Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: COc1cccc(C(=O)O)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(OC)c3)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 3-methoxybenzoic acid were coupled to give the title compound as a white solid (75 mg).
Reaction SMILES: [C@H]1(O)CC[C@H](O)CC1.[H-].[Na+].[Si]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])=[CH:28][C:27]=2[C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[N:39]([CH3:48])[CH:38]=2)[CH2:21][CH2:20]1)(C(C)(C)C)(C)C>CN(C=O)C>[CH2:35]([S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][C@H:22]2[CH2:21][CH2:20][C@H:19]([OH:18])[CH2:24][CH2:23]2)=[C:27]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[N:39]([CH3:48])[CH:38]=2)[CH:28]=1)(=[O:33])=[O:34])[CH3:36]
Reactant: CCS(=O)(=O)c1ccc(OC2CCC(O[Si](C)(C)C(C)(C)C)CC2)c(-c2cn(C)c(=O)c3ccccc23)c1
Agent: O[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(O[C@H]2CC[C@H](O)CC2)c(-c2cn(C)c(=O)c3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trans-1,4-cyclohexanediol (504.0 mg, 4.34 mmol) in anhydrous DMF (4 mL) was added NaH (139.0 mg, 3.47 mmol, 60% in mineral oil) at 0° C. and then stirred at 0° C. for 1 h. The compound from step 1 (100.0 mg, 0.29 mmol) was added. The mixture was stirred at 0° C. for 0.5 h and then at r.t. 18 hrs. It was then quenched with MeOH (4 mL) and filtered. The filtrate was purified by prep-HPLC to give the title compound (37.0 mg, 30.0%) as an off-white solid. 1H NMR (CDCl3, 40 MHz) δ 8.51 (d, J=7.6 Hz, 1H), 7.94 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.56 (t, J=6.8 Hz, 1H), 7.51 (t, J=6.8 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.43-4.18 (m, 1H), 3.67 (s, 3H), 3.65-3.62 (m, 1H), 3.16 (q, J=7.6 Hz, 2H), 2.00-1.90 (m, 2H), 1.71-1.65 (m, 2H), 1.42-1.30 (m, 7H). LCMS (M+H)+=442.0 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=2)[N:33]=1.[C:45](=[O:48])([OH:47])[O-].[Na+]>>[C:38]([OH:40])(=[O:39])/[CH:37]=[CH:35]/[C:45]([OH:47])=[O:48].[C:38]([OH:40])(=[O:39])/[CH:37]=[CH:35]/[C:45]([OH:47])=[O:48].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]([CH3:43])([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=4)[N:33]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCC(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccc(F)cc4)c4ccc(F)cc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O

Procedure:
1.62 g of 4-[bis(4-fluorophenyl)methoxy]-1-piperidinepropanamine and 0.803 g of ethyl 2-[6chloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate were stirred at 190-200° C. for 3 hours. After cooling, aqueous sodium bicarbonate and saline were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected, dissolved in 20 ml of ethyl acetate; a solution of 301 mg of fumaric acid in 10 ml of methanol was added, followed by concentration. Acetone was added to the residue; the crystal precipitate was collected by filtration, washed with acetone and dried to yield 0.966 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[C:12]([NH:14][C@@H:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]([OH:18])=[O:17])=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].Cl.[NH2:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1.CN(C)C=O.C(N1CCOCC1)C>>[C:16]([OH:18])(=[O:17])[CH3:15].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:25]([N:26]([CH3:27])[CH3:28])=[O:29])[C:12]([NH:14][C@H:15]([C:16](=[O:17])[NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([C:32]#[N:31])=[CH:34][CH:35]=2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: CN(C)C(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: N#Cc1ccc(CN)cc1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)O
Product: CN(C)C(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N[C@H](C(=O)NCc1ccc(C#N)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
To a solution of [3-(4-carbamimidoyl-phenyl)-2-(R,S)-dimethylcarbamoyl-propionylamino]-(S)-cyclohexyl-acetic acid (100 mg, 0.248 mmol, example 1 h) and 4-aminomethyl-benzonitrile hydrochloride (37 mg, 0.22 mmol) in dimethylformamide (10 ml) TOTU (79 mg, 0.24 mmol) and N-ethylmorpholine (50 mg, 0.44 mmol) were added at −15° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation the residue was purified by chromatography on Sephadex LH20 employing n-butanol (17): glacial acetic acid (1): water (2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water and the aqueous solution was lyophilized to yield 83 mg (65%) of the desired product. MS m/z: 517.4 (M+H)+.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH2:32][O:33]C)[CH:4]=[CH:5]2.O.[C:36](O)(=O)C>>[C:32]([O:31][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:11][CH2:10][C@@H:9]35)(=[O:33])[CH3:36]
Reactant: CC(=O)O
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCCC(=O)OC)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: O
Product: COC(=O)CCCCC(=O)O[C@H]1CC[C@H]2[C@H]3Cc4ccc(OC(C)=O)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4,5α-epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-3-methoxymethoxy-17-methyl-morphinane (0.43 g, 0.91 mmol) was mixed with H2O (15 ml) and glacial acetic acid (15 ml) and stirred for 6 hours at 100° C. The mixture was then evaporated down at 40° C. using a Rotavapor and the residue obtained was purified by flash chromatography (60 g silical gel; CH2Cl2 /MeOH=9/1). The product was dissolved in H2O (6 ml) and glacial acetic acid (0.6 ml) and lyophilised. Yield: 0.221 g (0.45 mmol, 49.7%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](=[S:11])[NH2:10])[CH2:5][CH2:4]1)=[O:2].[CH3:12][I:13]>CO>[IH:13].[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](=[NH:10])[S:11][CH3:12])[CH2:5][CH2:4]1)=[O:2]
Reactant: NC(=S)N1CCN(C=O)CC1
Reactant: CI
Solvent: CO
Product: CSC(=N)N1CCN(C=O)CC1
Product: I
Temperature: 25 °C

Procedure:
25.5 g of 4-formyl-1-piperazinecarbothioamide are suspended in 80 ml of methanol, treated with 22 g of methyliodide and refluxed. Within ca. 10 minutes a clear solution is obtained. The mixture is cooled to room temperature. The solvent is evaporated. Crystalline hydroiodide of 4-formyl-1-[imino(methylthio)methyl]piperazine is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14]Br)=[CH:9][CH:8]=1.C(N(CC)CC)C.O>CCOCC>[C:7]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH2:14][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Morpholine (1.67 g, 19.1 mmol) in anhydrous ether (20 mL) was added dropwise to a solution of 1-(4-biphenylyl)-2-bromoethanone (2.63 g, 9.56 mmol) and triethylamine (TEA) (2.90 g, 28.68 mmol) in anhydrous ether (50 mL) at 0° C. over 30 min. The reaction mixture was then warmed to room temperature. After stirring for 2 h, water (80 mL) was added and the aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic layer was dried over MgSO4 and concentrated to yield the title compound as a light yellow solid (2.52 g, 93%), which was used without further purification. MS (ES) m/e 281 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]([C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1.C(Cl)Cl.[Cl-].[Na+].O>[C:24]1([S:30]([NH:1][C:2]2[C:10]3[NH:9][C:8]([NH:11][C:12]([C:14]4[N:15]=[CH:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[O:13])=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nc2cccc(NS(=O)(=O)c3ccccc3)c2[nH]1)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
66 mg (0.2 mmol) of isoquinoline-3-carboxylic acid (4-amino-1H-benzoimidazol-2-yl)-amide was dissolved in pyridine (0.6 mL). To this stirred solution at 0° C., 0.2 mmol of phenylsulfonyl chloride in 0.2 mL of DCM was added in one portion. The reaction mixture was stirred at room temperature for 2 h. Brine (5 mL) was added and stirred for 10 min. The resulting solid was collected by filtration, washed with water (3×2 ml) and EtOAc (3×3 mL) and dried to yield 46 mg (52%) of isoquinoline-3-carboxylic acid (7-benzenesulfonylamino-1H-benzoimidazol-2-yl)-amide. LCMS: 444 (M+1)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:7][N:8]=1.[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:7][N:8]=2)=[O:33])=[CH:35][CH:36]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: Nc1nnc(SCc2ccccn2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCc3ccccn3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
Sodium hydride (0.3 g) and 2-amino-5-(2-pyridylmethyl) thio-1,3,4-thiadiazole (1.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.5 g) and carbonyldiimidazole (1.0 ) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.9 g of the aimed compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[O:28])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:11]1[CH3:29].[Li+].[OH-]>CO.C1COCC1.O>[CH3:27][S:24]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C:12]2[CH:13]=[C:14]([CH3:15])[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:30])=[O:2])[C:11]=2[CH3:29])=[O:28])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: COC(=O)c1ccccc1-n1c(C)cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c(C)n1-c1ccccc1C(=O)O
Yield: 101.5 %

Procedure:
To a solution of 2-[3-(4-methanesulfonyl-phenylcarbamoyl)-2,5-dimethyl-pyrrol-1-yl]-benzoic acid methyl ester (0.7 g, 1.6 mmol) in MeOH/THF (8 mL: 16 mL) was added LiOH (0.275 g, 6.4 mmol). After stirring 14h at room temperature, the reaction mixture was concentrated in vacuo. The crude reaction mixture was re-dissolved in water and washed with EtOAc. The water layer was separated and then acidified with 1N HCl. The resulting suspension was extracted twice with EtOac. The combined extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (0.67 g, 99%) as a white solid. 1H-NMR (DMSO-d6): δ 13.03 (1H, s), 9.81 (1H, s), 8.06 (2H, d, J=9.1), 8.02 (1H, d J=7.8), 7.87 (2H, d, J=8.6), 7.78 (1H, t, J=7.3). 7.68 (1H, t, J=7.8), 7.39 (1H, d, J=7.6), 6.65 (1H, s), 3.20 (3H, s), 2.23 (3H, s), 1.92 (3H, s); MS (ESI): 413 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16].[BH3-]C#N.[Na+].O.[OH-].[Na+]>CC(O)=O.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: OCCCC#Cc1cc2cc[nH]c2cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: OCCCC#Cc1cc2c(cc1F)NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of 109 mg (0.5 mmol) 5-(6-Fluoro-1H-indol-5-yl)-pent-4-yn-1-ol in 3 ml AcOH/TFA 2:1 was cooled to 0° C., treated with NaCNBH3 and stirred for 1 hour at room temperature. The mixture was poured into icy water, made strongly alkaline by the addition of 2M NaOH, and extracted with EtOAc. Drying of the combined organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with CH2Cl2/MeOH 49:1 gave 80 mg (73%) of 5-(6-Fluoro-2,3-dihydro-1H-indol-5-yl)-pent-4-yn-1-ol as a colorless oil, MS: 220 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:13][C:14]([Cl:16])=[O:15])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3]1.[CH2:21]1[O:36][C:35]2[CH:34]=[CH:33][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:24][C:23]=2[O:22]1>>[ClH:16].[O:1]=[C:2]1[C:6]([CH2:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([CH2:26][C:25]3[CH:33]=[CH:34][C:35]4[O:36][CH2:21][O:22][C:23]=4[CH:24]=3)[CH2:28][CH2:29]2)=[O:15])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3]1
Reactant: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccccc21
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: Cl
Product: O=C(CC1(c2ccccc2)C(=O)Oc2ccccc21)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
This compound was prepared from 2-(2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride and 4-(3,4-methylenedioxybenzyl)piperazine according to the process described in Example 9.
Reaction SMILES: C(OCC)(=O)CCC([O:6][C:7]1[C:16]2[CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=[N:12][C:11]=2[N:10]([CH3:23])[C:9](=[O:24])[CH:8]=1)=O.OC1C2C=C(C3C=CC=CC=3)N=NC=2N(C)C(=O)C=1.Cl[C:49](=[O:57])[CH2:50][CH2:51][C:52]([O:54]CC)=[O:53]>>[OH:6][C:7]1[C:16]2[CH:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:13]=[N:12][C:11]=2[N:10]([CH3:23])[C:9](=[O:24])[C:8]=1[C:49](=[O:57])[CH2:50][CH2:51][C:52]([OH:54])=[O:53]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CCOC(=O)CCC(=O)Oc1cc(=O)n(C)c2nnc(-c3ccccc3)cc12
Agent: Cn1c(=O)cc(O)c2cc(-c3ccccc3)nnc21
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(-c3ccccc3)nnc21

Procedure:
Ethyl 8-methyl-7-oxo-3-phenyl-7,8-dihydropyrido[2,3-c]pyridazin-5-yl succinate. The title compound is prepared by acylation of 5-hydroxy-8-methyl-3-phenylpyrido[2,3-c]pyridazin-7(8H)-one with ethyl 4-chloro-4-oxobutanoate according to that described in Method 4 (step b).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:10](=[O:12])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)[CH:19]=1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1cccc(NC(=O)COc2ccc([N+](=O)[O-])cc2)c1
Yield: 90.8 %

Procedure:
To a solution of the 4-nitrophenoxy acetic acid (100 mg, 0.5 mmol), 3-amino benzoic acid methyl ester (115 mg, 0.76 mmol), HOBt (102.81 mg, 0.76 mmol) and DIPEA (98.34 mg, 0.76 mmol) in DMF (4.0 mL) were added EDC (145.86 mg, 0.76 mmol) at room temperature. After reaction terminated, the reaction mixture in cool water was diluted with Ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate and dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (Ethyl acetate:Hexane=1:9˜1:1) gave 3-[2-(4-nitro-phenoxy)acetyl-amino]-benzoic acid methyl ester as a white solid (150 mg, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]1([C:13]2[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=2)[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[NH:17][N:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (30 g, 163 mmol), 5-cyclopropyl-1H-pyrazol-3-ylamine (20 g, 163 mmol), diisopropylethylamine (50 mL, 300 mmol) and 1-butanol (100 mL) was heated to 80° C. for 2 h. The solvents were removed on a rotary evaporator and the residue was taken up in ethyl acetate. The organic solution was washed with water and brine and dried over magnesium sulfate. The residue was concentrated on a rotary evaporator to give the desired product (40.7 g, 92%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](OC2C=CC=CC=2)=[CH:27][CH:26]=1.F>>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:28]3[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=3)=[CH:3][CH:4]=2)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: Cc1ccc(Oc2ccccc2)cc1
Agent: F
Product: Cc1ccc(Oc2ccc(C(c3ccc(C)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
reacting 2-(4-hydroxyphenyl)-2-(4-methylphenyl)hexafluoropropane with an aromatic, halogen-containing nitro compound or dinitro compound, or reacting 2-(4-methylphenyl)-2-hexafluoroisopropanol with 4-methyldiphenyl ether in the presence of anhydrous hydrofluoric acid to give 2-(4-methylphenyl)-2-[4-(4-methylphenoxy)phenyl]hexafluoropropane,
Reaction SMILES: C([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]1NC(=O)CCCCCNC(=O)C=C)(=O)C.[C:28]([NH2:32])(=[O:31])[CH:29]=[CH2:30]>O>[OH:31][CH:6]1[O:7][C@H:8]([CH2:13][OH:14])[C@H:9]([OH:12])[C@H:10]([OH:11])[C@H:5]1[NH2:4].[C:28]([NH2:32])(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)NCCCCCC(=O)N[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: C=CC(N)=O
Solvent: O
Product: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 249.8 %

Procedure:
Monomer 52 (150 mg, 0.4 mmol) and acrylamide (1.15 g, 1.6 mmol) were dissolved in 3 mL of water and purged with nitrogen for S min. The radical initiator V-50 (2.5 mg) was added to the reaction mixture and the solution was heated to 60° C. for 30 min. The solution became viscous during this period. The heating was discontinued and the reaction mixture was stirred for 24 hr at room temperature. The viscous solution was poured into 50 mL of isopropanol while stirring, causing the polymer to precipitate. The polymer was collected by filtration and dried under vacuum at room temperature to give 53 as a white powder (250mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.CCN(P1(N(C)CCCN1C)=N[C:36](C)([CH3:38])[CH3:37])CC.IC(C)C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH:36]([CH3:38])[CH3:37]
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CC(C)n1c(=O)[nH]c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
200 mg (0.531 mmol) of the compound from example 33 and 145 mg (0.531 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 90 mg (0.531 mmol) of 2-iodopropane ml of dimethylformamide was added dropwise at 0° C. within 10 min The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 117 mg of the title compound were obtained (50% of theory).