 5 minutes before being heated to reflux for 24 hours. The reaction was allowed to cool to room temperature and then reduced to low volume (ca 2 to 3 mL) at reduced pressure. The crude concentrate was then diluted with water (20 mL), this aqueous mixture was then treated with dilute HCl until pH 7 was attained at which point the remaining solvent was azeotroped out under reduced pressure. The resulting precipitate was cooled and filtered and the solid product dried to afford the title compound, 1.09 g, yield by HPLC=81%. M/Z=439 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12](/[C:15](=[N:28]\[OH:29])/[CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(=O)CO)cc3)c2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(/C(CO)=N\O)cc3)c2)CCOCC1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in Example 69, 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-hydroxyacetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-hydroxyacetophenone oxime in 59% yield, m.p. 145°-146° C.;
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][OH:14])[C:6]=2[N:5]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][OH:14])[C:6]=4[N:5]=[C:4]3[CH2:3][O:2][CH3:1])[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: COCc1nc2c(CO)cccc2[nH]1
Product: COCc1nc2c(CO)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 90.6 %

Procedure:
[step 4] Using [2-(methoxymethyl)-1H-benzo[d]imidazol-4-yl]methanol (203 mg, 1.06 mmol) obtained in step 3 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (386 mg, 1.08 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (451 mg, 91%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][CH2:7][CH:6]([CH3:10])[CH3:4])[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(CCC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 168.4 %

Procedure:
To a solution of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (15 g, 97.3 mmol) in 124 mL of N,N′-dimethylformamide at 0° C. was added sodium hydride (60% dispersion in mineral oil, 4.66 g, 2.80 mmol). The ice bath was then removed, and the reaction mixture was stirred at ambient temperature for 10 min. After the reaction mixture was cooled at 0° C., 1-bromo-3-methylbutane was added. The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 2 hours. Saturated ammonium chloride aqueous solution (200 mL) and ethyl acetate (600 mL) were added to quench the reaction. The organic layer was washed with water and saturated sodium chloride aqueous solution, dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-30% ethyl acetate in hexanes to afford 18.3 g of the title compound as a colorless oil. MS: (+) m/z 224.4 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1.[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[N:23]=[CH:22][S:21][C:19]=2[N:20]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:14][C:15]1[N:16]=[C:17]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])[CH:8]=2)[C:18]2[N:23]=[CH:22][S:21][C:19]=2[N:20]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: C[C@H]1CCCN1c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
Yield: 86.6 %

Procedure:
A mixture of (S)-3-(2-methylpyrrolidin-1-yl)benzenamine (0.9 g, 5.34 mmol), 5,7-dichlorothiazolo[5,4-d]pyrimidine (1.1 g, 5.34 mmol), DIEA (1.4 g, 10.68 mmol) in IPA (15 mL) was heated to reflux for 2 hours. Then the reaction mixture was concentrated and residue purified by column chromatography (petroleum ether:ethyl acetate=8:1) to give (S)-5-chloro-N-(3-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (1.6 g, 91.4%) as yellow solid. LC-MS: 346 [M+H]+, tR=1.82 min.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]C1CC(=O)NC1=O>CN(C)C=O>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: O=C1CC(Br)C(=O)N1
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Yield: 89.3 %

Procedure:
An amount of 13.65 (53.7 mmol) of 9-phenylanthracene was dissolved in 100 ml of N,N dimethylformamide. An amount of 10.5 g (59 mmol) of N bromosuccinimide was added and allowed to react for six hours. Then, distilled water was added to stop the reaction and the deposit was filtered. The recovered deposit was purified by column chromatography to obtain 15.97 g (48 mmol) of 9-bromo-10-phenylanthracene. The yield was 89.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C[Si]([C:15]#[C:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23])(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([C:15]#[C:16][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Reactant: COc1ccc(I)cc1Cl
Product: COc1ccc(C#Cc2cncc(C#N)c2)cc1Cl
Yield: 174.4 %

Procedure:
Prepare according to the general procedure outlined in EXAMPLE 72 using 2-chloro-4-iodo-1-methoxybenzene (520 mg, 19 mmol) and 5-trimethylsilanylethynyl-nicotinonitrile (350 mg, 1.75 mmol), (prepared as described in PREPARATION 3), to give the title compound (820 mg, 47%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F>C(#N)C>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CNCCNC1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCCNCC2)c(F)c1
Yield: 77.3 %

Procedure:
To homopiperazine (5 g, 0.05 mol) in acetonitrile (30 mL), 3.4-difluoronitrobenzene (3.17 g, 0.02 mol) was added and the reaction mixture was heated to reflux for 4 hrs. Then the solvent was evaporated and the residue taken in EtOAc and washed with water and brine solution. The EtOAc layer was dried over anhyd Na2SO4 and evaporated in vacuo. The residue was digested with ether-hexane (1:20), decanted and dried in vacuo to get 3.7 g of final product.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Li]CCCC.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=[O:19].[Li]>C1COCC1>[OH:19][CH:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)[C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1cc(Br)c2ccccc2n1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2cc(C)nc3ccccc23)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
4-Bromo-2-methylquinoline from (4a) (1.0 g, 4.5 mmol) was dissolved in 10 mL of anhydrous THF and the resulting solution was cooled to −78° C. A solution of n-BuLi (3.0 mL, 1.6 M, 4.8 mmol) was added slowly and the resulting solution was maintained at −78° C. for 5 min. Meanwhile, in another flask methyl 4-formylbenzoate (0.9 g, 5.4 mmol) was dissolved in 20 mL of anhydrous THF and the resulting solution was cooled to −78° C. before the lithium reagent made above was cannulated. The whole mixture was stirred for 30 min and quenched with MeOH. The solution was diluted with ethyl acetate and washed with H2O and brine. After dried over MgSO4, the organic solution was filtered and concentrated. The residue was purified on silica gel to provide methyl 4-[hydroxy(2-methyl-4-quinolinyl)methyl]benzoate (0.9 g, 65%). MS (AP+): 308 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:28]1([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36](Br)[N:35]=2)=[O:33])[CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:32](=[O:33])[NH:31][CH:28]5[CH2:30][CH2:29]5)[N:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(NC1CC1)c1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)NC5CC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-bromo-pyridine-2-carboxylic acid cyclopropylamide.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].N.[C-:23]#[C-:24].[K+].[K+]>CC(C)=O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:23]#[CH:24])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: [C-]#[C-]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: N
Agent: [K+]
Solvent: CC(C)=O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
500 Mg. of 13β-ethyl-gon-4-en-3,17-dione produced in Example 135, was dissolved in 10 ml. of a benzene-ether solvent mixture (1:1) and added to a solution of 50 ml. of liquid ammonia containing 0.1 ml. of acetone and 0.5 g. of potassium acetylide. The reaction mixture was agitated at the ammonia boiling point for 2 hours and then the ammonia was evaporated at room temperature. The organic materials were extracted with ether and then the solvent was evaporated in vacuo. The residue was purified by chromatography over 50 g. of silica gel and on elution with a benzene-ethyl acetate mixture, afforded 13β-ethyl-17α-ethynyl-17-hydroxy-gon-4-en-3-one.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](=O)[CH3:27]>C1COCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[C:26]([CH3:27])[CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17])[CH3:4]
Reactant: COc1ccccc1CC(C)=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Cc1ccccc1OC
Temperature: 25 °C

Procedure:
In a 3-neck round bottom flask, fitted with an internal thermometer and addition funnel, a mixture of sodium hydride (60% in mineral oil, 4.14 g) in THF (200 mL), under argon, was cooled to 10° C. (Diethoxyphosphoryl)acetic acid ethyl ester (21 mL) was added dropwise (heat and gas evolution), keeping the internal temperature below room temperature. After addition, the reaction mixture was stirred at room temperature for minutes, and then cooled to 0° C. A solution of 2-methoxyphenyl acetone (5 g) in THF (25 mL) was added dropwise over 5 minutes. The reaction was allowed to warm to room temperature overnight. With active cooling, the reaction was quenched with H2O (200 mL), then AcOH (to pH ˜6) and extracted with EtOAc. The combined organics were washed with NaHCO3, water, and brine, dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography to give the desired compound (5.73 g). 1H-NMR: 400 MHz, (CDCl3) δ: 7.24 (app dt, 1H), 7.10 (dd, 1H), 6.92 (d, 1H), 6.88 (d, 1H), 5.58 (s, 1H), 4.13 (q, 2H), 3.82 (s, 3H), 3.46 (s, 2H), 1.26 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:38]([CH:34]4[CH2:37][CH2:36][CH2:35]4)=[O:39])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(C1CCC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 30 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclobutanecarbonyl chloride (0.04 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 69 (37 mg, 30% yield) as a white fluffy solid. LC-MS (M+H=425, obsd.=425).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:17][C:14]1[N:13]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:12]2[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][N:40]3[CH2:39][CH2:38][N:37]([C:35]([C:29]4[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=4[F:27])=[O:36])[CH2:42][CH2:41]3)[C:16]=2[N:15]=1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: O=C(c1ccc(F)cc1F)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(C(=O)c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, (2,4-difluorophenyl)piperazin-1-yl-methanone hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give (4-(2-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)piperazin-1-yl)(2,4-difluorophenyl)methanone: LC/MS (M+1=493.1). 1H NMR (DMSO-d6, 400 MHz) δ 2.42 (m, 2H), 2.72 (t, 2H, J=6.0 Hz), 3.17 (m, 2H), 3.34 (m, 2H), 3.60 (m, 2H), 4.25 (t, 2H, J=6.0 Hz), NH2), 7.93 (s, 1H). Anal. calculated for (C24H22F2N8O2+0.5 H2O): C, 57.48; H, 4.62; F, 7.58; N, 22.34; O, 7.98. Found C, 57.40; H, 4.46; N, 22.29.