Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:25]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:25][C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)[C:9]=2[C:10]([O:15][CH3:16])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Cl)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (30.3 mg) obtained in Step A of Example 286 in DMF (2 mL) was added N-chlorosuccinimide (13.0 mg) at 0° C., and the mixture was stirred overnight at 80° C. To the reaction mixture was added N-chlorosuccinimide (6.0 mg), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added N-chlorosuccinimide (6.0 mg), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then HPLC (column: L-column2 ODS (trade name) 20 mmID×150 mmL, 5 μm, manufactured by Daicel Chemical Industries, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound (19.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:14]1[C:13](=[O:16])[CH:12]=[C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:15]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1
Reactant: BrCc1ccccc1
Product: COc1ccc(-c2cc(=O)n(Cc3ccccc3)nc2-c2ccc(OC)c(F)c2)cc1
Yield: 95.8 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one and benzyl bromide as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 95.8%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:31])C(=O)C1>C(Cl)Cl>[I:31][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To the solution of 1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole (2.3 g, 9.73 mmol) in CH2Cl2 (6 ml) was added TFA (3.0 ml, 38.9 mmol), and NIS (2.41 g, 10.71) at rt. After being stirred at rt for 3 h, the reaction mixture was diluted with CH2Cl2, quenched with NaHCO3 (aq), washed with aq Na2S2O3, water and brine. Dried over Na2SO4, filtered and concentrated to afford 5-iodo-1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole (3.4 g) which was used in the next step without further purification. LCMS: [M+1]+=363.0
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]2)=[O:16])[NH2:14])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=1)#[N:33]>>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]2)=[O:16])[NH:14][C:40]([C:37]2[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][N:38]=2)=[O:41])=[CH:8][CH:7]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H](N)Cc2ccc(OC(C)(C)C)cc2)CC1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)c2ccc(C#N)cn2)CC1
Yield: 47.8 %

Procedure:
Reaction of 2.5 g of t-butyl [[1-[3-(p-t-butoxyphenyl)-L-alanyl]-4-piperidinyl]oxy]acetate with 0.85 g of 5-cyano-2-picolinic acid (as in Example 1d) yields 1.55 g of t-butyl [[1-[3-(p-t-butoxyphenyl)-N-[[5-cyano-2-pyridyl]carbonyl]-L-alanyl]-4-piperidinyl]oxy]acetate. M.p. 122-123° C. (diethyl ether/petroleum ether 4:1). MS (FAB): 565 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:36])[CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:36])[CH:16]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 3-nitro-benzaldehyde (15.1 g, 0.1 mol) in CH2Cl2 (200 mL) was added dropwise (triphenyl-λ5-phosphanylidene)-acetic acid ethyl ester (34.8 g, 0.1 mol) in CH2Cl2 (100 mL) at 0° C. After the addition was complete, the resulting mixture was stirred for 1 h. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3-(3-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6% yield). 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.23 (dd, J=0.8, and 8.0 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 1.36 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=2[F:35])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(Cl)c1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.060 g, 0.162 mmol) in dry THF (5 mL) was added DIPEA (3 mL) and stirred for 20 minutes. The reaction mixture was cooled to 0° C. and 2-flurobenzoyl chloride (0.038 g, 0.243 mmol) was added and stirred for 3 h at room temperature. The reaction mass was quenched in water, extracted with DCM:MeOH and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.030 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 4.50-4.52 (d, J=8 Hz, 2H), 7.25-7.33 (m, 2H), 7.52-7.55 (m, 2H), 7.63-7.65 (m, 2H), 7.72-7.86 (d, J=2.4 Hz, 1H), 7.83-7.86 (d, J=11.6 Hz, 2H), 8.17-8.20 (d, J=11.6 Hz, 2H), 8.95-8.99 (t, 1H), 12.69 (br s, 1H); MS (m/z): 491.17 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[O:22]1[CH2:26][CH2:25][C@H:24](O)[CH2:23]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[C:3]([O:21][C@@H:24]2[CH2:25][CH2:26][O:22][CH2:23]2)=[C:4]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10]
Reactant: O[C@H]1CCOC1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1CCOC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of 17D (566 mg, 1.885 mmol), (S)-tetrahydrofuran-3-ol (365 mg, 4.15 mmol) and PPh3 (1088 mg, 4.15 mmol) in THF (5 mL) was added DIAD (0.822 mL, 4.15 mmol) dropwise. The reaction was stirred at 0° C. for 0.5 h and then at rt for 16 h. The mixture was concentrated and purified by prep HPLC to give 38A (700 mg, 1.890 mmol, 100% yield). MS (ESI) m/z: 371.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccccc2OC)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2OC)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 17, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([OH:29])[CH:27]=[CH2:28]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:29][CH2:26][CH:27]=[CH2:28])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: C=CCO
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: C=CCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 44a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) and allyl alcohol (4 ml) the subtitle compound was obtained (216 mg, 97%). 1H NMR (DMSO) δ 8.83(d, 1H), 8.38(dd, 1H), 8.06(d, 1H), 7.82(d, 1H), 7.69(m, 3H), 7.44(t, 3H), 7.33(t, 1H), 6.08(m, 1H), 5.60(dd, 1H), 5.30(dd, 1H), 4.90(m, 2H).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.O>CN(C=O)C>[C:17]1([CH:16]2[O:23][C:4]3[CH:5]=[N:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=3[NH:14][CH2:15]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(CNc1c(Br)cnc2ccccc12)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C2CNc3c(cnc4ccccc34)O2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Sodium hydride (obtained from 2 g of 50% suspension in mineral oil) was added to a solution of 3-bromo-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine (10 g) in 50 ml of DMF and the mixture was stirred at 90° C. for two hours. After cooling to room temperature, it was poured into 250 ml of water and the product extracted with two portions of 100 ml dichloromethane. The dichloromethane layer was dried over sodium sulfate and concentrated. The oily residue was dissolved in 80 ml of isopropanol, the solution was poured into 250 ml of ice water and the mixture was stirred for 1 hour. The solid was filtered and recrystallized from isopropanol. The yield was 3.1 g, mp 194°-195° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[N:13][NH:14][CH:15]=2)=[N:9][CH:10]=1)[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH2:17]([O:16][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[N:14][N:13]([CH3:19])[N:12]=2)=[N:9][CH:10]=1)[CH3:18]
Reactant: CCOC(OCC)c1ccc(-c2c[nH]nn2)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(OCC)c1ccc(-c2cnn(C)n2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.3 %

Procedure:
In acetonitrile (25 mL) was dissolved 5-(diethoxymethyl)-2-(1H-1,2,3-triazol-4-yl) pyridine (1.34 g, 5.40 mmol) obtained in Step 4. To the solution were added potassium carbonate (2.24 g, 5.40 mmol) and iodomethane (0.405 mL, 6.48 mmol) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 5-(diethoxymethyl)-2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (698 mg, 49% yield).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[S:31][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:29][N:28]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:35]1[CH2:34][CH2:33][N:32]([C:30]2[S:31][C:27]([C:26]([F:38])([F:25])[F:39])=[N:28][N:29]=2)[CH2:37][CH2:36]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 34 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (Example A22) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 34%). MS (m/e): 495.0 (M+H+, 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].Cl.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:37]3[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: F[C@@H]1CCNC1
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Agent: Cl
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(CCCCCCN3CC[C@@H](F)C3)c2n1

Procedure:
Prepared similarly to Intermediate 24 from 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(3,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine and (R)-3-fluoropyrrolidine hydrochloride
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[NH:8][C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:11]=2[CH3:12])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[O:41][CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[N:44]=1>CN(C)C=O>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([CH:7]2[N:8]([CH2:39][C:40]3[O:41][CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[N:44]=3)[C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[C:11]([CH3:12])=[C:6]2[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:31][CH:30]=1)#[N:29]
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1coc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1coc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4-{5-(cyclopropylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 22) (150 mg, 0.35 mmol) and potassium carbonate (98 mg, 0.71 mmol) in dimethylformamide (3 ml) is added methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (93 mg, 0.53 mmol). The reaction mixture is stirred at room temperature overnight, then an additional equivalent of potassium carbonate (0.35 mmol) and methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (0.35 mmol) are added, and the solution is stirred an additional 72 hours. The reaction mixture is quenched with water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by HPLC (RP18 column; eluent: acetonitrile/water 30:70→90:10).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][C@H:17]1[C:21](=[O:22])[O:20][CH2:19][C@@H:18]1[NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[Al](C)C>C1COCC1>[OH:20][CH2:19][C@H:18]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:17]([C:21](=[O:22])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([CH3:15])[CH:3]=1)[CH3:16]
Reactant: C[C@H]1C(=O)OC[C@@H]1NC(=O)OCc1ccccc1
Reactant: Cc1cc(N)ccc1N1CCOCC1=O
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)[C@H](C)[C@H](CO)NC(=O)OCc2ccccc2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 2b from 4-(4-amino-2-methyl-phenyl)-morpholin-3-one and benzyl [(3R,4R)-4-methyl-5-oxo-tetrahydrofuran-3-yl]-carbamate with trimethylaluminium in THF and subsequent purification by reversed-phase chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[N:16]=[CH:15][C:14]3[CH:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=O)[NH:10][C:9]=3[N:8]2[N:24]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:27])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Cl:27][C:11]1[N:10]=[C:9]2[C:14]([CH:15]=[N:16][C:7]3[N:8]2[N:24]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2ncc3cc(-c4ccccc4)c(Cl)nc3n2n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a 100 mL three necked round bottom flask was added 2-tert-butyl-7-phenyl-9H-1,4,9,9b-tetraaza-cyclopenta[a]naphthalen-8-one (1 g, 3.14 mmol, 1.00 equiv), CHCl3 (20 mL), thionyl chloride (0.94 mL, 4.00 equiv) and DMF (48 μL, 0.20 equiv) and the resulting solution was stirred for 1 h at 70° C. under nitrogen. After 1 h, additional thionyl chloride (0.47 mL, 2.00 equiv) and DMF (48 μL, 0.20 equiv) was added and the resulting solution was stirred for an additional 2 h at 70° C. After a total of 3 h, the resulting mixture was concentrated under vacuum and the pH value of the solution was adjusted to 7 with saturated aqueous NaHCO3 solution. The resulting solution was extracted with ethyl acetate and the organic layers were combined and dried and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether as the eluent to give the Compound [CCXXXIX] as a yellow solid. 1H NMR (300 MHz, DMSO, δ, ppm) 9.09 (s, 1H), 8.74 (s, 1H), 7.60-7.52 (m, 5H), 6.97 (s, 1H), 1.44 (s, 91-1); LC-MS: m/z=337 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[N:10]([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[C:5]([C:28]2[CH:29]=[CH:30][C:31]([F:32])=[C:26]([Cl:25])[CH:27]=2)=[N:6][N:7]2[CH2:12][CH:11]([C:13]([F:15])([F:14])[F:16])[N:10]([C:17]([O:19][CH2:1][CH2:4][CH2:8][CH3:9])=[O:18])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC1C(F)(F)F
Temperature: 100 °C
Reaction time: 18 h
Yield: 142 %

Procedure:
To a solution of Intermediate 346F (0.35 g, 0.761 mmol) and (3-chloro-4-fluorophenyl)boronic acid (0.215 g, 0.837 mmol) in DMF (2 mL) was added a solution of Na2CO3 (0.242 g, 2.282 mmol) in water (1 mL) and the reaction mixture was purged with nitrogen for 5 min. Pd(PPh3)4 (0.044 g, 0.038 mmol) was then added and the reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to RT and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 5% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 346G as a white solid (0.25 g, 68%). MS(ES): m/z=464.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.82 (m, 1H), 7.73-7.67 (m, 1H), 7.65-7.52 (m, 1H), 7.51-7.44 (m, 1H), 7.41-7.21 (m, 2H), 5.17-5.05 (m, 1H), 4.65-4.48 (m, 3H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:19]1([C:25]#[C:26][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:10]#[C:8][C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)=[CH:14][CH:13]=3)=[O:11])=[O:9])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(C(=O)c1ccc(C#Cc2ccccc2)cc1)c1ccc(C#Cc2ccccc2)cc1

Procedure:
A solution of 4,4'-dibromobenzil (15.8 g, 0.0431 mol), phenylacetylene (5.06 g, 0.0495 mol), (PPh3)2PdCl2 (0.151 g, 0.0002 mol) and CuI (0.820 g, 0.0043 mol) in diethylamine (150 mL) is heated at reflux overnight. The reaction mixture is concentrated to dryness, then taken up in CH2Cl2 (150 mL), washed with 1 M HCl, 10 percent Na2CO3 /H2O, brine and dried (Na2SO4), then concentrated. Crystallization from 2-propanol gives 7.92 g (45 percent) as a light tan solid, mp 168° C. to 170° C. 1H NMR (CDCl3) δ 7.97 (d, J=8.2 Hz, 4H), 7.64 (d, J=8.2 Hz, 4H), 7.55 (m, 4H), 7.37 (m, 6H); 13C NMR (CDCl3) δ193.03, 132.46, 132.03, 131.82, 130.21, 129.84, 129.06, 128.47, 122.37, 94.28, 88.55.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:21](Cl)(=[O:23])[CH3:22]>CC(N(C)C)=O>[C:21]([NH:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(C)O)c1I
Yield: 87 %

Procedure:
Analogously to Example 3, 5-amino-N-(2-hydroxypropyl)2,4,6-triiodoisophthalamic acid and acetyl chloride are reacted in dimethylacetamide. Yield: 87%, m.p. 276°-278° C., with decomposition.