Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:25]([I:35])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([O:16][C:18]2[C:19]3[C:26]([C:27]4[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=4)=[C:25]([I:35])[O:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCc1ccc(-c2c(I)oc3ncnc(Cl)c23)cc1
Reactant: O[C@@H]1CCCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1ccc(-c2c(I)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1

Procedure:
Add 106 mg (2.65 mmol) of sodium hydride (60% dispersion in mineral oil) to a solution of 483 mg (2.53 mmol) of (3R)-1-benzylpiperidin-3-ol [H. Tomori, Bull. Chem. Soc. Jpn. 69, 1, 207-216 (1996)] in 5 ml of THF. After stirring for ten minutes, add a solution of 1020 mg (70% purity, 1.86 mmol) of 4-chloro-5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidine in 5 ml of THF and 47 mg (0.13 mmol) of tetra-n-butylammonium iodide. Stir the reaction mixture at room temperature for five hours. After adding water and ethyl acetate, wash the removed organic phase with 1N hydrochloric acid and satd. sodium chloride solution and then concentrate under reduced pressure. Take up the residue in acetonitrile and purify by means of preparative RP-HPLC (gradient: water/acetonitrile). 266 mg (20% of theory) of the desired product are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]=CC)[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:9]=2)[CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([CH2:16][CH2:15][CH2:14][C:12]2[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:25]=3)[N:9]=[C:8]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[CH:13]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC=CCCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: C1CCNC1
Product: Cc1cc(Nc2cc(CCCN3CCCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1

Procedure:
Example 44 was prepared by an analogous method to that described in Example 43 starting from 4-(5-methyl-1H-pyrazol-3-ylamino)-6-(pent-3-en-1-yl)-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Example 34) and pyrrolidine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]2.Br[CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([O:23][CH2:25][C:26]#[N:27])[CH:17]=[CH:16]2
Reactant: N#CCBr
Reactant: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: Cn1c(-c2ccccc2)ccc1-c1ccc2cc(OCC#N)ccc2c1
Reaction time: 1.67 h
Yield: 97.3 %

Procedure:
In a similar manner as described in step 1 of Example 4, the title compound was prepared from 6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.45 g, 1.5 mmol), prepared in the previous step, bromoacetonitrile (0.216 g, 1.8 mmol) and cesium carbonate (2.45 g, 7.52 mmol) with the exception that the reaction was complete after 100 minutes at ambient temperature. The crude material was dissolved in methylene chloride and filtered through silica gel (45 g, 200–300 mesh). The solvent was removed under reduced pressure to give {[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as an off-white solid (0.494 g, 97%), mp 191.5–192.5° C. Elemental Analysis for C23H18N2O Calc'd: C, 81.63; H, 5.36; N, 8.28. Found: C, 81.06; H, 5.14; N, 8.04.
Reaction SMILES: [CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39](O)[CH:40]([OH:45])[CH2:41][CH2:42][CH2:43][OH:44].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:19]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:45][CH:40]([CH2:41][CH2:42][CH2:43][OH:44])[CH2:39][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Reactant: OCCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CCCO)O1
Temperature: 25 °C

Procedure:
A mixture of dilinoleyl ketone (I, previously prepared as described in Example 1, 1.0 g, 2 mmol), 1,2,5-pentanetriol (crude, 0.25 g, 2 mmol) and pyridinium p-toluenesulfonate (100 mg, 0.4 mmol) in 150 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (3×40 mL), brine (50 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent gave a yellowish oily residual (1.1 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with 0-1% methanol in dichloromethane as eluent. This afforded 0.90 g of pure II as colourless oil.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH2:17]([O:19][C:20]([C:22]1[N:23]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)[C:24]2[C:29]([C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[O:21])[CH3:18].[NH4+].[Cl-].Cl>CCOCC.C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I.CN1CCCC1=O>[CH2:17]([O:19][C:20]([C:22]1[N:23]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)[C:24]2[C:29]([C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:27]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1)=[CH:26][CH:25]=2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(Br)cc12
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCOC(=O)c1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(F)(F)F)cn3)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
t-BuLi (1.5 M in pentane, 4.5 mL, 3 mmol) was added dropwise at −78° C. to Et2O (15 mL). 2-Bromo-5-trifluoromethylpyridine (762 mg, 3.37 mmol) in Et2O (5 mL) was added via syringe. After 20 min at −78° C. the cold mixture was cannulated to cooled (−78° C.) ZnCl2 (1 M in Et2O, 7.4 mL, 7.4 mmol). The mixture was allowed to warm to rt and was stirred at rt for 3 h. The mixture was diluted with THF (15 mL) and added to a mixture of 5-bromo-1-(4-isopropoxyphenyl)indole-2,3-dicarboxylic acid diethyl ester (800 mg 1.69 mmol, see step (c) above), Pd(dppf)Cl2 (165 mg, 0.20 mmol), CuI (77 mg, 0.40 mmol) and NT-methylpyrrolidin-2-one (5.3 mL). The mixture was heated at 80° C. for 6 h, poured into NH4Cl (aq, sat, 50 mL) and extracted with t-BuOMe (3×30 mL). The combined extracts were washed with brine, dried (Na2SO4) and filtered through Celite®. The solids were washed with t-BuOMe and the combined filtrates were concentrated. The residue was dissolved in anhydrous Et2O and HCl (4 M in dioxane, 500 μL, 2.0 mmol) was added. After 10 min the mixture was concentrated and the residue was treated with anhydrous Et2O to give the sub-title compound. Yield 900 mg (92%).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH3:21][N:22](C=O)C>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:21]([C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[N:22]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
To a solution of 2-iodoadenosine (0.500 g, 1.27 mmol) in DMF (70 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.220 g, 0.19 mmol) and n-tributyltin cyanide (0.442 g, 1.39 mmol). The mixture was stirred at 120° C. for 20 h under nitrogen. The solvent was then evaporated and the residue was purified on silica gel to give 2-cyanoadenosine in 86% yield. 2-Cyanoadenosine was converted to I by using in sequence the following procedures: Procedure A (60% yield), Procedure B (89% yield), Procedure C (60% yield), Procedure D (63% yield), Procedure E (70% yield) and Procedure F (70% yield): mp 195°-197° C.; 13C NMR (Me2SO-d6) 625.4, 32.0, 62.6, 82.3, 84.7, 117.0, 120.7, 136.6, 141.5, 147.9, 156.2; 1H NMR (Me2SO-d6) δ2.06 (m, 2H), 2.39 (m, 2H), 3.56 (m, 2H), 4.13 (m, 1H), 4.92 (m, 1H), 6.24 (m, 1H), 7.90 (br.s, 2H), 8.59 (s, 1H); UV (H2O) λmax 297 nm (ε6470), 266 nm (ε9980), 260 nm (ε9270); FAB HRMS obsd (M+ +H) 261.1069, calcd for C11H12N6O2 261.1099.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][C:14]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]([OH:25])[CH2:17]3)[CH2:13]2)=[CH:4][CH:3]=1.[CH3:27][N:28]=[C:29]=[O:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][C:14]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]([O:25][C:29](=[O:30])[NH:28][CH3:27])[CH2:17]3)[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: O=C(CCCN1CCC2(CC(O)c3ccccc32)C1)c1ccc(F)cc1
Solvent: ClCCl
Product: CNC(=O)OC1CC2(CCN(CCCC(=O)c3ccc(F)cc3)C2)c2ccccc21
Reaction time: 20 h

Procedure:
9.0 g of p-fluoro-4-(3-hydroxyspiro[indan-1,3'-pyrrolidin]-1'-yl) butyrophenone and 2.0 g of methyl isocyanate are dissolved in 50 cc of methylene chloride. After allowing the reaction solution to stand at room temperature for 20 hours, it is concentrated by evaporation, and the resulting oil is converted into the hydrogen fumarate. After recrystallization from ethanol/ether, the hydrogen fumarate of the title compound has a M.P. of 167°-169°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1nc2ccccc2s1
Product: CCOC(=O)C(=O)Nc1nc2ccccc2s1
Yield: 44 %

Procedure:
A mixture of 2-aminobenzothiazole (5.0 g., 0.033 mol) and diethyl oxalate (50 ml.) is heated at reflux for 2.5 hours. A white solid precipitates from the cooled reaction mixture. The solid is recrystallized from ethanol (with a hot filtration) to give the desired product (3.72 g., m.p. 185°-186°, 44%).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[CH:4]([CH3:6])[CH3:5].[BH4-].[Na+]>CO>[CH2:3]([O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][CH2:1][NH2:2])[CH:4]([CH3:6])[CH3:5]
Reactant: CN
Reactant: COc1cccc(C=O)c1OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CCN)c1OCC(C)C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of methylamine (64 mL of a 2.0 M solution in MeOH, 128 mmol) was added to 2-isobutoxy-3-methoxybenzaldehyde (2.45 g, 11.9 mmol) and the solution was stirred for 18 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (64 mL) and treated with NaBH4 (0.616 g, 16.3 mmol). After stirring for 7 h, the mixture was concentrated under reduced pressure and then dissolved in 1 N NaOH (57 mL). The mixture was extracted with Et2O (3×75 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (2.43 g, 91%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.01-6.88 (m, 3H), 3.76 (s, 3H), 3.63 (t, J=6.4 Hz, 3H), 2.25 (s, 3H), 2.00-1.93 (m, 1H), 1.84 (br s, 1H), 0.98 (d, J=6.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH:3]([C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[C:16]([Cl:22])[CH:15]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.[CH:57]1([C:60](Cl)=[O:61])[CH2:59][CH2:58]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:24][C:2]([F:1])([F:23])[CH:3]([C:14]1[CH:15]=[C:16]([Cl:22])[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH:13][C:60]([CH:57]2[CH2:59][CH2:58]2)=[O:61])=[CH:8][CH:7]=1
Reactant: NNc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Reactant: O=C(Cl)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NNc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1)C1CC1
Yield: 50.1 %

Procedure:
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine (0.1 g, 0.3 mmol) in CH2Cl2 (10 mL) was added DIEA (65 mg, 0.51 mmol), HOBt.H2O (59 mg, 0.38 mmol), EDC.HCl (73 mg, 0.38 mmol) and cyclopropanecarbonyl chloride (0.024 g, 0.28 mmol), and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with satd aq NaHCO3 solution and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 5-25% EtOAc in petroleum ether) afforded the title compound as a solid (65 mg, 55%): mp 138-140° C.; 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, J=8.4 Hz, 2H), 6.65 (d, J=15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd, J=15.6, 8.8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); ESIMS m/z 461.32 ([M−H]−).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([NH:19][CH3:20])=[O:18])[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([NH:19][CH3:20])=[O:18])[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CNC(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CNC(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzamide (A-35) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=390.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].Cl[CH2:11][O:12][CH3:13]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:11][O:12][CH3:13])[CH:9]=1)=[O:4]
Reactant: COCCl
Reactant: COC(=O)c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCn1cnc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
Imidazole-4-carboxylic acid methylester (5.00 g) was dissolved in acetonitrile (100 mL), and under ice cooling and stirring, were added TEA (11.1 mL) and then chloromethylmethylether (4.47 mL), followed by heating to reflux for 3 days. After being allowed to cool to room temperature, the mixture was diluted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (methanol/chloroform=0%→7%) using silica gel column (product name: Hi-Flash Column 5 L, manufactured by Yamazen Corporation) to afford the title compound (3.64 g).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[N:29]=[CH:30][S:31][CH:32]=3)[CH:25]=[C:24]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:23]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])C.Cl>CCO.[OH-].[Na+]>[C:39]([CH2:38][CH2:37][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[N:29]=[CH:30][S:31][CH:32]=3)[CH:25]=[C:24]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])([OH:41])=[O:40]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cscn3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cscn2)c1
Temperature: 70 °C
Yield: 46.5 %

Procedure:
To a solution of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-methanesulfonyl-5-thiazol-4-yl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (280 mg, 0.434 mmol) in EtOH (20 mL), 3N NaOH (1 mL) was added and heated at 70° C. for 2 h. The reaction was acidified with 3N HCl (1.1 mL). Concentration under reduced pressure gave an oil. Preparative HPLC provided title compound (119 mg, 46% yield). LC/MS indicated a purity of 92% as measured by UV 214 nM. HR-ES(+): calculated for C29H36NO8S2 (M+H)1+ 590.1877, found 590.1876.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[C:3]=1[C:4]#[N:5]
Reactant: CN1CCNCC1
Reactant: N#Cc1c(F)cccc1F
Product: CN1CCN(c2cccc(F)c2C#N)CC1

Procedure:
2,6-Difluorobenzonitrile is reacted with N-methyl piperazine following the procedure of Example 5. The reaction mixture is extracted with methylene chloride after addition of water. The methylene chloride is extracted with dilute HCl which is basified and extracted with methylene chloride. The resulting crude oil after evaporation is taken in ethanol and i-PrOH-HCl is added to give the title compound as the hydrochloride salt, 1.4 g m.p. 245°-247° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]([NH:23][CH3:24])=[O:22])=[CH:16][N:17]2[CH3:20])=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[CH3:24][NH:23][C:21]([C:15]1[C:14]2[C:18](=[CH:19][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:17]([CH3:20])[C:16]=1[Cl:1])=[O:22]
Reactant: CNC(=O)c1cn(C)c2cc(OC)ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(Cl)n(C)c2cc(OC)ccc12
Temperature: 60 °C
Yield: 86.6 %

Procedure:
N-Chlorosuccinimide (0.150 g, 1.12 mmole) was added to a solution of 6-methoxy-N,1-dimethyl-1H-indole-3-carboxamide 75a (0.243 g, 1.11 mmole) in CCl4 (10 ml) and DMF (3 ml). The reaction mixture was heated to 60° C. for 3 h and concentrated. The residue was purified by reverse phase chromatography eluting with 0–1% CH3OH in 1:1 EtOAc and CH2Cl2 to give a brown colored oil (0.243 g, 87% yield); 1H NMR (300 MHz, CDCl3) δ 7.61 (1H, d, J=8.6 Hz), 6.38 (1H, d, J=8.6 Hz), 6.19 (1H, s), 3.35 (3H, s), 2.96 (3H, s), 2.52 (3H, s); ESIMS (MH+): 253.05.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11][C:10]=1[C:25]([OH:27])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:28]([O:35][CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Si:28]([O:35][CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C:25]([C:10]1[NH:11][C:12]([CH2:16][C:17]2[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:23])=[N:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Reaction time: 0.67 h
Yield: 56.9 %

Procedure:
5-(Benzyloxy)-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (62) (0.2 g, 494 μmol, Eq: 1.00) and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-2-amine (118 mg, 543 μmol, Eq: 1.1) were dissolved in pyridine (3 ml) and cooled in an ice/NaCl bath. POCl3 (227 mg, 138 μl, 1.48 mmol, Eq: 3) was added dropwise. After the addition was complete, stirring of the reaction mixture was continued at 0° C. for approx. 40 minutes. The reaction mixture was quenched with ice and extracted twice with ethyl acetate. The organic layers were washed with NaHCO3, were combined, dried over Na2SO4, filtered and concentrated. The remaining oil was purified by SiO2 flash chromatography (24 g SiO2, hexanes/ethyl acetate 0-50% ethyl acetate). Product containing fractions were combined and concentrated. The remaining oil was treated with hexanes and concentrated again to afford 5-benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (63) (0.17 g, 281 μmol, 57.0% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:3].[Li+].[OH-]>CO.O.C(O)(C(F)(F)F)=O>[NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:3]
Reactant: CCOC(=O)CCc1ccc(NC(=O)c2cccc(NC(N)=O)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1cccc(C(=O)Nc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The Compound of Example 22 (0.12 g, 0.34 mmol) was dissolved in MeOH (2 mL) and 1 M LiOH (1 mL) was added. The reaction was stirred at room temperature over 16 hours. The reaction was concentrated in vacuo to give a white solid. The solid was dissolved in a small amount of H2O and acidified with 1 drop of TFA. The mixture was concentrated in vacuo and the residue was purified by HPLC—Method 1 to give a white solid (0.06 g,).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CC(C)CN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and isobutylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.57 Hz, 6H) 1.87 (dt, J=13.52, 6.63 Hz, 1H) 2.44 (s, 3H) 3.13 (t, J=6.32 Hz, 2H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.18 (br. s., 1H) 8.43 (d, J=6.82 Hz, 2H) 8.70 (t, J=5.31 Hz, 1H) 8.92 (s, 1H) 13.18 (br. s., 1H). MS m/z [M+H]+ 376.2.