Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)[C:7](=[O:14])[N:6]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:23]#[N:24])[CH2:18][CH2:17]1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>C(Cl)Cl>[C:23]([CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=1)[N:19]1[CH2:20][CH2:21][CH:16]([O:15][NH:6][C:7]([NH:43][C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=2)=[O:14])[CH2:17][CH2:18]1)#[N:24]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: N#CC(c1ccc(OC(F)(F)F)cc1)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: O
Product: N#CC(c1ccc(OC(F)(F)F)cc1)N1CCC(ONC(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.6 %

Procedure:
Hydrazine monohydrate (0.063 ml, 1.303 mmol) was added to a solution of 2-(4-(1,3-dioxoisoindolin-2-yloxy)piperidin-1-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile (258 mg, 0.434 mmol) in CH2Cl2 (5 ml) and the whole was stirred at room temperature for 16 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 ml), treated with 4-fluorophenyl isocyanate (0.023 ml, 0.200 mmol) and stirred at room temperature for 14 hours. The reaction mixture was concentrated in vauo and the residue was purified by column chromatography (ethyl acetate/hexane: 50/50 to 0/100) and the resulting solid was triturated with ethyl acetate/hexane to give 1-(1-(cyano(4-(trifluoromethoxy)phenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)urea (110 mg, 56%) as a white solid: LCMS: 442 [M+1]+. 1H NMR (DMSO-d6) δ: 1.67 (m, 1H), 1.81 (m, 1H), 1.94 (m, 2H), 2.33 (m, 2H), 2.58 (m, 1H), 2.88 (m, 1H), 3.76 (m, 1H), 5.47 (s, 1H), 7.10 (m, 2H), 7.46-7.60 (m, 6H), 8.62 (s, 1H), 9.43 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]2)=[O:20])[C:6]([C:9](O)=[O:10])=[N:7][CH:8]=1.[Cl-].[NH4+].Cl.C([N:36]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@H:21]2[CH2:22][CH2:23][C@H:24]([C:27]([F:28])([F:29])[F:30])[CH2:25][CH2:26]2)=[O:20])[C:6]([C:9]([NH2:36])=[O:10])=[N:7][CH:8]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cnc(C(N)=O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (150 mg, 0.35 mmol, EXAMPLE 31 Step 4) and ammonium chloride (56 mg, 1.05 mmol) in dichloromethane (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (100 mg, 0.52 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (53 mg, 0.35 mmol) and triethylamine (176 mg, 1.74 mmol) respectively. After being stirred at room temperature for 24 h, water was added to the mixture. The mixture was extracted with dichloromethane, and the extract was dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by NH gel column chromatography (methanol/dichloromethane 1:30) followed by preparative high pressure liquid chromatography (prep. HPLC) (acetonitrile/0.01% aq. ammonia 96:4 to 4:96) to afford 75 mg (50%) of the title compound as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][CH3:22])[C:15]([O:23][CH3:24])=[CH:14]3)=[C:5]([N+:25]([O-])=O)[CH:4]=1>C(OCC)(=O)C.[Pd]>[NH2:25][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:21][CH3:22])[C:15]([O:23][CH3:24])=[CH:14]2
Reactant: COc1cc(-c2ccc3cc(OC)c(OC)cc3c2)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)c(-c2ccc3cc(OC)c(OC)cc3c2)cc1OC
Yield: 108 %

Procedure:
6-(4,5-Dimethoxy-2-nitrophenyl)-2,3-dimethoxynaphthalene (12 mg, 0.03 mmol) was hydrogenated overnight in ethyl acetate (20 mL) at 40-45 lb./sq. in. under catalysis of palladium (10 wt % on activated carbon, 10 mg). The solution was passed through celite bed and the catalyst was washed with ethyl acetate (3×10 mL). Concentration in vacuo gave the crude product. Chromatography using 65:35 hexanes:ethyl acetate gave compound 18 (11 mg) in nearly 100% yield; 1H NMR (CDCl3) d 3.84(3H, s), 3.89(3H, s), 4.01(3H, s), 4.02(3H, s), 6.41(1H, s), 6.80(1H, s), 7.14(1H, s), 7.15(1H, s), 7.43(1H, dd, J=8.4, J=1.6), 7.75(1H, d, J=1.5), 7.75(1H, d, J=8.4); 13C NMR d 56.4, 57.2, 101.3, 106.6, 106.8, 115.2, 119.9, 126.2, 126.8, 127.3, 128.5, 129.9, 135.7, 138.0, 142.7, 149.8, 150.1, 150.3.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=O)[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[O:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2)co1
Solvent: c1ccncc1
Product: Clc1nc(-c2ccccc2)co1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
To a solution of 4-phenyl-1,3-oxazol-2(3H)-one (1.00 g, 62.0 mmol) in phosphorus oxychloride (18 ml) was added pyridine (0.974 ml, 12.0 mmol), and the mixture was stirred at 100° C. for 1 hour and 20 minutes. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1) to give 176 mg (15.7%) of the desired product as a solid.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=[O:8])=CC=1.[O:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=NO)[CH2:14][CH2:13]1>N1C=CC=CC=1>[O:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:8])[CH2:14][CH2:13]1
Reactant: ON=C1CCOc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.5 %

Procedure:
p-Toluenesulfonyl chloride (52.5 g, 275 mmol) was added to a solution of chroman-4-one oxime (44.9 g, 275 mmol) in pyridine (275 ml) and the mixture was stirred for 12 hours at room temperature. Solvent was evaporated under reduced pressure and the residue was partitioned between water and chloroform. The organic layer was washed with 1N aqueous hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropylether, and dried to afford chroman-4-one O-p-toluenesulfoxime (85.1 g, 268 mmol, 97%) as white crystals.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>CC(O)C.N1CCCCC1>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2c(I)cccc2N1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Temperature: 23 °C
Yield: 65.2 %

Procedure:
A mixture of 1,3-dihydro-4-iodo-2H-indol-2-one (404.1 mg, 1.56 mmol) (see Fukuyama et al., supra) and pyrrole-2-carboxaldehyde (163.2 mg, 1.72 mmol) (Aldrich) in 2-propanol (6.2 mL) was treated with 2 drops of piperidine. The reaction mixture was heated at reflux for 24 h and then allowed to cool to 23° C., at which time, the reaction mixture was filtered. The solid was washed several times with cold distilled water and then allowed to air dry to provide pure (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (341.8 mg, 65%) as a yellow solid which was used without further purification. (MP 256-258° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[C:17]([N+:27]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:10]=1.O.O.[Sn](Cl)Cl>CCO>[NH2:27][C:17]1[C:18]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[N:19][C:14]([C:12]2[NH:13][C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[N:10][C:11]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:15][CH:16]=1
Reactant: CC(C)S(=O)(=O)Nc1nc(-c2[nH]c(-c3c(Cl)cccc3Cl)nc2-c2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)S(=O)(=O)Nc1nc(-c2[nH]c(-c3c(Cl)cccc3Cl)nc2-c2ccccc2)ccc1N
Temperature: 25 °C
Yield: 85.3 %

Procedure:
Heat a mixture of propane-2-sulfonic acid {6-[2-(2,6-dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-nitropyridin-2-yl}amide (0.262 g, 0.49 mmol) and tin (II) chloride dihydrate (0.55 g, 2.46 mmol) in EtOH (10 mL) at 100° C. for 1 h. Cool to RT and concentrate to a slurry. Pour the reaction mixture into saturated NaHCO3 (20 mL) and add a filtering agent. Filter and wash with EtOAc. Separate the layers and extract successively with saturated NaHCO3 and saturated aqueous NaCl. Dry the organic layer over Na2SO4 and concentrate to give the title compound (0.21 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[O:18][CH2:19][C:20](=[O:27])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][N:35]=2)[C:30]([CH:37]=O)=[CH:29]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:28]1[C:36]2=[N:35][CH:34]=[CH:33][CH:32]=[C:31]2[C:30]([CH:37]=[C:19]2[O:18][C:17]([NH:16][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[CH:7][C:2]=3[CH3:1])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]2=[O:27])=[CH:29]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(OCc3cccnc3)cc2C)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCc3cccnc3)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.1 %

Procedure:
To a solution of ethyl 2-{[2-methyl-4-(3-pyridinylmethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.032 g, 0.20 mmol) in ethanol (5.0 mL), L-proline (0.0050 g, 0.043 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@H:6]([NH:13][C:14](=[O:36])[CH2:15][NH:16][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-])=O)=[S:24])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)C.N>[Pd].CO>[CH3:1][O:3][C:4](=[O:37])[CH2:5][C@H:6]([NH:13][C:14](=[O:36])[CH2:15][NH:16][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32])=[S:24])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)CCCCNC(=S)Nc1ccccc1[N+](=O)[O-])c1cccnc1
Agent: [Pd]
Agent: N
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)CNC(=O)CCCCNC(=S)Nc1ccccc1N)c1cccnc1
Reaction time: 18 h

Procedure:
10% Pd/C (50 mg) and 24-6 (103 mg, 0.194 mmol) were added to methanol saturated with ammonia and the mixture hydrogenated at 1 atm. for 18 hr. The reaction was filtered and concentrated to provide 24-7 as a pale yellow gum which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.C(OCC)(=O)C>[NH2:13][CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:9]([C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(-c2c(C#N)c(N)nc3ccccc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CN)c(N)nc3ccccc23)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
A solution of 2-amino-4-p-tolyl-quinoline-3-carbonitrile (46 mg, 0.177 mmol) in THF (0.5 ml) was added slowly to a suspension of LiAlH4 (67.3 mg, 1.77 mmol) in THF (1 ml) under an atmosphere of argon. The mixture was stirred for 2 h at 40° C. Upon cooling to −20° C., 0.3 ml water added and stirring was continued for 15 min at r.t. The mixture was taken up in ethyl acetate and filtered through dicalite. The filtrate was washed with water and brine, dried (Na2SO4), and evaporated. Purification of the re-dissolved (DMF, 1 ml) residue by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) gave 5 mg (11%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[C:4]([C:17]2[C:25]3[C:20](=[C:21]([O:26][CH3:27])[N:22]=[CH:23][CH:24]=3)[N:19]([CH3:28])[CH:18]=2)[CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C.[OH-].[Na+]>ClCCl.O1CCOCC1>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][C:4]=2[C:17]2[C:25]3[C:20](=[C:21]([O:26][CH3:27])[N:22]=[CH:23][CH:24]=3)[N:19]([CH3:28])[CH:18]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: CS(=O)(=O)Cl
Reactant: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(C#N)cc3)cn(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nccc2c(-c3cc(NS(C)(=O)=O)ccc3Oc3ccc(C#N)cc3)cn(C)c12
Temperature: 80 °C

Procedure:
A mixture of Example 16D (0.03 g, 0.081 mmol), methanesulfonyl chloride (0.028 g, 0.243 mmol), and triethylamine (0.049 g, 0.486 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 2 hours. The solvent was removed, and the residue was treated with sodium hydroxide (0.656 mL, 1.31 mmol) and dioxane (3 mL). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(O)c1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 20 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
Compound 4b (50.0 g, 228 mmol) along with 300 ml dichloromethane was charged into 2 liter round bottom flask. Crushed pyridinum dichromate (171.0 g, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 20° C. The resulting reaction mixture was filtered through celite and washed with ether (500 ml×3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica gel pad (3 inches in length) with 10% EtOAc in hexane. The resulting product (42.0 g, yield=84%) was used for the following step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:39][CH2:40]I)=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:39][CH2:40][N:12]3[C:11](=[O:15])[CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=[N:13]3)=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCI)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccccc4)cc3=O)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 245 mg (1.21 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) in 1.2 mL DMF is added 791 mg (2.43 mmol) cesium carbonate and after 15 min 470 mg (1.21 mmol) 7-(2-iodoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 8). The reaction mixture is stirred overnight at RT and the precipitate is removed by filtration. The solvent is evaporated, the residue is dissolved in DMF and purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:4]5[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1cn(C)nc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cn(C)nc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 68.9 %

Procedure:
In the same manner as in Example 18-4 and using 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (127 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (86.7 μL, 0.994 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (60.0 mg, 0.194 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (57.7 mg, 69%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12](F)[C:13]([NH:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[C:13](=[CH:14][CH:15]=3)[NH:19][CH2:20][CH2:21][O:22]4)[O:10][C:9]=2[CH:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1
Reactant: CC(C)c1oc2c(F)c(NCCO)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)NCCO3
Temperature: 25 °C

Procedure:
To a solution of 3-(4-chlorophenyl)-8-fluoro-7-(2-hydroxyethylamino)-2-isopropyl-chromen-4-one (0.195 g, 0.52 mmol) in dimethylformamide (5 ml) is added sodium hydride (0.053 g, 1.32 mmol, 60% dispersion in mineral oil, 2.55 eq.). The mixture is irradiated in a microwave instrument at 150° C. for 70 min. The solvent is removed by evaporation in vacuo to afford a brown oil. This is dissolved in hot ethyl acetate and allowed to cool to room temperature, whereupon a brown solid precipitates. More product can be recovered from the mother liquor by flash chromatography (cyclohexane/ethyl acetate=9:1). The solid products are combined and dried at 60° C. overnight under high vacuum to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].N1C=CN=C1.C(N(CC)CC)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O.O>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:5][O:6][CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCC(C)(C)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1 g of 2,2-dimethyl-3-methoxy-1-propanol was admixed with 10 ml of N,N-dimethyl formamide, and 0.29 g of imidazole was added thereto. The mixture was cooled in ice-water bath, and 1.65 ml of triethyl amine was added thereto. After stirring for 5 minutes, 1.65 g of tert-butyldimethylsilyl chloride in 10 ml of N,N-dimethyl formamide was slowly added to the reaction mixture, and the mixture was stirred in ice-water bath for further 4 hours. The reaction mixture was diluted with 10 ml of water, and extracted twice with 20 ml of dichloromethane for each time. The combined dichloromethane extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness to give 1.78 g of concentrate of 2,2-dimethyl-1-methoxy-3-[(tert-butyldimethylsilyl)oxy]-propane. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20]>CN(C)C=O>[C:19]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][CH:3]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: Brc1cnc(-c2ccccc2)c2ccccc12
Solvent: CN(C)C=O
Product: N#Cc1cnc(-c2ccccc2)c2ccccc12
Yield: 35.3 %

Procedure:
20.5 g of 1-phenylisoquinoline are dissolved in 100 ml of carbon tetrachloride, and 16 g of bromine are added at room temperature. The temperature is raised slowly and the mixture is kept under reflux for 1 hour. 7.9 g of pyridine in 10 ml of carbon tetrachloride are added dropwise to the boiling reaction mixture in the course of 2 hours, and the mixture is then heated at reflux temperature for a further 18 hours. The reaction solution is decanted off from the resinous precipitate and is concentrated, and the residue is crystallized from diisopropyl ether. 11.7 g of 4-bromo-1-phenylisoquinoline of melting point 123°-125° C. are obtained. 0.7 g of 4-bromo-1-phenylisoquinoline, 0.45 g of copper cyanide and 10 ml of dimethylformamide are heated at 160° C. for 6 hours. The reaction solution is decanted off, diluted with methylene chloride and washed with water. 0.75 g of crude product are isolated from the methylene chloride phase, and 0.2 g of 4-cyano-1-phenylisoquinoline of melting point 138°-140° is obtained from this crude product by column chromatography over silica gel using a 98:2 mixture of chloroform and ethyl acetate. 0.2 g of 4-cyano-1-phenylisoquinoline is heated with 10 ml of 20% strength sodium hydroxide solution at 100° C. for 4 hours. The solution is cooled and acidified with acetic acid. The precipitate is filtered off and dried. 0.18 g of 1-phenylisoquinoline-4-carboxylic acid of melting point 215°-217° is isolated.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:40]=[N:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:40]=[N:41][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:43][CH:44]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30]([NH2:7])=[O:31]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)nc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)nc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 225-228° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.75 (br, 2H), 8.04 (d, J=8.1 Hz, 1H), 7.92-7.89 (m, 2H), 4.61 (s, 2H), 4.06-3.99 (m, 2H), 3.58-3.53 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 386.2 (M+1).