Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[CH3:32][N:33](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:32]#[N:33])[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(C#N)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 18, [5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 19) was reacted with zinc cyanide and tetrakis-(triphenylphosphine)-palladium in DMF to give the title compound as colorless foam. MS: 448.2 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=2)=[C:8]([CH:10]=1)[NH2:9])(=[O:3])[CH3:2].[OH-].[Na+].[CH:26](O)=O>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:13]=3)[CH:26]=[N:9][C:8]=2[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c(N)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1

Procedure:
5-acetyl-2-(3-(3-pyridyl)phenylamino)aniline (5 g, 16.5 mmol) in formic acid (50 ml) is stirred at 90° C. for 1.5 hours. The cooled reaction mixture is made alkaline by addition of 12 M NaOH. 5-acetyl-1-(3-(3-pyridyl)phenyl)benzimidazole is filtered off washed with water and dried. Quantitative yield. m.p. 195-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1)([O-:14])=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[C:22](=[O:21])[C:17]2[C:18](=[CH:24][CH:25]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:19]1=[O:20]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCc1ccc(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 2 h

Procedure:
2-(2,4-dichlorophenyl)ethanamine was suspended in toluene with 4-nitrophthalic anhydride (1 eq) and heated to 150° C. After 2 hours, the reaction was cooled and checked for completion by LC/MS. The solvent was then removed in vacuo and the resulting product was taken on to the next step without further purification. Rt 3.91 minutes, LC/MS m/z 365.1 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:5]([C:7]1[CH:12]=[C:11]([C:13](OC)=O)[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[F:25])=[CH2:6])([CH3:4])[CH3:3].CN(C=O)C.S(Cl)([Cl:33])=O>C(Cl)Cl>[Cl:33][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[C:7]([C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[CH2:6])[CH:12]=1
Reactant: C=C(c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(c1cc(CCl)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To a stirred solution of 66.18F (0.050 g, 0.16 mmol) in DCM (2.00 mL) at 0 C was added DMF (0.0012 mL), followed by thionyl chloride (0.023 mL, 0.32 mmol). The reaction was then stirred for 1.5 hours and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 69.15A as a colorless oil (0.050 g, 94% yield).
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:26]([O:25][C:23]([C:3]1[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=[CH:5][S:6][C:2]=1[NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[C:38]([F:37])[CH:39]=1)=[O:24])[CH3:27]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCOC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)csc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)csc1NC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
To a solution of 55 (˜2 mmol) in DCM (10 ml) was added DIEA (0.7 ml, 4 mmol), 3-fluorobenzoyl chloride (0.48 ml, 4 mmol) and catalytic amount of DMAP. The mixture was stirred at rt for 17 hrs, diluted with DCM (50 ml), washed with water, saturated sodium bicarbonate (aq.), water, 1N HCl (aq.) and brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum. The crude product was purified on a silica gel column to give 56 as a yellow oil (0.48 g). LC-MS for C27H27FN2O5S: 510; found: 511.
Reaction SMILES: C(O[N:9](C12C(C)(C)C1CCC(C)C2=O)[CH2:10][CH2:11][CH2:12][P:13]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:15])[OH:14])C1C=CC=CC=1.C1OC1C>Cl.CO>[NH2:9][CH2:10][CH2:11][CH2:12][P:13]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[OH:15]
Reactant: CCCCP(=O)(O)CCCN(OCc1ccccc1)C12C(=O)C(C)CCC1C2(C)C
Agent: CC1CO1
Agent: Cl
Solvent: CO
Product: CCCCP(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A solution of 6.7 g of 3-(benzyloxycaronylamino)propyl(n-butyl)phosphinic acid in 125 ml of 36% hydrochloric acid is heated at reflux for 1.5 hour. The mixture is evaporated to an oil and the oil is co-evaporated with water (2×50 ml) to give a white solid. This solid is then dissolved in 50 ml of dry methanol, 1-3 ml of propylene oxide is added and the solution is stirred at room temperature. The precipitated product is collected by filtration and dried to give 3-aminopropyl(n-butyl)phosphinic acid, m.p. 231°-234° (dec.), 31P-NMR : δ=+44.6 ppm (D2O).
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[CH3:19][C:20]1[N:25]=[C:24]([C:26]#[C:27][C:28]2[CH2:32][C:31]3([CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)[O:30][N:29]=2)[CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:19][C:20]1[N:25]=[C:24]([C:26]#[C:27][C:28]2[CH2:32][C:31]3([CH2:36][CH2:35][NH:34][CH2:33]3)[O:30][N:29]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(C#CC2=NOC3(CCN(C(=O)OC(C)(C)C)C3)C2)n1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C#CC2=NOC3(CCNC3)C2)n1
Yield: 94.5 %

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with Compound 35a and running the reaction in chloroform. The crude brownish oily residue was used without further purification in the next reaction step. Yield: 94.5%.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][C@@H:19]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[O:21]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a solution material from Example 97 (4.7 g, 9.10 mmol) in anhydrous DMF (30 mL) is added piperidine (15 mL, 152 mmol). The resulting solution is stirred at room temp for 45 rain and the solvent is removed in vacuo. The resulting residue was redissolved in 1,4-dioxane (50 mL), the solvent was removed in vacuo again and the resulting solid was dried under high vacuum for 18 h to give the title compound as a white solid in quantitative yield that contains 1 equivalent of 1-((9H-fluoren-9-yl)methyl)piperidine as a side product. LC/MS (Condition A): ret. T=2.30 rain, (M+H)+ 295.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[CH2:16][CH2:17][CH3:18]>C(Cl)Cl.CCOC(C)=O>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(CO)nc2ccccn12
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(CCl)nc2ccccn12
Reaction time: 1 h

Procedure:
Thionyl chloride (125 mg, 1.06 mmol) is added to a solution of 2-hydroxymethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine (100 mg, 0.53 mmol) in CH2Cl2 (3 mL) at 0° C. under nitrogen with magnetic stirring. After 1 hour, the reaction is diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and brine (10 mL). The solution is then dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain 2-chloromethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine as a colorless oil. TLC (10% MeOH/CH2Cl2) Rf=0.60. Step 5. Preparation of 3-{1-[(3-propylimidazo[1,2-a]pyridin-2-yl)methyl]-1H-imidazol-2-yl}benzonitrile
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[N+:13]([O-:15])=[O:14]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: O=[N+]([O-])c1ccccc1C=NNC(=S)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 2-nitrobenzaldehyde (85 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow solid (20 mg, 11%). 1H NMR (CDCl3): 9.37 (s, 1H), 8.27 (s, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 6.24-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.07 (s, 1H), 2.97 (s, 1H), 1.94-1.86 (m, 1H), 1.67 (d, J=8.4 Hz, 1H), 1.52 (d, J=9.0 Hz, 1H), 1.46-1.40 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH3:16])[CH:9]=2)=[O:4].[NH2:18][CH2:19][C:20]([O-:22])=[O:21].[Na+]>COCCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([CH3:16])=[CH:11][CH:12]=2)[S:7][C:6](=[O:17])[C:5]=1[C:3]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(C)cc2sc1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: Cc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)sc2c1
Yield: 94.8 %

Procedure:
A mixture of 4-hydroxy-7-methyl-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (80 mg, 0.32 mmol) and sodium glycinate (310 mg, 3.2 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. The reaction mixture was concentrated and the crude residue dissolved in water (50 mL), acidified to pH 3-4 using 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide [(4-hydroxy-7-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (89 mg). MS ESI(−) m/e: 292.12 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:11][C:10]=1[CH3:20])([CH3:7])[CH3:6])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]#[C:19][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:20])([CH3:6])[CH3:7])[CH3:2]
Reactant: Clc1ccc(I)cc1
Reactant: C#CCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC#Cc2ccc(Cl)cc2)cc1C

Procedure:
In analogy to the procedure described in example 13B], 2-(4-but-3-ynyloxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 16A]) and 1-chloro-4-iodo-benzene gave the title compound as a light yellow viscous oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:34]=[CH:33][C:12]([O:13][C:14]3[N:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:35]1[CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH:36]12>CO>[OH:35][C@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[N:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)=[CH:33][CH:34]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: C1CCC2OC2C1
Reactant: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCNCC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCN([C@H]4CCCC[C@@H]4O)CC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Reaction time: 24 h

Procedure:
To a solution of N-{6-[4-(piperazine-1-carbonyl)phenoxy]-pyridin-3-yl}-4-trifluoromethyl-benzamide (430 mg, 0.91 mmol) in methanol was added 1,2-epoxycyclohexane (180 mg, 1.83 mmol), and the resulting solution was stirred for 1 day under reflux. The resulting reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=35:1), and then ethyl acetate was added. The precipitated white powder was filtered off and washed with ethyl acetate, to thereby yield 284 mg of the title compound.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4](O)=[O:5])[CH3:3]>O1CCCC1>[C:10]([O:9][C:7](=[O:8])[NH:1][C@H:2]([CH3:3])[CH2:4][OH:5])([CH3:13])([CH3:11])[CH3:12]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of Boc-D-Ala-OH (1.0 g, 5.28 mmol) in tetrahydrofuran (10 ml) was added dropwise to a stirred solution of BH3, 1M in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred for a further hour at 0° C., then quenched with 10% acetic acid in methanol. After solvent evaporation, the crude product was dissolved in ethyl acetate and washed with 1M HCl, water and then 1M sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield 0.39 g, 42%.: NMR 1H (300 MHz, CDCl3): 0.97 (d, 3H), 1.36 (s, 9H), 3.14 (m, 1H), 3.29 (m, 1H), 3.40 (m, 1H), 4.57 (m, 1H)
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13]CCCC)(=[O:12])[CH:10]=[CH2:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O-:13])(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)OCCCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1C
Product: C=CC(=O)[O-]
Reaction time: 1 h

Procedure:
20 Parts of the above-obtained polymer resin having a higher molecular weight and 100 parts of xylene were charged into a flask, and dissolved. The inner atmosphere of the flask was replaced with nitrogen gas, and the mixture was heated up to the boiling point of xylene. While the mixture was stirred under the reflux of xylene, a mixture containing 68 parts of styrene, 12 parts of n-butyl acrylate and 3.3 parts of benzoyl peroxide (polymerization initiator) were dropwise added over 2 hours to carry out a solution polymerization. After the addition was completed, the reaction mixture was aged for 1 hour with stirring under the reflux of xylene, to give a styrene/acrylate copolymer resin having molecular weight maximal values, measured by GPC, of 6,000 and 1.0×106 and containing 20% by weight of the polymer having a higher molecular weight, for use in an electrophotographic toner of the present invention.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[OH:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[O:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc2oc(=O)cc(Cl)c2c1
Reactant: Oc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2oc(=O)cc(Oc3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A stirred mixture of 4-chloro-6-methoxycoumarin (1.0 g, 4.75 mmole), 2,6-dichlorophenol (0.85 g, 5.22 mmole) and K2CO3 (0.98 g, 7.12 mmole) in acetonitrile, under N2, is heated at reflux temperature for 16 hours, cooled to room temperature and poured into ice water. This mixture is extracted several times with ether. The extracts are combined and concentrated in vacuo to give a tan solid residue. The residue is crystallized from ethyl acetate/hexane to afford the title product as tan crystals, 1.17 g (73% yield), mp 170°-171° C., identified by IR, 1HNMR, 13CNMR, and mass spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([F:27])[CH:29]=4)[NH:33][N:32]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=Cc1n[nH]c2ccc(F)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccc(F)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) synthesized in Example B13, Step 2 in methanol (1 mL) was added with 5-fluoro-1H-indazole-3-carbaldehyde (0.0428 g, 0.261 mmol) synthesized in Example B8, Step 3, and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), and suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-2-[(5-fluoro-1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.050 g, 36%).
Reaction SMILES: [F-:1].[K+].[C:3]([S:22][CH2:23][CH2:24][NH:25][C:26]([C:28]1[CH:39]=[CH:38][C:31]([CH2:32]OS(C)(=O)=O)=[CH:30][CH:29]=1)=[O:27])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C(#N)C>[F:1][CH2:32][C:31]1[CH:38]=[CH:39][C:28]([C:26]([NH:25][CH2:24][CH2:23][S:22][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)OCc1ccc(C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(CF)cc1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
A solution of Kryptofix (Fluka, 15 mg, 40 μmol) in dry acetonitrile (200 μl) was added to solid potassium fluoride (2.3 mg, 80 μmol). The mixture was shaken for 5 min. The Kryptofix/KF-solution was added to a solution of methanesulphonic acid 4-[2-(tritylsulphanyl)ethylcarbamoyl]benzyl ester (21 mg, 40 μmol) in acetonitrile (400 μl). The mixture was heated at 65° C. for 10 min. An aliquot was analysed by HPLC (column Phenomenex Luna 3 μm C18(2) 50×4.60 mm; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TWA; gradient 40-80% B over 10 min; flow 2.0 ml/min, UV detection at 214 and 254 nm), showing complete conversion of starting material (tR 5.6 min) to a new product (tR 6.3 min). Purification by reverse phase preparative HPLC (column: Phenomenex Luna C18(2) 5 μm 250×21.2 mm, solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 40-80% B over 60 min; flow 10.0 ml/min, UV detection at 214 nm) gave 4.5 mg of white solid. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][C:11]([SH:15])([CH2:13][CH3:14])[CH3:12].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:15][C:11]([CH3:12])([CH3:10])[CH2:13][CH3:14])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCC(C)(C)S
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC(C)(C)CC

Procedure:
Ethyl 2-bromoisobutyrate (33.9 g, 0.174 mole), 2-methyl-2-butanethiol (20.0 g, 0.192 mole), potassium hydroxide (12.2 g, 0.192 mole), ethyl alcohol (100 g) were combined and the reaction mixture was refluxed for approximately 10 hours prior to quenching. Crude yield: 63.5%; after column chromatography 18.1%.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:10]([C:3]2[N:4]([CH3:9])[CH:5]=[CH:6][C:7](=[O:8])[C:2]=2[OH:1])[C:11]([F:14])([F:13])[F:12])[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Product: Cn1ccc(=O)c(O)c1C(NC1CC1)C(F)(F)F
Yield: 40 %

Procedure:
In a similar manner, Apo7074 was prepared from 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) and cyclopropylamine (0.62 mL, 9.0 mmol). The title compound Apo7074 (470 mg) was obtained after purification by flash chromatography (5% MeOH in CH2Cl2 as eluant). Yield=40%; 1H NMR (400 MHz, DMSO+a few drops of D2O) δ (ppm): 7.67 (d, J=6.8 Hz, 1H), 6.25 (d, J=7.1 Hz, 1H), 4.70 (q, J=8.1 Hz, 1H), 3.74 (s, 3H), 2.04 (br. s., 1H), 0.34-0.43 (m, 4H); MS m/z 263 [M+1]+, 206 (100%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[F:20][CH2:21][C:22]([CH2:26][F:27])([OH:25])[C:23]#[CH:24]>CS(C)=O.C(N(CC)CC)C.O>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([CH2:26][F:27])([OH:25])[CH2:21][F:20])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(O)(CF)CF
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1nc2c(s1)CCOc1cc(F)c(C#CC(O)(CF)CF)cc1-2

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.58 mmol, 1.00 equiv), 1-fluoro-2-(fluoromethyl)but-3-yn-2-ol (280 mg, 1.75 mmol, 3.00 equiv) and Pd(PPh3)Cl2 (82 mg, 0.20 equiv) in DMSO (0.7 mL) and triethylamine (0.7 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 70° C. The resulting solution was diluted with 15 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM:MeOH (10:1). This resulted in 72.9 mg (32%) of 8-Fluoro-9-(4-fluoro-3-fluoromethyl-3-hydroxy-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid. LC-MS: (ES, m/z): 383[M+H]+; 1H-NMR: (400 MHz, CD3OD, ppm) δ 8.735 (d, 1H), 6.875 (d, 1H), 4.559 (d, 4H), 4.400 (t, 2H), 3.450 (t, 2H).