Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].[I-].[K+]>O>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1)[CH3:22]
Reactant: O=C(c1ccccc1)c1ccc(OCCCCCl)cc1
Reactant: CCNCC
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CCCCOc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 19 h

Procedure:
Combine 4-(4-chlorobutoxy)benzophenone (740 g, 1.59 mol), diethylamine (3.7 L), and potassium iodide (50 g) in water (3.7 L). Heat to reflux. After 19 hours, evaporate the reaction mixture in vacuo to give an aqueous residue. Extract two times with ethyl acetate. Extract the combined organic layers with aqueous 10% hydrochloric acid solution and separate the acidic aqueous layer. Combine the acidic aqueous layer and ethyl acetate. Slowly add aqueous 10% sodium hydroxide solution until the pH of the aqueous layer is about 9. Separate the organic layer, extract twice with water and then aqueous saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 4-(4-diethylaminobutoxy)benzophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:24])=[C:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:17]=3)[C:12](=[O:25])[N:11]([O:26]CC3C=CC=CC=3)[C:10]2=[O:34])[CH:6]=[CH:7][CH:8]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:24])=[C:16]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH:17]=3)[C:12](=[O:25])[N:11]([OH:26])[C:10]2=[O:34])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)cc32)c1
Agent: [Pd]
Product: COc1cccc(-n2c(=O)n(O)c(=O)c3cc(F)c(N4CCCC4)cc32)c1
Yield: 93.2 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.04 g) with 1-(3-methoxyphenyl)-6-fluoro-3-benzyloxy-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example T-1, 0.12 g, 0.26 mmol) afforded 0.09 g of the title compound as a solid, mp 216-218° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2/[CH:18]=[CH:19]/[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(/C=C/c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 1-(4-fluorophenyl)-2-(2,3,6-trifluorostyryl)-1H-imidazole-5-carboxylate (17) (60 mg, 0.16 mmol) in ethanol (10 mL) was added Pd/C (10% Degussa type, 10 mg). A balloon of hydrogen gas was attached and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 1-(4-fluorophenyl)-2-(2,3,6-trifluorophenethyl)-1H-imidazole-5-carboxylate (18).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[CH:21][C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[CH:21][C:22]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Reactant: C1COCCN1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2cccc3c(N4CCOCC4)ccc(c23)C(=O)N1OCc1ccccc1

Procedure:
2-Benzyloxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.8 g, 2.1 mmol, from Example M) was reacted in morpholine (3.0 mL) in the presence of DBU (0.05 mL) following the procedure of Example 18 to give 0.6 g of 2-benzyloxy-6-(morpholin-4-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-6-(morpholin-4-yl)-benzo[de]isoquinoline-1,3-dione (0.4 g, 0.9 mmol) in the presence of 10% Pd/C (0.2 g) in DMA (30 mL) afforded 0.2 g of the title compound, mp 235-237° C.; 1H NMR (DMSO-d6): δ 10.6 (1H, s), 8.5-8.4 (3H, m), 7.8 (1H, t, J=7.9), 7.4 (1H, d, J=8.1), 3.9 (4H, m), 3.2 (4H, m).
Reaction SMILES: CC[O-].[Na+].S(O)(O)(=O)=O.[CH3:10][N:11]([CH3:15])[C:12]([NH2:14])=[NH:13].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=1[C:25](=[C:28](OC)[C:29]([F:32])([F:31])[F:30])[C:26]#[N:27]>CCO>[NH2:27][C:26]1[C:25]([C:18]2[CH:19]=[C:20]([Cl:24])[CH:21]=[C:22]([Cl:23])[C:17]=2[Cl:16])=[C:28]([C:29]([F:32])([F:31])[F:30])[N:14]=[C:12]([N:11]([CH3:15])[CH3:10])[N:13]=1
Reactant: CN(C)C(=N)N
Reactant: COC(=C(C#N)c1cc(Cl)cc(Cl)c1Cl)C(F)(F)F
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of NaOEt (from 0.144 g of Na) in EtOH (12.5 ml) was added 1,1-dimethylguanidine sulphate (1.4 g), (Aldrich). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of 2-(2,3,5-trichlorophenyl)-4,4,4-trifluoro-3-methoxybut-2-eno-nitrile (see Example 1.6) (0.85 g) in EtOH (2.5 ml) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered, and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel, eluting with CHCl3, gave the desired product, 0.61 g, mp. 124°-126° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C>C(O)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(Cl)cc2)C1
Solvent: O=CO
Product: Clc1ccc(COC2CCNC2)cc1
Yield: 68.2 %

Procedure:
A solution of 3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.28 g, 0.9 mmol) in aqueous 90% formic acid (7.5 mL) was stirred at (0° C.) for 30 min. then at room temperature overnight. The solvents were removed under reduced pressure and the residue was treated with saturated aqueous potassium carbonate and extracted twice with n-butanol. The combined organic extracts was concentrated and the residue was purified by flash chromatography (SiO2, dichloromethane-methanol-ammonium hydroxide, 8:8:1 then 50:10:1) to afford the subtitle compound 3-(4-Chloro-benzyloxy)-pyrolidine (0.13 g, 70%).
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[I:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1ccc(I)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(I)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
63 g (723 mmol) of manganese dioxide are added to a solution of 17 g (72 mmol) of (6-iodopyrid-3-yl)methanol in 600 ml of dichloromethane. The reaction medium is stirred at room temperature for 20 hours and then filtered through Celite. The precipitate is washed thoroughly with water and the filtrate is evaporated under vacuum. The residue obtained is taken up in dichloromethane and the insoluble material is again filtered off. After evaporation of the filtrate, 13.2 g (78%) of 6-iodopyridine-3-carbaldehyde are obtained in the form of a pale yellow solid with a melting point of 141° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:51])[CH:28]([C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:51])[CH:28]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)C(Cc1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(Cc1ccccc1)c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 3-phenyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=[O:5].[CH3:14][Mg]Br.CCOCC.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH:4]([OH:5])[CH3:14]
Reactant: C[Mg]Br
Reactant: O=Cc1c(Cl)cccc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)benzaldehyde (266.9 mg, 1.280 mmol, 1 eq) in anhydrous THF (5 mL) at 0° C. under nitrogen, a 3.0 M solution of methylmagnesium bromide in Et2O (0.50 mL, 1.5 mmol, 1.2 eq) was added and the reaction was allowed to stir and warm to ambient temperature overnight. The reaction mixture was again cooled to 0° C. and saturated NH4Cl was added. Diethyl ether was also added and the layers were separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The colorless oil crude was purified by chromatography on silica gel [0.5″×10″ glass column, eluting with 1:1 CH2Cl2:Heptane]. Fractions containing product were combined and concentrated in vacuo, affording the title material as a clear and colorless oil. 1H NMR (400 MHz, CDCl3) δ=1.73 (d, J=6.8 Hz, 3H), 3.04 (br s, 1H), 5.43 (q, J=6.8 Hz, 1H), 7.33 (ddq, J=8.0, 8.0, 0.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H). MS (ES+): m/z 248.01/250.03 (100/37) [MNa+]. HPLC: tR=3.26 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:3].[NH2:27][C:28]1[N:33]=[C:32]([NH2:34])[C:31]([C:35]#[N:36])=[C:30](Cl)[N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:27][C:28]1[N:29]=[C:30]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH3:3])[C:31]([C:35]#[N:36])=[C:32]([NH2:34])[N:33]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 95 °C
Yield: 35.8 %

Procedure:
To a 25 mL pear flask were added tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (0.076 g, 0.21 mmol) and 2,4-diamino-6-chloropyrimidine-5-carbonitrile (0.054 g, 0.32 mmol) in DMSO (1 mL) to give a yellow suspension. Triethylamine (0.088 mL, 0.63 mmol) was added and the mixture was heated to 95° C. for 2 hours. The reaction appeared to stall so 1 equivalent of triethylamine was added. After a total of 4 hours of heating, the mixture was cooled and the reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by preparative HPLC (acid mode, 20-25% ACN/water gradient). The product-containing fractions were combined, neutralized with a small amount of saturated NaHCO3, concentrated in vacuo to remove ACN, and then extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a pale beige solid (37 mg, 36%). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 11H), 1.87 (br s, 2H), 2.72 (br s, 2H), 2.97 (br s, 2H), 3.70 (s, 3H), 4.80-5.11 (m, 4H), 5.92 (br s, 1H), 6.59 (d, J=2.27 Hz, 1H), 6.76 (d, J=6.06 Hz, 1H), 7.16 (d, J=2.78 Hz, 2H), 7.32 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C24H32N10O2, 493. found 493.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:8]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 67.8 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.94 g, 3.8 mmol), sodium hydride (60% in oil, 0.148 g, 3.7 mmol) and cyclopentyl-bromide (0.43 mL, 4.0 mmol) to give the title compound (0.80 g) as a white solid,
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:16])([F:17])[F:15])=[CH:11][CH:12]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])[CH2:46][CH2:45]1)=[O:19]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccc(OC(F)(F)F)cc3)noc2N)CC1
Yield: 70.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (603 mg, 1.30 mmol, 71%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:12][CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: C[O-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(Br)cc1F

Procedure:
Reaction of 4-bromo-2-fluorobenzonitrile 11 with sodium methoxide in methanol gives 35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:26][CH3:27])[C:19]([NH:20][CH2:21][CH:22]3[CH2:25][CH2:24][O:23]3)=[C:15]2[CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[CH:30]1([CH2:33]Br)[CH2:32][CH2:31]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:30]1([CH2:33][N:20]([C:19]2[C:18]([S:26][CH3:27])=[N:17][N:16]3[C:11]([C:4]4[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=4[O:2][CH3:1])=[CH:12][CH:13]=[CH:14][C:15]=23)[CH2:21][CH:22]2[CH2:25][CH2:24][O:23]2)[CH2:32][CH2:31]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CCO3)c(SC)nn12
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CCO3)c(SC)nn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
After dissolving N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)amine (8 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 1.6 mg) was added while cooling on ice, and then cyclopropylmethyl bromide (3.8 μL) was added and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (1.8 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a yellow oil.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=O>>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]2[C:17]=1[CH2:23][CH2:24][CH2:25][C:26]2=[O:28]
Reactant: O=C(O)CCCc1ccc(F)cc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C1CCCc2c(F)cc(F)cc21
Reaction time: 2 h

Procedure:
120 g of Polyphosphoric acid and 12 g of phosphorous pentoxide are stirred to homogeneity at 60°. 43 g of 4-(2,4-Difluorophenyl)butyric acid are added and the mixture stirred for 11/2 hours at 80°, poured onto ice-water and extracted with ether. The combined organic phases are washed with sodium carbonate solution and sodium chloride solution, dried, stirred with a little active charcoal and evaporated. The crude product can be purified by silica gel chromatography (eluant:hexane/ethylacetate=4/1) or vacuum sublimation at 0.65 mbar/100°, m.p. 89°-91°.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Br:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[N:24]([C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:23][CH2:22]2
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 130-132° C.; 1H NMR (300 MHz, CDCl3): δ 6.92 (d, J=2.6 Hz, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 6.73 (s, 1 H), 4.81 (brs, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.11 (t, J=7.7 Hz, 2 H), 1.87-1.73 (m, 2 H), 1.70-1.60 (m, 2 H), 0.89 (s, 6 H); HRMS (ESI) calcd for C18H22N3O2BrCl (M+H)+: 426.0584; found m/z 426.0606.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[CH3:23][S-:24].[Na+]>CO>[CH3:15][C:14]([C:12]1[CH:13]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:24][CH3:23])[N:7]=2)[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:17])[CH3:16]
Reactant: C[S-]
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Agent: [Na+]
Solvent: CO
Product: CSCc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Temperature: 75 °C

Procedure:
A mixture of 2.3 g (0.007 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.7 g (0.009 mole) of sodium thiomethoxide in methanol (90 ml) is heated at 75° C. for 1.5 hours. The solution is concentrated to one-third the volume (~30 ml) and diluted with water (50 ml), acidified (pH 4) with 1N hydrochloric acid and extracted with ethyl acetate (2×50 ml). The organic phase is washed with saturated sodium chloride (2×40 ml), dried (anhydrous magnesium sulfate) and evaporated to give a solid. Recrystallization from ethyl acetate and hexane affords 1.3 g (55%) of analytically pure (2,6-bis(1,1-dimethylethyl)-4-[3-[(methylthio)methyl]-1,2,4-oxadiazol-5-yl]phenol, mp 97°-98° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[O:16][CH:17]=[C:18]([C:20]([OH:22])=O)[N:19]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(=O)([O-])O.[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1([C:15]2[O:16][CH:17]=[C:18]([C:20](=[O:22])[NH2:24])[N:19]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(c2nc(C(=O)O)co2)CC1)OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1coc(C2(NC(=O)OCc3ccccc3)CC2)n1
Temperature: 60 °C
Yield: 83.3 %

Procedure:
To a solution of 2-(1-benzyloxycarbonylamino-cyclopropyl)-oxazole-4-carboxylic acid (0.20 g, 0.66 mmol) in DMF (3 mL) was added HATU (0.25 g, 0.66 mmol) and Et3N (0.16 g, 2.0 mmol). Ammonium hydrogen carbonate was then added and the reaction vessel sealed. The mixture was heated at 60° C. for 18 h. The reaction was allowed to cool to room temperature and diluted with water. The mixture was extracted with EtOAc (3×100 mL) and the combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give [1-(4-carbamoyl-oxazol-2-yl)-cyclopropyl]-carbamic acid benzyl ester (0.17 g, 0.55 mmol).
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7](=[C:13](/[NH2:15])\[CH3:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])C>CN(C)C=O>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[CH:5][C:4](=[O:3])[NH:15][C:13]=1[CH3:14])=[O:9])[CH3:12]
Reactant: CCOC(=O)/C=C/C(C(=O)OCC)=C(\C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(=O)[nH]c1C

Procedure:
A solution of intermediate (5a), (E)-4-[1-amino-eth-(Z)-ylidene]-pent-2-enedioic acid diethyl ester (51 g, 225 mmol) in N,N-dimethylformamide (250 mL) was heated at 175° C. for 24 hours to give a dark brown solution. The resulting solution was allowed to cool and a pale brown precipitate slowly formed. The precipitate was removed by filtration and the solids washed with dichloromethane (75 mL) and hexane (100 mL) to give a pale yellow powder. The solids were dried in vacuo (60° C.) to give the title compound as a pale yellow powder, 14.45 g (36%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=[CH:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=[CH:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC1CCCN(Cc2ccccc2)C1
Reactant: c1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN2CCCC2Cn2ccc3cccnc32)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of 1-benzyl-3-chloropiperidine (3.83 g, 18.3 mmol), 1H-pyrrolo[2,3-b]pyridine (4.4 g, 36.5 mmol) and cesium carbonate (17.8 g, 54.8 mmol) in DMSO is stirred at 80° C. under a nitrogen atmosphere for 24 h. The reaction is monitored by thin layer chromatography. Two additional amounts of 1-benzyl-3-chloro-piperidine (3.83 g and 1.91 g) are added at 12 h intervals. After 48 h, the mixture is cooled, treated with water and extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine and concentrated in vacuo. The resultant residue is purified by flash chromatography (4–5% methanol in CH2Cl2 as eluent) to afford the title compound as an oil, 6.5 g (60% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[F:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(F)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(F)c(CBr)c1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
3.00 g of ethyl 4-fluoro-3-methylbenzoate was dissolved in 50.0 mL of carbon tetrachloride, and 4.40 g of N-bromosuccinimide and 1.35 g of 2,2′-azobisisobutyronitrile were added thereto, followed by heating under reflux for 4 hours. The reaction liquid was cooled to room temperature, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to obtain 1.73 g of ethyl 3-(bromomethyl)-4-fluorobenzoate.