Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].Cl>C1(C)C=CC=CC=1>[Cl:10][CH2:11][C:12]1[CH:20]=[C:19]([CH:18]=[CH:17][C:13]=1[C:14](=[O:15])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:21]#[N:22]
Reactant: N#Cc1ccc(C(=O)Cl)c(CCl)c1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CCl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 4-fluoro phenylmagnesium bromide (0.73M in THF, 170 ml) was added to a cooled solution of 2-chloromethyl-4-cyano-benzoyl chloride (25.0 g) in toluene (200 ml) so that the temperature did not raise above 0° C. The mixture was stirred at 0° C. for 2 hours. An aqueous solution of HCl (250 ml) was added and stirring continued for 0.5 hours. The phases were separated and the aqueous phase was extracted with toluene (200 ml). The combined organic phases were washed with saturated NaHCO3 solution (200 ml) and water (100 ml). The solvents were evaporated in vacuo to give a brownish oil (29.0 g, 90%). Spectral and analytical data were in accordance with the example above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[C:5](=[N:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[NH2:6].Cl[CH2:18][CH:19]=O.C(=O)(O)[O-].[Na+].CC(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:18]=[CH:19][N:6]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: N/C(=N/c1ccccc1)c1cccc(Br)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Brc1cccc(-c2nccn2-c2ccccc2)c1
Temperature: 25 °C
Yield: 37 %

Procedure:
(E)-3-bromo-N′-phenylbenzimidamide (6.95 g, 25.3 mmol), 2-chloroacetaldehyde (6.94 g, 44.2 mmol) and sodium bicarbonate (5.30 g, 63.1 mmol) were charged into the reaction flask with 200 mL of 2-propanol. This reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to room temperature, was diluted with 200 mL of water then was extracted with ethyl acetate. The extracts were washed with aqueous lithium chloride then were dried over magnesium sulfate. These dried extracts were then filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 30-35% ethyl acetate/hexanes yielding 2-(3-bromophenyl)-1-phenyl-1H-imidazole (2.8 g, 9.36 mmol, 37% yield).
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](O)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:6][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:25]1[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][CH:26]=1
Reactant: Cc1ccc(C(O)(c2ccccc2)c2ccccc2)cc1
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C(NC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
A mixture of 140.14 g Z-Gln-OH (0.5 mole) and 274.4 g 4-methyltriphenylcarbinol (1 mole) in 1.5 l acetic acid and 93.4 ml acetic anhydride (1 mole) is stirred at room temperature for 7 minutes. Upon addition of 2.5 ml concentrated sulfuric acid the temperature is raised to 50° C.; a clear, yellow solution results after 15 minutes. After 21/2 hrs the solution is allowed to cool and poured into 5 l ice-cold water. The precipitate formed is filtered off, washed thoroughly with water and dissolved in 1 l ethylacetate. The resulting solution is washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to an oil (400 ml) which crystallized on addition of diisopropylether.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=O)[C:15]([F:21])([F:20])[CH2:16][C:17]([OH:19])=[O:18].C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>CO.O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[N:29][OH:30])[C:15]([F:21])([F:20])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CC(F)(F)C(=O)c1ccc2oc3ccccc3c2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CC(F)(F)C(=NO)c1ccc2oc3ccccc3c2c1

Procedure:
A solution of 4-dibenzofuran-2-yl-3,3-difluoro-4-oxo-butyric acid (1 equivalent, Example 1) and sodium acetate (1.2 equivalents) in methanol is treated with a solution of hydroxylamine hydrochloride (1.2 equivalents) in water. The solution is heated to reflux for 3 hours, then cooled, concentrated, and filtered. The filter cake is washed with water and dried in vacuo. The crude product is recrystallized from an organic solvent, such as ethyl acetate, to give the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH3:51])[N:44]=1)CCC>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH3:51])[N:44]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OCC)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCOc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)s2)n1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and tri-n-butyl (6-ethoxy-2-pyridyl) tin (see WO 00/74681) were treated in a manner similar to Example 128-(5) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl) benzene as colorless crystals. APCI-Mass m/Z 660/662 (M+H). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene (245 mg) was dissolved in tetrahydrofuran (5 ml), added thereto was a solution of sodium hydride (oil, 9 mg) in ethanol (5 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene (145 mg) as colorless powder. APCI-Mass m/Z 492/494 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([O:42]CC3C=CC=CC=3)=[O:41])[C:35]3[C:30](=[CH:31][C:32]([CH3:50])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([OH:42])=[O:41])[C:35]3[C:30](=[CH:31][C:32]([CH3:50])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3c2)CC1
Reaction time: 1 h

Procedure:
To a solution of 710 mg 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-7-methyl-naphthalene-2-carbonyl)-amino]-4-tert-butoxycarbonyl-butyryl}-piperazine-1-carboxylic acid butyl ester in 15 ml ethyl acetate were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 1 h. Then the reaction mixture was filtrated over a plug of Celite®, washed with ethyl acetate and concentrated. Yield: 670 mg colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=O.[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].CC([O-])=O.[Na+].CC(O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOc1ccc(C=O)cc1OC
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1ccc(C=C2SC(=S)NC2=O)cc1OC
Temperature: 90 °C
Yield: 71.1 %

Procedure:
To a N2-purged flask was added 3-methoxy-4-(2-methoxy-ethoxy)-benzaldehyde from Step A (162 mg, 771 mmol), rhodanine (103 mg, 1 equiv), NaOAc (190 mg, 2.31 mmol) and HOAc (3 mL). The mixture was stirred and heated at 90° C. for 14 h under a condenser, resulting in a yellow precipitate. The reaction mixture was diluted with water (100 mL) and the solid precipitate was filtered in a Buchner funnel. The solid was washed with water, washed with hexane, and dried under high vacuum to yield the intermediate compound (179 mg, 72% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][CH:38]([OH:40])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][CH:38]([OH:40])[CH3:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(O)CCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: CC(O)CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-2-butanol using methods similar to Example 563 to provide a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-1.12 (m, 3 H), 1.53-1.68 (m, 6 H), 2.04 (t, J=5.90 Hz, 2 H), 3.22-3.30 (m, 2 H), 3.48 (dt, J=13.48, 6.74 Hz, 4 H), 3.62-3.76 (m, 1 H), 4.16 (s, 2 H), 4.39 (t, J=6.21 Hz, 2 H), 4.64 (d, J=4.63 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.38-7.44 (m, 2 H), 8.19 (s, 1 H), 8.56 (d, J=1.26 Hz, 1 H), 10.33 (t, J=5.48 Hz, 1 H), 17.27 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:11][CH:12]=1
Reactant: Nc1ccccn1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Nc1ccc(S(=O)(=O)Cl)cn1
Temperature: 150 °C
Reaction time: 7 h
Yield: 32.2 %

Procedure:
To 123.8 g (1.06 mol) of chlorosulfonic acid was added 10.00 g (0.106 mol) of 2-aminopyridine by portions under ice-cooling. Thionyl chloride (50.56 g, 0.425 mol) was added thereto, followed by heating under reflux for 2.5 hours and further stirring at 150° C. for 7 hours. The reaction solution was poured onto ice water, neutralized by adding sodium bicarbonate thereto and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution, water and brine successively, dried over magnesium sulfate and then concentrated to dryness. The resulting residue was suspended in ethyl ether and the insoluble matters were filtered off. The filtrate was concentrated to dryness and the resulting residue was recrystallized from ethyl ether-hexane to give 6.58 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1>[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:4]3[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=3[CH3:2])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Reactant: Cc1ccc(C)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Product: Cc1ccc(C)c(Cc2ccc(-c3ccc(Cc4cc(C)ccc4C)cc3)cc2)c1
Temperature: 25 °C

Procedure:
A 100mL flask was charged with 4,4′-bis(chloromethyl)-1,1′-biphenyl (1.0 g) and p-xylene (25 mL). To the clear solution stirring at room temperature was added titanium tetrachloride (6 drops) and the mixture instantly became dark brown. After stirring overnight at room temperature, ethanol (2mL) was added to kill the catalyst, and the mixture became a light, cream colored suspension. The mixture was transferred to a separatory funnel and washed with dilute aqueous HCl followed by saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, and concentrated to dryness under vacuum on a rotary evaporator. The tan solid was recrystallized from toluene yielding a white crystalline product, mp=144.6 C. GC/MS, HNMR, CNMR and IR were all consistent with the desired product.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:11]([CH2:12]O)=[CH:10][CH:9]=[CH:8][N:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:3][CH2:12][C:11]1[C:6]([CH3:5])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncccc1CCl
Temperature: 85 °C
Yield: 94.5 %

Procedure:
In a 50 ml round bottomed flask, under argon at 0° C., thionyl chloride (12 mL, 164 mmol) was cautiously added to (2-methyl-3-pyridinyl)methanol (8 g, 65.0 mmol). Process was exothermic and white fumes were formed. At the end of the addition the obtained brown solution was heated at 85° C. for 40 minutes. The reaction mixture was evaporated to get the crude material as solid yellow slurry that was then taken up with NaHCO3 saturated solution (300 ml)/DCM (300 ml). The phases were separated and the aqueous one back extracted with DCM (2×200 ml). The combined organics were dried over Na2SO4 and evaporated to dryness to get 3-(chloromethyl)-2-methylpyridine (8.7 g) as a black/brown waxy solid that was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:23])[C:10]=1[C:24]([O:26]C(C)(C)C)=[O:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:23])[C:10]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(C(=O)OC(C)(C)C)c(C)nc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(C(=O)O)c(C)nc2n1
Temperature: 60 °C
Yield: 100.3 %

Procedure:
To a stirred solution of 6-tert-butyl 2-ethyl 5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2,6-dicarboxylate (1.14 g, 2.53 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction was heated to 60° C. for 30 h and concentrated under reduced pressure to obtain 5-(2,4-dichlorophenyl)-2-(ethoxycarbonyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid (1 g, 100% crude yield) as a yellow oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][CH2:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([O:31][CH3:32])[C:23]([CH2:33][CH3:34])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([S:18]([CH2:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([O:31][CH3:32])[C:23]([CH2:33][CH3:34])=[CH:22][CH:21]=2)=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(CC)c1OC
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)c2ccccc2)ccc(CC)c1OC
Yield: 67.6 %

Procedure:
3-Chloroperbenzoic acid (0.07 g) was added to a stirred solution of ethyl 6-(phenylthiomethyl)-3-ethyl-2-methoxybenzoate (Intermediate 19, 0.315 g) in DCM (5 ml) and the resultant mixture was stirred at room temperature overnight. The solution was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give ethyl 6-(benzenesulphinylmethyl)-3-ethyl-2-methoxybenzoate (0.095 g) as a clear gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].F[C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=1[CH:19]=[O:20]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:17]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=2[CH:19]=[O:20])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using the following starting materials: (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester and 2-fluoro-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:13]2[C:22]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:22]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1
Reactant: CCOC(=O)CCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N(CC)CC)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCC(=O)O)c12
Yield: 78 %

Procedure:
To a solution of ethyl 3-[2-[2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propanoate (Reference Example 28; 100 mg, 0.223 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) was added 1N sodium hydroxide solution (0.446 mL, 0.446 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 1 hr, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound as a solid (73.3 mg, 0.174 mmol, 78%).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:8][CH2:7][C:6](=[O:9])[O:5][C:3]1=[O:4].[CH3:11][OH:12]>>[CH3:11][O:12][C:3](=[O:4])[C:2]([F:10])([F:1])[CH2:8][CH2:7][C:6]([OH:9])=[O:5]
Reactant: CO
Reactant: O=C1CCC(F)(F)C(=O)O1
Product: COC(=O)C(F)(F)CCC(=O)O
Reaction time: 18 h

Procedure:
A solution of 3 g of 2,2-difluoroglutaric anhydride in 25 ml of dry methanol is allowed to remain at 25° for 18 hrs. At the end of this period the methanol is removed in vacuo leaving behind 2,2-difluoroglutaric 1-methyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10])[CH3:19]
Reactant: COc1cccc(C(C)=O)c1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3′-methoxyacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: [CH3:1][C:2]([CH3:53])([CH3:52])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[N:26]=[CH:25][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:23]=4)[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:8]=1)=[O:6].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:23]1[C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([C:5]([NH:4][CH2:3][C:2]([CH3:53])([CH3:52])[CH3:1])=[O:6])[CH:12]=[CH:11][CH:10]=2)=[N:26][CH:25]=[N:24]1
Reactant: CC(C)(C)CNC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)CNC(=O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 60 °C
Yield: 21.2 %

Procedure:
To a stirred solution of N-(2,2-dimethylpropyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenyl methyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.337 g, 0.481 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 60° C. for 4 h. The mixture was cooled and poured into aqueous saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate layer was pipetted off. Filtration of the crystals and washing with hexanes gave the title compound (0.0381 g, 21% yield). 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.60 (br t, 1H), 8.45 (t, 1H), 8.20 (dt, 1H), 8.12 (br d, 1H), 7.89 (dt, 1H), 7.70 (d, 1H), 7.67 (t, 1H), 3.27 (s, 2H), 1.01 (s, 9H). ES-MS (m/z) 375 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:17]=[C:16]4[N:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[N:28]=[CH:27][CH:26]=[CH:25]6)[N:19]=[N:20][C:15]4=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5](C(OC(C)(C)C)=O)[N:4]=1)[CH3:2].C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:17]=[C:16]4[N:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[N:28]=[CH:27][CH:26]=[CH:25]6)[N:19]=[N:20][C:15]4=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1nn(C(=O)OC(C)(C)C)c2cc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1n[nH]c2cc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of Example 181 (0.050 g, 0.099 mmol) in dichloromethane (1 ml) cooled to 0° C., TFA (0.5 ml) was added and warmed to RT. After 2 h, the reaction mixture was poured in ice water and pH was adjusted to ca. 11 with 10% NaOH solution and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as a yellow solid (0.023 g, 61%). M.P.: 211-213° C. MS (m/z): 406.08 (M+).