Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:7]2[C:12]([CH:13]=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[F:20][C:21]([F:28])([F:27])[S:22]([O:25]C)(=[O:24])=[O:23]>CCCCCCC>[O-:25][S:22]([C:21]([F:28])([F:27])[F:20])(=[O:24])=[O:23].[CH:18]1[C:19]2[C:14](=[CH:13][C:12]3[C:7]([C:6]=2[S+:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:21])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:15]=[CH:16][CH:17]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCCCSc1c2ccccc2cc2ccccc12
Solvent: CCCCCCC
Product: CCCC[S+](C)c1c2ccccc2cc2ccccc12
Product: O=S(=O)([O-])C(F)(F)F
Yield: 33.2 %

Procedure:
10.0 g (37.5 mM) of 9-butylthioanthracene was dissolved in approximately 100 mL heptane. To this was slowly added 6.2 g (4.3 mL, 37.8 mM) of methyl trifluoromethanesulfonate. There was a slight color change due to local orange color produced on addition, no exotherm, and haziness after a short time. The reaction was left to stir over the weekend during which time a precipitate formed. The reaction was cooled in an ice bath, then filtered and rinsed with hexanes, then air dried. This material was recrystallized from IPA, filtered, then dried in a 65° C. vacuum oven overnight to yield 2.7 g of 9-anthryl n-butyl methyl sulfonium triflate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[C:10](F)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1>>[Cl:8][C:9]1[C:10]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:20])([F:19])[F:21])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccccn1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccccn3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-hydroxypyridine and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 234.2-235.4° C. 1H NMR (acetone-d6 /300 MHz) 8.14 (dd, 1H, J=4.8 Hz, 1.4 Hz), 7.92 (m, 2H), 7.70 (s, 1H), 7.14 (m, 2H), 6.99 (s, 1H), 5.88 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=7.2 Hz). ESLRMS m/z 372 (M+H). ESHRMS m/z 372.0252 (M+H, Calc'd 372.0250). Anal. Calc'd for C16H9ClF3NO4 : C, 51.70; H, 2.44; N, 3.77; Cl, 9.54. Found: C, 51.70; H, 2.44; N, 3.71; Cl, 9.65.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:20][C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:23][C:22]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:29]2[CH2:30][CH2:31][N:26]([C:24]3[S:25][C:21]([CH3:20])=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:23]=3)[CH2:27][CH2:28]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: Cc1sc(N2CCNCC2)nc1-c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)c(C)s3)CC2)cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (277 mg, 0.848 mmol), 1-(5-methyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.148 ml, 0.848 mmol) in dimethylsulfoxide (2.6 ml) was stirred at 70° C. for 18 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 161 mg (47.8%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20]COC)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CO>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCc1ccc(OCc2ccccc2)c(C(N)=O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(CCO)ccc1OCc1ccccc1
Yield: 83.7 %

Procedure:
To a solution of 2-benzyloxy-5-(2-methoxymethoxyethyl)benzamide (721 mg) in methanol (10 ml) was added concentrated hydrochloric acid (0.7 ml), and the mixture was heated under reflux for 1 hour with stirring. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, diethyl ether was added to the residue, and the resulting insoluble material was collected by filtration to give 2-benzyloxy-5-(2-hydroxyethyl)benzamide (519 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[C:20]([CH3:25])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C(O)(=O)C.O.[Zn]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of N-[4-(benzyloxy)phenyl]-4-methyl-3-nitropyridin-2-amine (154.5 g) in THF (1300 mL), acetic acid (260 mL) and water (13 mL) was slowly added zinc powder (300 g) over 35 min. After zinc was added, the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through celite, and insoluble materials were washed with THF (3 L). The filtrate was combined and concentrated. To the residue were added EtOAc (1.2 L) and 2.5 N NaOH (1.2 L) under ice cooling, and then the mixture was stirred at room temperature for 30 min. The mixture was filtered through celite, and insoluble materials were washed with EtOAc (3 L). The organic layer was separated, washed with water (300 mL) and brine (300 mL×2), dried over MgSO4 and concentrated to give a crude N2-[4-(benzyloxy)phenyl]-4-methylpyridine-2,3-diamine (137 g) as black oil. This product was subjected to the next reaction without further purification.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[CH:8]=[CH:9][C:2]=12.Cl.[OH-].[Na+]>>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]3)[CH:8]=[CH:9][C:2]=12
Reactant: c1cc2nonc2cc1CCN1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCN(CCc2ccc3nonc3c2)CC1
Yield: 87.9 %

Procedure:
A solution of 8-[2-(benzofurazan-5-yl)ethyl]1,4-dioxa-8-aza spiro[4.5]decane (20.0 g, 69.1 mmol) in 1N aqueous HCl (200 mL, 200 mmol) was heated to reflux for 1.5 hr. The cooled solution was adjusted to pH 8.5 with 40% aqueous sodium hydroxide and extracted with ethyl acetate (250 mL then 100 mL). The combined extracts were washed twice with 1N aqueous HCl (200 mL combined). The acid layers were heated to reflux for 1 hr and then cooled. Basification as above, extraction into ethyl acetate, drying (Na2SO4), concentration, and trituration with hexanes afforded 1-[2-(benzofurazan-5-yl)ethyl]piperidin-4-one as a solid 14.9 g (88%). HPLC: Rt=3.0 min, 90:10 (0.1% H3PO4 in water: acetonitrile) flow=2.0 mL/min, Waters C18 micro bondapak 25 cmL.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][C:15]1[S:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:18]2[S:19][C:15]([CH3:14])=[CH:16][CH:17]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: Cc1ccc(B(O)O)s1
Product: COc1cc(OC)c(-c2ccc(C)s2)cc1C=O
Yield: 100 %

Procedure:
Ex-40A: 2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and 5-methyl-thiophene-2-boronic acid in a similar manner as described in Ex-3A, 100% yield. 1H-NMR (CDCl3) δ 10.33 (s, 1H), 8.05 (s, 1H), 7.22 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.49 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 2.50 (s, 3H). HMRS (EI) calcd. for C14H14O3S: 262.0664; found: 262.0665.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][Cl:15]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(OC)c(CCl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
In a nitrogen atmosphere, 2.00 g (11.9 mmol.) of 2,5-dimethoxybenzyl alcohol was dissolved in 10 ml of dichloromethane. The obtained solution was placed in an ice-bath, and to this was dropwise added a solution of 0.87 ml (12.0 mmol.) of thionyl chloride in 2 ml of dichloromethane. The mixture was then stirred at room temperature for 1.5 hour. The mixture wasplaced under reduced pressure at room temperature to distill off the solvent to give 2.22 g of the desired compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:13][O:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: COc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Product: COc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-methoxy-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 218°-221° C.) and piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20]>CC(C)=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH3:20])=[CH:4][C:3]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCI
Reactant: CC(C)Oc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCOc1ccc(Br)c(OC(C)C)c1
Yield: 85.8 %

Procedure:
To a solution of 4-bromo-3-isopropoxy-phenol (0.50 g, 2.16 mmol) in acetone (3 mL) were added potassium carbonate (0.30 g, 2.16 mmol) and ethyl iodide (0.35 mL, 4.33 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to give a white paste. It was then taken in diethyl ether (50 mL). The white solids were filtered off and the filtrate was concentrated. Purification of the residue by Biotage flash chromatography eluting with 10% ethyl acetate in hexanes gave 1-bromo-4-ethoxy-2-isopropoxy-benzene (0.48 g, 86%).
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][C:8]1([OH:22])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.O[Li].O.O.CO>CCO>[OH:22][C:8]1([CH2:7][C:6]([OH:23])=[O:5])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CC1(O)CC2CCC1C=C2c1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.4 %

Procedure:
To a solution of 4.0 g of rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester in 25 mL EtOH were added 2.1 g of LiOH.H2O, 8 mL H2O and 22 mL MeOH. The reaction mixture was stirred at rt for 3 d and then concentrated. The residue was partitioned between water and Et2O. The aq. layer was separated and acidified with 1N HCl resulting in the formation of a white solid. The solid was filtrated, washed with 5 mL aq. HCl and dried in vacuo to obtain 3.2 g of rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid as white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][N:6]=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])(=[O:11])=[O:10])[N:4]=1.[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH3:24])[N:7]2[N:6]=[C:5]([NH:8][S:9]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[Cl:19])(=[O:10])=[O:11])[N:4]=[C:3]2[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1nc(NS(=O)(=O)c2cc(Cl)ccc2Cl)n[nH]1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(NS(=O)(=O)c3cc(Cl)ccc3Cl)nc2n1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 4.60 g (13.3 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2,5-dichlorobenzenesulfonamide hydrochloride and 4.0 g (40 mmol) of 2,4-pentanedione in 60 ml of glacial acetic acid was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and poured into 500 ml of ice water to separate a solid. The solid was collected by filtration and dried to yield 4.53 g (92 percent) of the desired product as a white solid, m.p. 216.5°-218.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH2:15][CH3:16]>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:15][CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1cc2[nH]ccc2c(Cl)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ccc2c(Cl)nc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A solution of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (250 mg, 1.34 mmol) in tetrahydrofuran (4 mL) at 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (64.2 mg, 2.67 mmol) followed by iodoethane (229 mg, 1.47 mmol). After stirring at 0° C. for 0.5 h, the reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. At this time, the resulting mixture was quenched with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (30% ethyl acetate/hexane) afforded 4,6-dichloro-1-ethyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 69.6%). LC-MS calcd. for C9H8Cl2N2 [(M)+] 214, obsd. 214.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH:12]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])([CH3:14])[CH3:13]>ClCCl>[ClH:8].[CH:12]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:10]([NH:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[CH3:1])=[O:11])([CH3:14])[CH3:13]
Reactant: CC(C)NCCCN
Reactant: Cc1ccc(Cl)cc1N=C=O
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1NC(=O)NCCCNC(C)C
Product: Cl
Reaction time: 0.33 h

Procedure:
A solution of 16.7 g. of 2-methyl-5-chlorophenylisocyanate and 50 ml. of dichloromethane was added to a stirred, cooled solution of 35 g. of N-isopropyl-1,3-diaminopropane and 250 ml. of dichloromethane. The temperature was kept at -5° to 0° C. during addition. Stirring was continued at room temperature for 20 minutes. The precipitated solid was separated by filtration. The filtrate was extracted with water, then with 200 ml. of 15% hydrochloric acid (v/v). The acid extract was made basic with saturated sodium carbonate solution, then extracted with dichloromethane. The dichloromethane solution was dried over magnesium sulfate, then evaporated to dryness. The residue was dissolved in ethanol and saturated with hydrogen chloride. The solution was evaporated to dryness in vacuo. The residue was triturated with ether until it solidified. The solid was recrystallized from EtOH/Et2O to obtain N-[3-(isopropylamino)propyl]-N'-(5-chloro-2-methylphenyl)urea hydrochloride, m.p. 180°-183° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:19]=1)=[O:2].[BH4-].[Na+]>C1COCC1.C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:14])([F:15])[F:13])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:19]=1
Reactant: O=Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(CO)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a chilled (ice bath), stirred solution of 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 75, Step 2) (0.133 g, 0.489 mmol) in THF (1 mL) and ethanol (1 mL) in a 10 mL round bottom flask was added NaBH, (0.020 g, 0.528 mmol) in two portions. The reaction was allowed to warm to room temperature and more NaBH4 (0.050 g, 1.322 mmol) was added. The total reaction time was 3 hours. The reaction was quenched with aqueous HCl (1 N solution) and was extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated in vacuo yielding a foam. This crude product was purified by flash chromatography (silica gel 60, eluant 1:1, hexane-ethyl Acetate with 2% acetic acid). The product collected from the chromatography was recrystallized from hexanes and ethyl acetate, and collected by vacuum filtration yielding the title compound (0.042 g, 31%) as a very pale yellow powder: mp 177.5–180.8° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 7.44 (s, 1H), 7.41 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=8.3 Hz), 5.80 (q, 1H, J=7.3 Hz), 4.59 (s, 2H). FABLRMS m/z 275 (M+H). EIHRMS m/z 274.0417 (M+, Calc'd 274.0453). Anal. Calc'd for C12H9F3O4: C, 52.57; H, 3.31. Found: C, 52.43; H, 3.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[NH:23][C:22]5[CH:24]=[CH:25][C:26]([C:28](O)=[O:29])=[CH:27][C:21]=5[N:20]=4)=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.ClC1C=CC(C2(C3C=CC(C=O)=CC=3)OCCO2)=CC=1.[NH2:51]C1C=C(C=CC=1N)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[NH:23][C:22]5[CH:24]=[CH:25][C:26]([C:28]([NH2:51])=[O:29])=[CH:27][C:21]=5[N:20]=4)=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C(O)c1ccc2[nH]c(-c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc3)nc2c1
Agent: O=Cc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc3)nc2c1

Procedure:
2-{4-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-phenyl}-1H-benzoimidazole-5-carboxylic acid. This compound was prepared as described in Example 1 Step C from 4-[2-(4-chloro-phenyl)-[1,3]dioxolan-2-yl]-benzaldehyde (100 mg, 0.34 mmol) and 3,4-diamino-benzoic acid (53 mg, 0.34 mmol). The title compound was obtained as a tan solid 135 mg (92%). MS (ESI): mass calculated for C23H17ClN2O4, 420.1; m/z found, 421.1 [M+H]+, 419.1 [M−H]−. HPLC (Method B): Rt=2.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:39])[CH2:10][N:11]([CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH2:29][C:30](=[CH:34][C:35]([O:37]C)=[O:36])[CH:31]=[CH:32][CH:33]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[Cl:23])=[CH:5][CH:4]=1.ClC1C=CC=CC=1C(C)CN(CCCOC1CC(=CC(O)=O)C=CC=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[ClH:23].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:39])[CH2:10][N:11]([CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH2:29][C:30](=[CH:34][C:35]([OH:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[C:14]=2[Cl:23])=[CH:7][CH:8]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccc(OC)cc2)C1
Agent: CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: COc1ccc(C(C)CN(CCCOC2=CC=CC(=CC(=O)O)C2)Cc2cccc(C(F)(F)F)c2Cl)cc1
Product: Cl
Yield: 66 %

Procedure:
The titled compound was prepared from N-(2-[4-methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in 66% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine in Example 184g. MS (ESI) 550 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C@H:24]1[O:30][C:31](=[O:33])[CH3:32].[N:34]#CBr.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([C:29]#[N:34])[CH2:25][C@H:24]1[O:30][C:31](=[O:33])[CH3:32]
Reactant: N#CBr
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1OC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C#N)C[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To compound of example 126 (2.9 g, 6.15 mmol) in dry CHCl3 (40 mL) at 0° C. was added cyanogen bromide (2.1 g, 19.8 mmol). The reaction mixture was stirred at room temperature for 8 h. It was poured into water (100 mL) and extracted with CHCl3 (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. The solid residue obtained was purified using a silica gel column and 2% IPA+1% liquor NH3 in CHCl3 as eluant to obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:26])[N:15]([CH3:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]=1[S:19][CH3:20])[CH3:2].C(=O)([O-])[OH:28].[Na+].ClC1C=C(C=CC=1)C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:26])[N:15]([CH3:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]=1[S:19]([CH3:20])=[O:28])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCc1cc(CC)c(-c2c(SC)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(CC)c(-c2c(S(C)=O)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Yield: 97.3 %

Procedure:
To a 100 ml volume four-necked flask, 4-(2,4,6-triethylphenyl)-2-methyl-5-methylsulfanyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-46)-(1)-40) (0.683 g) and chloroform (24 ml) were added at room temperature, and stirred. Sodium hydrogen carbonate (0.597 g) and meta-chlorobenzoic acid (0.615 g) was added and the resulting mixture was stirred at room temperature for 4 hours. Then, the reaction mixture was poured into water (30 ml), added sodium sulfite (0.4 g), and extracted with t-butyl methyl ether (30 ml) 4 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane:ethyl acetate=5:1 to hexane:ethyl acetate=1:1) to give 0.692 g of 4-(2,4,6-triethylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-40).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](CO)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:16][Br:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1CBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
To a solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (2.0 g) in anhydrous tetrahydrofuran (50 ml) was added carbon tetrabromide (6.2 g) and triphenylphosphine (4.88 g). the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered through celite. The filtrate was taken up in ethyl acetate, washed with water then brine, dried (MgSO4) and the solvent removed in vacuo give a crude product. This was purified using flash chromatography which yielded Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.287 g).