Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH:12][C:13]([C:15]13[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]1)[CH2:22]3)=[O:14])=[N:5]2)[CH3:2].[CH3:25][O:26][CH2:27][CH2:28]Br>>[CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7]/[C:6](=[N:12]\[C:13]([C:15]13[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]1)[CH2:22]3)=[O:14])/[N:5]2[CH2:28][CH2:27][O:26][CH3:25])[CH3:2]
Reactant: CCOC12COCC1SC(NC(=O)C13CC4CC(CC(C4)C1)C3)=N2
Reactant: COCCBr
Product: CCOC12COCC1S/C(=N\C(=O)C13CC4CC(CC(C4)C1)C3)N2CCOC

Procedure:
The product of Example 72C and 2-bromoethyl methyl ether were processed according to the method of Example 1B to afford the title compound. MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.C(O)(=O)C.CN(B)C>O.C1(C)C=CC=CC=1>[Cl:11][C:12]1[S:16][C:15]([CH2:17][NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: BN(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCc2ccc(Cl)s2)cc1
Temperature: 40 °C

Procedure:
A mixture containing 46.6 grams (0.34 moles) of p-aminobenzoic acid, 50 grams (0.34 moles) of 5-chloro-2-thiophenecarboxaldehyde and 400 ml. of toluene was heated to reflux for about three and a half hours. The water formed was collected in a Dean-Stark trap. The reaction mass was cooled at the end of this period and the Schiff base collected as a tan solid. To a mixture of the intermediate Schiff base and 1.2 liters of glacial acetic acid 21.2 grams (0.36 moles) of dimethylaminoborane was added. The reaction mass was warmed to 40° C. for about 30 minutes and poured in 2 liters of ice water. The white precipitate of 4-(((5-chloro-2-thienyl)methyl)amino)benzoic acid was washed in water, dried, and recrystallized from toluene. The melting point was 177°-178° C.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH:30]=O)=[O:25]>>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)=[O:25]
Reactant: O=CCCCNC(=O)NC1Cc2ccccc2C1
Reactant: CCCNC1CCc2ncsc2C1
Product: CCCN(CCCCNC(=O)NC1Cc2ccccc2C1)C1CCc2ncsc2C1
Yield: 11 %

Procedure:
Compound 60 is prepared from 1C and 60C as described for 1. The salt of maleic acid is crystallized from acetonitrile/diethylether.
Reaction SMILES: N[CH:2]1[CH:7]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH3:20])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]1[C:31]([CH2:36]Br)=[CH:32][CH:33]=[CH:34][CH:35]=1.[ClH:38].C(#[N:41])C>C(O)C>[ClH:38].[ClH:38].[F:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH:7]3[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH2:20][N:41]4[CH2:36][C:31]5[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:29]4)[CH2:3][CH2:2]3)=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: BrCc1ccccc1CBr
Reactant: CC(O)CN1CCC(c2noc3cc(F)ccc23)C(N)C1
Reactant: CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1Cc2ccccc2C1

Procedure:
To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.24 g, 7.6 mmol), K2CO3 (1.61 g, 11.7 mmol) in acetonitrile (100 ml) was added α,α'-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered. The dark red solution was concentrated down. The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated with a solution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solids were collected and recrystallized again in ethanol to yield off-white crystals (1.01 g), m.p. 240°-243° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20]/[C:21](/[NH2:24])=[N:22]/[OH:23])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:25].[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31](Cl)=O.C(O)C>C1COCC1>[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31]1[O:23][N:22]=[C:21]([NH:20][C:15]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([C:4]3[C:3](=[O:25])[N:2]([CH3:1])[C:11]4[C:6]([CH:5]=3)=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=4)[CH:14]=2)[N:24]=1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: O=C(Cl)c1nccs1
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4nccs4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17 (0.1 mmol) in THF (1 mL) was added thiazole-2-carbonyl chloride (0.1 mmol). The reaction mixture was stirred at rt for 30 min. Then ethanol (1 mL) was added and heated at reflux for 3 h. After filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-(thiazol-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A9) MS m/z 431.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:17]1[C:18]([O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
3,4-Dichlorophenol (110 mg, 0.67 mmol) and potassium carbonate (20 mg, 1.42 mmol) were stirred in dimethylsulfoxide (20 mL). After 5 minutes, 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 10, 200 mg, 0.71 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with a 1M aqueous solution of sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo to give a white solid. The solid was purified by silica gel column chromatography (50% ethyl acetate in heptane elution) to afford the title compound as a white solid (286 mg, 95%).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=O.C([O:14][CH:15](N(C)C)[N:16]([CH3:18])[CH3:17])(C)(C)C>>[CH3:17][N:16]([C:15](/[CH:1]=[CH:2]/[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:14])[CH3:18]
Reactant: CC(=O)C1CCCCC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C(=O)/C=C/C1CCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 3.0 g (23.8 mmol) of cyclohexyl methyl ketone and 4.56 g (26.2 mmol) of t-butoxybis(dimethylamino)methane (Bredereck's reagent) was stirred at 60° C. overnight. The reaction mixture was then concentrated to give 4.0 g (93% yield) of 1-cyclohexyl-3-dimethylamino-propenone as an orange oil as indicated by 1H NMR. This product was used in the next reaction without any further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[OH-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CO.O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][CH2:18][CH:17]=[CH2:16])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: C=CCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 70 °C
Reaction time: 27 h

Procedure:
41.5 g of 3-methyl-xanthine are added with stirring at 70° C. to a solution of 10.2 g of NaOH in 400 ml of methanol/water (1:1). After mixing with 35.1 g of 4-bromobut-1-ene the mixture is stirred under a nitrogen atmosphere for 27 hours at 70° C. The reaction mixture is then cooled to 20° C. and the precipitate formed is filtered off. By re-precipitation from alkaline solution (pH 13.5) and acidification with dilute sulphuric acid to pH 10, 29.6 g (89.7% of theory relative to reacted 3-methyl-xanthine) of the title compound of melting point 245° to 246° C. are obtained after drying.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[S:4].[CH3:17][I:18]>CC(C)=O>[IH:18].[CH3:17][S:4][C:3](=[N:2][CH3:1])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CNC(=S)Nc1ccccc1N1CCCC1
Reactant: CI
Solvent: CC(C)=O
Product: CN=C(Nc1ccccc1N1CCCC1)SC
Product: I

Procedure:
A mixture of 1-methyl-3-[2-(1-pyrrolidinyl)phenyl]thiourea (18.5 g) and methyl iodide (12.3 g) and acetone (100 ml) was heated under reflux for 2.5 hours to give 2-methyl-1-[2-(1-pyrrolidinyl)phenyl]-3-methyl-2-thiopseudourea hydroiodide (m.p. 161°-162° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]1([O:21][C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:23][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: OB(O)c1ccc(OC2CCCC2)cc1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1-c1ccc(OC2CCCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(c), using 5-bromo-1H-indole-2-carboxylic acid ethyl ester and 4-cyclopentoxy-phenylboronic acid (see step (b) above).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([O:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[O:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:14])=[O:13].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[S:12]([O:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[O:19][CH2:20][CH2:21][CH:22]=[O:23])(=[O:14])=[O:13]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(C(F)(F)F)ccc2Cl)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[3-(2-chloro-5-trifluoromethylphenylsulfonyloxy)-5-methylphenoxy]propanol (600 mg, 1.4 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.6 mL, 4.7 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (410 mg, 69%). 1H-NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 8.24 (d, J=2.1 Hz, 1H), 7.84 (dd, J=8.4, 2.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)[O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:3])[NH2:2].Cl.O1CCOCC1>C(Cl)Cl.CO>[NH:32]1[C:33]2[C:29](=[C:28]([C:6]3[O:7][C:8]([C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]5)=[CH:13][CH:14]=4)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4cccc5[nH]ccc45)nc3C(N)=O)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc3[nH]ccc23)oc1-c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a suspension of tert-butyl 4-(4-(4-carbamoyl-2-(1H-indol-4-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.027 g, 0.06 mmol) in DCM (1 ml) was added 4M HCl in dioxane (0.5 ml, 2.0 mmol) and the reaction stirred at room temperature for 2 hours. The mixture was then diluted with MeOH and purified by SPE using a MP-TsOH cartridge (500 mg) to afford 2-(1H-indol-4-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.0078 g, 0.02 mmol, 36%). 1H NMR (DMSO) δ 2.86 (4H, br. t), 3.22 (4H, br. t), 7.06 (2H, d), 7.21 (1H, t), 7.35 (1H, br. t), 7.56-7.60 (2H, m), 7.62 (1H, d), 7.79 (1H, br. s), 7.86 (1H, dd), 8.30 (2H, d), 11.51 (1H, br. s). LCMS (2) Rt: 2.36 min; m/z (ES+) 388.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.O>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 1-diphenylmethylazetidin-3-ol (300 mg, 1.25 mmol) in THF (4.5 mL) was cooled to 0° C. t-BuOK (1M in THF, 3.75 mL) was added dropwise and the reaction mixture was stirred at room temperature for 1 h then cooled to 0° C. 1-Iodopentane (816 μL, 6.25 mmol) was added and the solution was stirred at room temperature for 18 h. The reaction mixture was diluted with H2O and extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The residue was purified on column chromatography (eluent: pentane/EtOAc, 95/5) to give the title compound (267 mg, 69%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Br:23])[C:21]=1[OH:22])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](O)=[O:16])[CH:13]=2)[NH:8][C:7]1=[O:18].C(P(=O)([O:30][CH2:31][CH3:32])OCC)#N.C([N:36](CC)CC)C>CN(C=O)C>[OH:30][CH2:31][CH2:32][NH:36][C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:18])[C:6]2=[CH:5][C:4]1[CH:19]=[C:20]([Br:23])[C:21]([OH:22])=[C:2]([Br:1])[CH:3]=1)=[O:16]
Reactant: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1cc(Br)c(O)c(Br)c1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C(=O)NCCO)cc2C1=Cc1cc(Br)c(O)c(Br)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylic acid (0.34 9, 0.77 mmol) (Example 156) and ethanofamine (0.08 g, 1.3 mmol) were dissolved in DMF (2 mL) and cooled with stirring to 5° C. Diethyl cyanophosphonate (0.172 g, 1 mmol), followed by triethylamine (0.25 g, 2.5 mmol) were added and stirring continued for 0.5 h at 50° C. and then the reaction allowed to warm to room temperature. After 1.5 h the reaction was quenched with water (10 mL) and extracted four times with a 4/1 mixture of chloroform/isopropanol (25 mL). The organic phases were combined, dried over magnesium sulfate and concentrated to dryness. Recrystalization from ethanol gave 22 mg of 3-(3,5-dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylic acid (2-hydroxyethyl)amide; 1H-NMR (DMSO-d6): δ10.9 (s, 1H), 10. 7 (bs, 1H), 8.81 (s, 2H), 8.25 (t, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.77 (s, 1H), 7.72 (d, J=8.0 Hz, 1 H), 6.86 (d, J=8.0 Hz, 1 H), 4.73 (bs, 1H), 3.52 (m, 2H), 3.37 (m, 2H). Mass spectrum (negative ion electrospray): m/z=479 (M−1, 22%), 481 (M−1, 35%), 483 (M−1, 30%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[Yb]>C(Cl)Cl>[C:25]([O:24][C:22]([N:16]1[CH2:21][CH2:20][N:19]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:18][CH2:17]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Yb]
Solvent: ClCCl
Product: Cc1nc2cc(OCC(O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester as a clear oil (9.5 g, 23 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[N:10][C:9]=2[N:8]([CH3:36])[C:7]1=[O:37].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[C:13]3[C:14](=[O:15])[N:6]([CH2:5][CH2:4][CH2:3][NH:2][S:39]([CH3:38])(=[O:41])=[O:40])[C:7](=[O:37])[N:8]([CH3:36])[C:9]=3[N:10]=[C:11]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(=O)n(CCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCNS(C)(=O)=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
1-(3-Aminopropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.10 g, 0.19 mmol, example 357) and TEA (0.80 mL, 0.57 mmol) were combined in THF (1 mL). Methanesulfonyl chloride (0.30 mL, 0.38 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to an oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 5% methanol/DCM. Target band was scraped off plate and eluted off silica gel with eluent to give N-(3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propyl)methanesulfonamide (0.045 g, 39% yield) as a tan solid. LCMS retention time=4.048 minutes and 99% purity, LCMS MH+ 602. 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8 Hz), 7.45-7.48 (m, 1H), 7.39-7.43 (m, 5H), 7.31 (d, 1H, J=8 Hz), 6.96 (t, 1H), 5.43 (s, 2H), 3.91 (t, 2H, J=8 Hz), 3.29 (s, 3H), 2.96 (dd, 2H, J=4 Hz and 12 Hz), 2.87 (s, 3H), 1.69-1.79 (m, 2H).
Reaction SMILES: BrCCC1C=C([Cl:10])C=[CH:6][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1CCBr.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[ClH:10].[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:5][CH2:6][NH:25][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1
Reactant: Clc1ccc(Oc2ccc(Cl)cc2CCBr)c(CCBr)c1
Reactant: CC(C)N
Product: CC(C)NCCOc1ccc(Cl)cc1
Product: Cl

Procedure:
Following the procedure of Preparation 11, 2-bromoethyl-4-chlorophenyl ether and isopropyl amine (excess) were reacted and the reaction mixture processed to give an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride to give the hydrochloride salt, m.p. 162°-164° C. in 69.3% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].C(N(CC)CC)C>C1COCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=[C:17]([O:22][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(=CCc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 4-(4-benzyloxyphenyl)-1,1,1-trifluoro-2-butanone (2.25 g, 7.26 mmol) and trimethylsilyl chloride (1.84 ml, 14.5 mmol) in THF (20 ml) at 0° C. was added dropwise triethylamine (3.1 ml, 21.8 mmol). The mixture was stirred at room temperature for 1 hour, diluted with hexane (200 ml), filtered and washed with hexane. The filtrate was washed with brine (2×50 ml), dried over sodium sulfate for 2 minutes and concentrated in vacuo to give the title material (2.58 g, 93%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[NH:9][N:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:11]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:8][N:9]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccn3)n[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.3 %

Procedure:
tert-Butyl 4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidine-1-carboxylate (1.46 g, 4.45 mmol) was dissolved in 15 ml DCM. Trifluoroacetic acid (5 ml) was added gradually and the resulting solution was stirred at ambient temperature for 3 h and was then concentrated in vacuo. The residue was dissolved in 4:1 MeOH/water and treated with MP-carbonate resin (5 g, 2.55 mmol/g). After stirring overnight the reaction was filtered and the filtrate was concentrated in vacuo to provide 1.1 g of 2-(3-piperidin-4-yl-1H-pyrazol-5-yl)pyridine (1-4) as a tan solid. 6 8.56 (d, J=3.9 Hz, 1H), 7.84 (m, 2H), 7.21 (m, 1H), 6.65 (s, 1H), 3.22 (m, 3H), 2.87 (m, 2H), 2.03 (d, J=12.8 Hz, 2H), 1.71 (d, J=10.3 Hz, 2H). m/z (m+1): 229.3.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([Br:22])=[CH:16][CH:17]=3)[C:12]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])(O)[C:11]=2[CH:10]=1.SC(C)C(O)=O.S(=O)(=O)(O)O>O.CO.C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([Br:22])=[CH:16][CH:17]=3)[C:12]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])([C:4]3[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=3)[C:11]=2[CH:10]=1
Reactant: Cc1ccc(C)c(C2(O)c3cc(Br)ccc3-c3ccc(Br)cc32)c1
Reactant: Oc1ccccc1
Agent: CC(S)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1ccc(C)c(C2(c3ccc(O)cc3)c3cc(Br)ccc3-c3ccc(Br)cc32)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
9.5 g of phenol were mixed with 22.2 g of 2,7-dibromo-9-(2,5-dimethylphenyl)fluoren-9-ol, 25 ml of toluene and 0.1 ml of mercapto-propionic acid. 5 ml of concentrated sulfuric acid were subsequently added dropwise. The batch was then stirred at 60° C. for about 2 hours, and finally 100 ml of MeOH and 100 ml of water were added. The solid was filtered off with suction and further purified by stirring with ethanol.