Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH3:22].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH3:22])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:31])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=NC1CCCCC1
Solvent: c1ccncc1
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)NC1CCCCC1
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of the compound of Example 46, 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.67 mmol) in 30 mL of pyridine was chilled in an ice water bath. With vigorous stirring, the solution was treated with cyclohexyl isocyanate (0.340 mL, 2.67 mmol). After 1 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 748 mg of N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexylurea as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:16]([OH:19])(=[O:18])=[O:17].Cl.C[O-].[Na+:23]>C(Cl)(Cl)Cl>[S:16]([O-:19])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:18])=[O:17].[Na+:23]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCC(C)CCCCCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical siring and nitrogen outlet is added chloroform (300 ml) and 7-methyldodecanol (100 g, 0.5 mol). Chlorosulfonic acid (60 g, 0.509 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot ethanol (55° C., 2 L). The mixture is vacuum filtered immediately. The filtrate is concentrated to a slurry on a rotary evaporator, cooled and then poured into 2 L of ethyl ether. The mixture is chilled to 5° C., at which point crystallization occurs, and vacuum filtered. The crystals are dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (119 g, 92% active by cat SO3 titration).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[O:22])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[O:22])[C:5]2[O:10][CH:9]([C:11]([F:13])([F:14])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Reaction time: 40 h
Yield: 61.5 %

Procedure:
To a stirred solution of the ester (Step 3)(0.284 g, 0.849 mmol) in THF:EtOH:H2O (7:2:1, 5 mL) was added aqueous NaOH solution (0.41 mL of 2.5 M, 1.02 mmol). After stirring 40 hours, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H2O, washed with diethyl ether, sparged with nitrogen to remove trace diethyl ether, and acidified with concentrated HCl yielding a suspension. Vacuum filtration of the suspension yielded the title compound as a pale yellow powder (0.160 g, 23%) mp 243.3–252.4° C. 1H NMR (acetone-d6/300 MHz) 10.39 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H, J=2.6 Hz), 7.75 (d, 1H, J=2.6 Hz), 6.08 (q, 1H, J=6.9 Hz). FABLRMS m/z 307 (M+H). ESHRMS m/z 304.9839 (M−H, Calc'd 304.9828). Anal. Calc'd for C12H6Cl1F3O4: C, 47.01; H, 1.97. Found: C, 46.64; H,1.86.
Reaction SMILES: [C:1]([N:4]([CH:6]1[CH:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:21]([F:22])=[C:20]3[C:15]([C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[CH:14][C:13]=2[F:30])[CH2:7]1)C)(=O)C.[ClH:31]>>[ClH:31].[CH:23]1([N:19]2[C:20]3[C:15](=[CH:14][C:13]([F:30])=[C:12]([N:8]4[CH2:9][CH:10]([CH3:11])[CH:6]([NH:4][CH3:1])[CH2:7]4)[C:21]=3[F:22])[C:16](=[O:29])[C:17]([C:26]([OH:28])=[O:27])=[CH:18]2)[CH2:25][CH2:24]1
Reactant: CC(=O)N(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1C
Agent: Cl
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1C

Procedure:
7-[3-(N-Acetyl-N-methylamino)-4-methyl-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.56 g) was dissolved in 20% aqueous hydrochloric acid solution (5 ml) and refluxed for 2 hours. Then the reacting mixture was concentrated under reduced pressure, to the resulting residue was added ethanol (10 ml) and crystallized with cooling. The resulting precipitate was collected by filtration and recrystallized from methanol to give the title compound as pale yellow powder, mp 242°-246° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH:29]([CH3:31])[CH3:28])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(C(C)C)CC2)cc1
Reaction time: 40 h
Yield: 43.2 %

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.27 g, 0.739 mmole), acetone (0.09 g, 1.48 mmol), and acetic acid (0.04 g, 0.739 mmol) in 10 mL of dry dichloromethane was added sodium triacetoxyborohydride (0.31 g, 1.48 mmol) under nitrogen. The mixture was stirred for 40 hours, and then aqueous 1 N NaOH (20 mL) solution was added. After 1 h of stirring, the layers were separated, and the aqueous layer was extracted twice with dichloromethane (15 mL). The organic extracts were combined, washed twice with 1 N NaOH (20 mL), dried (Na2SO4), and concentrated to give a brown-black glass. This material was purified on a flash silica gel column (5% methanol-chloroform to 10% methanol-chloroform) to provide 0.13 g (43%) of N,N-diethyl-4-[benzyl(1-isopropylpiperidin-4-yl)amino]benzamide as a colorless oil. MS (ES), m/z 408 (MH+). 300 MHz 1H NMR (CDCl3) δ1.06 (d, J=6.4 Hz, 6H), 1.17 (t, J=7.0 Hz, 6H), 1.68-1.92 (m, 4H), 2.29 (br t, 2H), 2.69-2.85 (br m, 1H), 2.97 (br d, J=10.3 Hz, 2H), 3.32-3.52 (m, 4H), 3.74-3.89 (br m, 1H), 4.53 (s, 2H), 6.65 (d, J=8.8 Hz, 2H), 7.18-7.42 (m, 7H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)[C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1>C1C(Cl)=CC=C(Cl)C=1>[CH3:1][C:2]1([CH3:24])[CH:3]=[C:4]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)[C:23]2[CH:22]=[C:19]([C:20]#[N:21])[CH:18]=[CH:17][C:16]=2[O:15]1
Reactant: CC(C)(C#Cc1ccc2ccccc2n1)Oc1ccc(C#N)cc1
Solvent: Clc1ccc(Cl)cc1
Product: CC1(C)C=C(c2ccc3ccccc3n2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
5.8 g of 4-[1,1-dimethyl-3-(2-quinolyl)-2-propynyloxy]benzonitrile were heated at reflux for 2 hours in 50 ml of dichlorobenzene. The mixture was allowed to cool to room temperature and was then evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) for the elution. The product was recrystallized from isopropanol to give 2.1 g of 2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile of melting point 102°-104° C.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[C:21]([O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH:9][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:17][CH:16]=1)(=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NCCc1ccc(O)cc1)c1cccnc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1
Temperature: 0 °C

Procedure:
To an ice cold suspension of 4.84 g (0.02 mol) N-nicotinoyl tyramine in 100 ml chloroform, 3.6 g (0.03 mol) of trimethylacetyl chloride was dropped while stirring. The mixture was refluxed overnight and the non-reacted nicotinoyl dopamine was filtered off. The filtrate was washed with water until free from chloride ions, washed once with 5% solution of NaHCO3 and then with water. Chloroform was evaporated on rotavap and the residue was crystallized from ether/pet. ether. Yield 3.9 g (60%), m.p. 80°-82°. PMR (CDCl3)δ 8.66-6.93 (m, 8H, C5H4N+C6H4), 3.56 (q, 2H, J=7 Hz, ##STR43## 2.86 (t, 2H, J=7 Hz, CH2), 1.33 (s, 9H, C--(CH3)3).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:3][NH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CN(C=O)C>O.CCOC(C)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[N:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ncccn1)C2
Temperature: 102.5 °C

Procedure:
A 2 L round-bottom flask was charged with tert-butyl 2,6-diazaspiro[3,3]heptane-6-carboxylate (64.3 g, 0.32 mol), cesium carbonate (317.0 g, 0.97 mol), 2-chloropyrimidine (45.5 g, 0.4 mol), and DMF (759.0 mL). The reaction mixture was heated to 100-105° C. for 20 min. The reaction mixture was cooled to ambient temperature, diluted with water (759.0 mL) and EtOAc (759.0 mL). The organic layer was washed with water (2×500.0 mL) and brine (500.0 mL). The organic layer was dried over sodium sulfate and filtered through Celite™. The filtrate was concentrated under reduced pressure. Column chromatography of the resulting crude product on silica gel, eluting with EtOAc and heptane (50-100%) afforded the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH3:25])[CH2:14][CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[CH3:25][C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCCNC1
Yield: 72.3 %

Procedure:
Benzyl 3-(tert-butoxycarbonylamino)-3-methylpiperidine-1-carboxylate (1.4 g, 4.0 mmol) and 10% Pd/C (0.21 g, 0.2 mmol) in MeOH (20 mL) were stirred under an H2 atmosphere (1 atm) for 1 hour. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated to give tert-butyl 3-methylpiperidin-3-ylcarbamate (0.62 g, 72% yield) as a solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][CH2:4][O:5][S:6]([CH3:9])(=[O:8])=[O:7].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:25]([O:1][C@@H:2]([CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][CH2:4][O:5][S:6]([CH3:9])(=[O:8])=[O:7])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)OCC[C@@H](O)COS(C)(=O)=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](O[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methanesulfonic acid (R)-3-hydroxy-4-methanesulfonyloxy-butyl ester (7.5 g) obtained in Step 1 in N,N-dimethylformamide (30 mL) were added imidazole (2.9 g) and tert-butylchlorodiphenylsilane (10.3 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature for 12 hours. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:2 to 1:1) to give methanesulfonic acid (R)-3-(tert-butyldiphenylsilanyloxy)-4-methanesulfonyloxy-butyl ester (11.4 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[CH2:16][C:17](O)=[O:18].O.[OH-].[Na+]>C(OCC)C>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[CH2:16][CH2:17][OH:18]
Reactant: O=C(O)Cc1c(F)ccc(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCc1c(F)ccc(F)c1F
Yield: 102.5 %

Procedure:
Lithium aluminum hydride (0.8 g) is suspended in dry diethyl ether (5 ml) and the mixture is stirred. To the mixture is added dropwise a solution of 2-(2,3,6-trifluorophenyl)acetic acid (2.0 g) in dry diethyl ether (15 ml), and the mixture is refluxed for 30 minutes. To the reaction mixture are added water (0.8 ml), 10% aqueous sodium hydroxide (0.8 ml) and water (1.6 ml) in this order, and the mixture is stirred at room temperature. To the mixture is added diethyl ether (10 ml), and the resulting precipitates are separated by filtration and washed with tetrahydrofuran. The washing liquid and the filtrate are combined and then concentrated under reduced pressure to give 2-(2,3,6-trifluorophenyl)ethyl alcohol (1.9 g), as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)CC(=O)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Sc2cccc(O)c2)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccc(Sc2cccc(OCCCCBr)c2)cc1

Procedure:
A stirred mixture of methyl 4-(3-hydroxyphenylsulfanyl)benzoate (13.0 g, 50.0 mmol) and 1,4-dibromobutane (21.0 g, 0.1 mol), anhydrous potassium carbonate (16.0 g) and 4-methylpentane-2-one (150 ml) was refluxed for 13 h. The hot mixture was filtered, the filtrate was evaporated to dryness and the partially crystalline residue was dissolved in a mixture of dichloromethane-petroleum ether (1:1) and then purified by column chromatography on silica gel using the same solvent mixture. The title ester was obtained as the main fraction (15.2 g, 76.9%), m.p. 43-45° C. For C16H19BrO3S (395.3) calculated: 54.69% C, 4.84% H, 20.22% Br, 8.11% S; found: 54.71% C, 4.80% H, 20.09% Br, 8.07% S.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20]CC2C=CC=CC=2)[CH:19]=1)[C:8]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[N:12]=1)=[O:9])[CH3:3].C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:20][C:18]1[CH:17]=[C:7]([CH:6]=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:19]=1)[C:8]([NH:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[N:12]=1)=[O:9]
Reactant: Cc1nsc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Cc1nsc(NC(=O)c2cc(O)cc(OC(C)C)c2)n1
Yield: 50.7 %

Procedure:
A solution of 3-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)-5-[(phenylmethyl)oxy]benzamide (33 g, 86 mmol), trifluoroacetic acid (160 mL) and thioanisole (50.5 mL) was stirred at ambient temperature for 48 hours. The TFA was removed in vacuo and the residue poured into saturated sodium bicarbonate solution (300 mL) and extracted into ethyl acetate (twice). The combined organic extracts were washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was triturated with DCM and washed with 5% ethyl acetate in isohexane to give the desired compound (12.8 g). 1H NMR δ (d6-DMSO): 1.31 (d, 6H), 2.51 (s, 3H), 4.67 (sept, 1H), 6.58 (s, 1H), 7.08 (s, 1H), 7.24 (s, 1H), 9.88 (s, 1H), 13.25 (brs, 1H). m/z 294 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)=O)=[CH:13][CH:12]=1.O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([C:17](=[C:5]2[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4]2)[C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)=[CH:20][CH:21]=1
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=C2CCC(C)(C)CC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a slurry of zinc powder (0.26 g, 4.01 mmol) in dry tetrahydrofuran (9 mL) was slowly added titanium tetrachloride (0.21 mL, 1.95 mmol). The reaction mixture was heated at reflux for 2.5 h, then a solution of 4,4-dimethyl-cyclohexanone (0.2 g, 1.58 mmol) and 4-(4-hydroxy-benzoyl)-benzoic acid methyl ester (24) (0.135 g, 0.53 mmol) in dry tetrahydrofuran (9 mL) was added. The reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, water (5 mL) was added followed by 10% K2CO3 (5 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was loaded onto silica and purified by flash chromatography with a hexanes:EtOAc gradient (100:0 to 80:20) to give 0.162 g (88%) of the title compound 171 as an oil. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6H), 1.31-1.33 (m, 4H), 2.12-2.19 (m, 4H), 3.81 (s, 3H), 6.66 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 9.36 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:36])([F:35])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][OH:34])[CH:28]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[O:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:36][C:7]([F:6])([F:35])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])[CH:28]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ccnc(CO)c3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1

Procedure:
Methansulfonyl chloride (0.2 mL, 2.46 mmol) is added to a solution of 5-(2-hydroxymethyl-pyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide, Example 25-D, (700 mg, 1.64 mmol) and triethylamine (0.7 mL, 4.92 mmol) in DCM (50 mL) at rt. After 1 h the reaction is partitioned between DCM and saturated aqueous NaHCO3. Organic layer is removed, dried over anhydrous Na2SO4, concentrated and then separated via FCC (EtOAc/heptanes 2:4 to EtOAc/heptanes 9:1) to give the title compound. MS (ESI) m/z 506.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[2-(3,4-dichlorophenylmercapto)-ethoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:31])[C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)=[O:31]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)c2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[1-(2,6-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (96 mg, 0.197 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (94.2 mg, 2.2 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight. After this time, the reaction mixture was concentrated. Water (˜20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (3.9 mL). The resulting white precipitate was collected by vacuum filtration, washed with hexanes, and then further dried under vacuum to {4-[1-(2,6-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (66 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84-7.97 (m, 2H), 7.68 (s, 1H), 7.55-7.66 (m, 2H), 7.44-7.53 (m, 1H), 7.34 (s, 1H), 4.69-4.80 (m, 1H), 3.76 (br. s., 2H), 3.32 (br. s., 6H), 2.43 (s, 2H), 1.57-1.85 (m, 2H). MS cald. for C25H23Cl2FNO3 [(M+H)+]: 474, obsd. 474.1.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=1[C:11]#[N:12]>CN(C=O)C>[CH:17]([C:14]1[CH:15]=[CH:16][C:9]([O:5][C@@H:2]([CH3:1])[CH2:3][CH3:4])=[C:10]([CH:13]=1)[C:11]#[N:12])=[O:18]
Reactant: CC[C@H](C)O
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)Oc1ccc(C=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
(2S)-2-Butanol (0.99 g, 0.013 mol) was dissolved in DMF (50 ml) and the solution cooled to 0° C. To this was added sodium hydride, (60% dispersion in mineral oil, 1.54 g, 0.036 mol) in a portion-wise manner, the mixture was stirred at 0° C. for 10 minutes after complete addition. 2-Fluoro-5-formylbenzonitrile (2.0 g, 0.013 mol) was then added and the reaction mixture allowed to warm to room temperature (slowly within the ice bath) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then cooled to 0° C., quenched with brine and diluted with EtOAc (˜25 ml). The mixture was partitioned and the organic fraction extracted with water (˜30 ml), the combined organics were dried by passing through a phase separating cartridge and then evaporated to dryness under reduced pressure to give the crude product. The crude residue was purified on a 40+M Biotage cartridge, eluting with a 20 to 50% mixture of EtOAc in hexane. This gave the title compound (220 mg) as a white solid. δH (d6-DMSO, 400 MHz): 9.88 (1H, s), 8.30 (1H, s), 8.15 (1H, d), 7.49 (1H, d), 4.73-4.81 (1H, m), 1.63-1.79 (2H, m), 1.33 (3H, d), 0.95 (3H, t). MS (ES): C12H13NO2 requires 203; found 204 (MH+).