Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH2:24][CH3:25].C(OC1C=C(C2[C@H]3[C@H](CC=CC3)C(=O)NN=2)C=CC=1OC)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][CH2:24][CH3:25])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCBr
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: CCOc1cc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)ccc1OC
Product: CCCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and 1-bromopropane as described for compound 6. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60-95° C.). M.p. 95-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16]C)[CH:10]=[CH:9][CH:8]=3.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([OH:16])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3oc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1c2ccc(Cl)cc2oc2c(O)cccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-chloro-5-methoxyxanthone (12.5 g.) [see Examples 32 and 33] in dry dichloromethane at 0° C. is slowly added boron tribromide (24 ml.). The mixture is stirred at room temperature for 24 hours, then poured into water. The resulting precipitate if filtered off and dried to give 3-chloro-5-hydroxyxanthone which is used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[NH:9][CH2:8][CH2:7][CH2:6][N:17]=[N+:18]=[N-:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN=[N+]=[N-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a solution of compound 5 (12.56 g: 60 mmol) in dry DMF (150 mL) was added in small portions NaN3 (11.7 g: 180 mmol) with stirring over 30 min. The resulting solution was heated to 50° C. for 1 h and then stirred overnight at room temperature. Water (50 mL) was added with stirring, the solvent was removed, and the residue was extracted with ethyl acetate (2×175 mL). The combined organic layers were washed sequentially with water (2×50 mL) and brine (2×50 mL). The organic extract was dried over anhydrous sodium sulfate and evaporated to give compound 6 as a light yellow oil (10.54 g; 87% yield). 1H NMR (CDCl3-d6) δ 4.9 (s, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 1.7 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:17]([CH3:19])[CH3:18])[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CNC.[I-].[Na+].C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1Cl)[CH:42]=O.N1(C2CCCCC=2)CCCC1>Cl>[ClH:1].[CH2:42]([C:11]1([OH:16])[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[N:17]([CH3:19])[CH3:18])[C:41]1[CH:44]=[CH:45][CH:46]=[CH:39][CH:40]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C(c1ccc(Cl)c(Cl)c1)C1CCCCC1=O
Agent: C1=C(N2CCCC2)CCCC1
Agent: CNC
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(c1ccc(Cl)c(Cl)c1)C1CCCCC1(O)Cc1ccccc1
Temperature: 0 °C
Yield: 128.2 %

Procedure:
2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanone 7.92 g (97.1 mmole) of freshly dried dimethylamine hydrochloride were added while stirring to 214 ml (214 mmole) of sodium iodide solution (1 M in acetonitrile) cooled to 0° C. with an ice bath, followed by the dropwise addition of 27 ml (194 mmole) of triethylamine and 27 ml (214 mmole) of chlorotrimethylsilane, and the whole was stirred for a further hour at RT. 17.0 g (97.1 mmole) of 3,4-dichlorobenzaldehyde were added while cooling with ice, and the whole was stirred for a further hour at RT. The reaction mixture was cooled again to 0° C. with an ice bath, following which 14.7 g (97.1 mmole) of 1-(pyrrolidino)-1-cyclohexene were added, and the whole was stirred for a further two hours at RT. The reaction mixture was worked up by adding 130 ml of semi-concentrated hydrochloric acid, stirred for 10 minutes, washed twice with in each case 125 ml of ether, and adjusted in the alkaline range (pH ca. 9) with 300 ml of dilute ammonia solution (5 vol. %). The reaction mixture was extracted three times with 125 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar) without heating. 26.6 g of crude base (91% of theory) were obtained in this way. 26.7 g of the hydrochloride of 2-[(3,4-dichlorophenyl)dimethylaminomethyl]cyclohexanone (81.8% of theory) were obtained from the crude base according to the procedure described in Example 1 (2nd stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]([F:12])([F:11])[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ncc(Br)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Yield: 87 %

Procedure:
A mixture of the above 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (9.90 g, 41.1 mmol), commercially available 4-(trifluoromethyl)benzeneboronic acid CAS-No. [128796-39-4] (8.58 g, 45.2 mmol), 1N aqueous Na2CO3-solution (98.6 mL, 98.6 mmol) and Pd(PPh3)4 (475 mg, 1 mol %) in DME (205 mL) was refluxed under argon atmosphere for 1 h. Poured into 5% citric acid, extracted with EtOAc, washed the organic layers with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a grey solid (13.96 g) which was purified by silica gel flash chromatography with heptane/EtOAc 4:1 to 2:1 to give the title compound as a light yellow solid (10.90 g, 87%). MS (ISN) 305 [(M−H)−]; mp 168° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([O:23][C:24]([NH:26][NH:27][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
54.3 g 4-bromo-3-methyl-benzoyl chloride was added to 23.3 g triethylamine and 30.4 g hydrazinecarboxylic acid tert-butyl ester in 1 L dichlormethane. The reaction was stirred 1 h at RT and extracted with water. The organic layer was evaporated and the residue was crystallized with diisopropylether to give 70 g desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][C:32]=1[O:40][CH2:41][CH2:42][Cl:43]>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[CH:33][C:32]=1[O:40][CH2:41][CH2:42][Cl:43]
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCCCl)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCCl)c3)n2)c1)C(F)(F)F
Yield: 34 %

Procedure:
The compound was synthesized from N-{3-[3-(2-chloro-4-pyrimidinyl)-pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (see Example 1, Step C) and 1-chloro-2-[(2-chloroethyl)oxy]-4-nitrobenzene as described in Example 10, Step C to afford a dark yellow solid in 34% yield. ES-LC/MS m/z 587 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:33][S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH:10]=1.N#N.Br[C:43]1[S:44][C:45]([CH3:48])=[N:46][N:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:43]4[S:44][C:45]([CH3:48])=[N:46][N:47]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:33][S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH:10]=1
Reactant: Cc1nnc(Br)s1
Reactant: CC1(C)OB(c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: Cc1nnc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)s1
Yield: 4.2 %

Procedure:
A solution of N-(2′,4′-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (0.15 g, 0.272 mmol) in 1,2-dimethoxyethane (5 ml) was degassed by N2 bubbling for 5 min. 2-Bromo-5-methyl-1,3,4-thiadiazole (0.058 g, 0.326 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.011, 0.013 mmol, 0.05 eq.) and aqueous sodium carbonate (0.072, 0.680 mmol, 2.5 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexane) to yield the desired title product in 4.2% yield (0.006 g). 1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.81 (s, 1H), 8.34-8.33 (s, 1H), 8.00-7.98 (dd, 1H), 7.84 (d, 1H), 7.79-7.73 (m, 1H), 7.54 (s, 1H), 7.49-7.42 (m, 2H), 7.29-7.24 (m, 1H), 3.17-3.16 (d, 2H), 2.85-2.84 (m, 1H), 2.79 (s, 3H), 1.01-0.99 (m, 4H); LC-MS (ESI): Calculated mass: 523.58; Observed mass: 523.7 [M+H]+ (rt: 1.50 min).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH:8]1[CH2:18][CH:17]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:10]([CH2:11][C:12]3[NH:13][N:14]=[CH:15][C:16]=32)[CH2:9]1)=O)C>C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:19]2[CH:10]3[CH2:9][CH:8]([CH2:6][OH:5])[CH2:18][CH:17]2[C:16]2[C:12]([CH2:11]3)=[N:13][NH:14][CH:15]=2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2Cc3n[nH]cc3C1CC(CO)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium borohydride (17 mg, 0.80 mmol) was added to a solution of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid ethyl ester (328 mg, 0.80 mmol) in THF (3 mL). The resulting solution was stirred at room temperature for 18 h then heated to 60° C. for 2 h. The reaction was quenched by the addition of water (5 mL) and the resulting mixture was extracted with EtOAc (3×5 mL). The combined organic phases were dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (eluant hexane/EtOAc, 9/1 to 1/1) and preparative HPLC to give [12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2,5-dien-10-yl]-methanol as a white solid. Retention time (min)=1.242, method [1], MS(ESI) 368.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.58 (s, 1H), 7.38 (d, J=8.2 Hz, 2H), 5.33 (s, 1H), 4.48 (d, J=7.1 Hz, 1H), 3.41 (d, J=2.7 Hz, 2H), 3.08 (dd, J=17.6, 7.7 Hz, 1H), 2.62 (d, J=17.6 Hz, 1H), 1.81-1.54 (m, 5H).
Reaction SMILES: [CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:22][C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25]([N:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[N:10]2[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7]1)=[O:26]
Reactant: c1ccc2c(c1)NCCc1cccn1-2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of 0.28 g of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 6 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.50 g of 2-chloro-4-nitrobenzoyl chloride in 0.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour then quenched with 5 ml of saturated NaHCO3. The methylene chloride is evaporated in vacuo and the residue is diluted with 5 ml of water and extracted with 20 ml of ethyl acetate. The organic layer is separated, washed with saturated NaHCO3 and brine, dried with Na2SO4 and evaporated in vacuo to give 0.59 g of a yellow foam which is triturated with ether-hexanes to give 0.56 g of the desired product as off-white solid. MS(CI): 368(M+H)(Cl35) 370(M+H) (Cl37)
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[N:14]1C=CC=CC=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3([C:37]4[N:41]=[C:40]([C:42]5[CH:43]=[N:44][N:45]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49](O)=O)[CH:46]=5)[O:39][N:38]=4)[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:23][N:22]=1.O.[OH-].[Li+]>C(Cl)Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C.CO.O.C1COCC1>[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3([C:37]4[N:41]=[C:40]([C:42]5[CH:43]=[N:44][N:45]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]#[N:14])[CH:46]=5)[O:39][N:38]=4)[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:25][N:26]=1
Reactant: CC(C)(Cn1cc(-c2nc(C3(c4ccc(-c5cnc(N)nc5)nc4)CCC3)no2)cn1)C(=O)O
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)Cn1cc(-c2nc(C3(c4ccc(-c5cnc(N)nc5)nc4)CCC3)no2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
TFAA (73 μL, 0.522 mmol) is treated with CH2Cl2 (1.0 mL) and pyridine (42.2 μL, 0.522 mmol) and cooled to 0° C. To this mixture is added a solution of Example 147 (48.0 mg, 0.104 mmol) in CH2Cl2 (0.5 mL) and the resulting mixture is warmed to room temperature and stirred for 1 hour. The reaction is then quenched by the addition of saturated NaHCO3 and stirred for 30 minutes. The mixture is diluted with CH2Cl2 and water and the layers separated. The aqueous layer is extracted again with CH2Cl2 and the combined organics are dried over Na2SO4, filtered, and concentrated. The crude residue is then treated with THF (1.0 mL), water (0.5 mL), methanol (0.2 mL), and lithium hydroxide monohydrate (8.6 mg, 0.21 mmol) and the resulting mixture is heated at 40° C. for 30 minutes. The mixture is then diluted with saturated NaHCO3 and ethyl acetate and the layers separated. The aqueous is then extracted with ethyl acetate again and the combined organics are dried over Na2SO4, filtered, and concentrated. The resulting residue is triturated with acetonitrile to give the title compound (12.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(CC2(c3cccc(OC)c3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 4-methoxybenzyl chloride (0.15 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-methoxy-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.19 g, 80.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]O)[CH2:24][CH2:23]1.Cl.C(O)CCO>CCOCC>[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH:25]([CH:28]=[CH:29][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)[CH2:26][CH2:27]1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: OCCC1CCC(CCC2OCCCO2)CC1
Agent: Cl
Solvent: OCCCO
Solvent: CCOCC
Product: Fc1cc(C=CC2CCC(CCC3OCCCO3)CC2)ccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A Grignard reagent prepared from 3-fluoro-4-trifluoromethoxybromobenzene (9.3 g, 38.7 mmol) and dried Mg (0.97 g 39.9 mmol) in a 50 ml ether solvent, was cooled down 0° C., followed by dropwise adding thereto, a 40 ml ether solution of the above 2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)ethanol (6.3 g, 26.2 mmol), heating the mixture up to room temperature, stirring it for 3 hours, adding this reaction solution to 6N HCl (100 ml), extracting the resulting product with ethyl acetate, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying over MgSO4, distilling off the solvent, adding toluene (150 ml) and Amberlist (3.0 g) to the residue, refluxing for 5 hours, while removing water formed by the reaction by means of Dean-Stark, adding trimethylene glycol (1.0 g, 13.1 mmol), further refluxing for one hour, filtering off Amberlist, distilling off the solvent, purifying the residue according to column chromatography treatment using ethyl acetate/toluene (1/2) as a developing solvent, on silica gel, and distilling off the solvent, to isolate 1-(2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)vinyl-3-fluoro-4-trifluoromethoxybenzene (5.5 g, 13.7 mmol). The yield of this product from 2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)ethanol was 52.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].[B].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2>>[CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C@H:4]1[OH:9]
Reactant: COC1(OC)CCOCC1=O
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [B]
Product: COC1(OC)CCOC[C@H]1O

Procedure:
reacting 4,4-dimethoxydihydro-2H-pyran-3(4H)-one with a boron reducing agent and S-(−)-2-methyl-CBS-oxazaborolidine, over a period of at least six hours to provide the (R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol, wherein (R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol is formed in at least 90% enantiomeric excess.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]([O:16][CH3:17])[C:8]=2[O:18][CH3:19])[N:6]=1.C(OC(C[N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH:29]1[C:37](O)=[O:38])=O)(C)(C)C.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:19][O:18][C:8]1[C:9]([O:16][CH3:17])=[C:10]([CH3:15])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[C:5]1[N:6]=[C:2]([NH:1][C:37]([C:29]2[NH:28][C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:38])[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)CN1c2ccccc2CC1C(=O)O
Reactant: COc1cc(C)c(OC)c(OC)c1-c1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(OC)c(OC)c1-c1csc(NC(=O)c2cc3ccccc3[nH]2)n1
Reaction time: 48 h
Yield: 33.1 %

Procedure:
0.16 g of 2-amino-4-(2,3,6-trimethoxy-4-methylphenyl)thiazole is dissolved in 10 ml of DMF. 0.18 g of N-(tert-butyloxycarbonylmethyl)-2-indolinecarboxylic acid, 0.2 ml of triethylamine and 0.38 g of BOP are added, and the reaction mixture is left stirring for 48 hours. 100 ml of water are added, the resulting mixture is extracted with AcOEt, and the organic phase is separated after settling has taken place, dried over sodium sulphate and concentrated under vacuum. The residue is dissolved in 10 ml of CHCl3, 10 ml of TFA are then added and the reaction mixture is stirred at r.t. for 2 hours 30 minutes. It is concentrated under vacuum, adding three times 20 ml of benzene. The residue is dissolved in 20 ml of dimethoxyethane, 0.1 ml of triethylamine and 0.112 g of DDQ are then added and the reaction mixture is left overnight at room temperature. It is concentrated under vacuum, and the residue is taken up in AcOEt and washed successively with 1N NaOH solution, with KHSO4 solution and with sodium chloride solution; the organic phase is separated after settling has taken place, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is chromatographed on silica gel, eluting with CHCl3 /AcOEt (50:50; v/v). The fractions of pure products are concentrated under vacuum, and the residue is solidified in pentane to yield 0.08 g of the expected product; m.p.=200° C.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[N:19]=[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[N:12]2[N:11]=1.CN(C)C=O.[C:25]1([C:31]2[N:32]=[C:33]([SH:36])[NH:34][N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-]>CCOC(C)=O>[CH3:18][C:17]1[N:12]2[N:11]=[C:10]([CH2:9][S:36][C:33]3[NH:34][N:35]=[C:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:32]=3)[N:19]=[C:13]2[CH:14]=[CH:15][CH:16]=1
Reactant: Sc1nc(-c2ccccc2)n[nH]1
Reactant: Cc1cccc2nc(CCl)nn12
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2nc(CSc3nc(-c4ccccc4)n[nH]3)nn12
Temperature: 60 °C
Reaction time: 0.03 h

Procedure:
Triethylamine (0.7602 mL, 5.454 mmol) was added to a solution of [2-Chloromethyl-5-methyl-(1,2,4]triazolo[1,5-a]pyridine (495 mg, 2.73 mmol) in N,N-Dimethylformamide (12 mL, 150 mmol) and the solution was stirred aprox 2 mins. 5-Phenyl-2H-1,2,4-triazole-3-thiol (532 mg, 3.00 mmol) was added to the mixture as a solid. The reaction mixture was subsequently heated at 60° C. for 0.5 hours. The mixture was rotovaped. EtOAc (60 mL) and sat. bicarbonate (20 mL) were added to the residue and the phases were separated. The organic phase was washed with brine (20 mL). After drying (MgSO4), the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Eluent: EtOAC:N-heptane 50-100%). This afforded 542 mg (61%) of the title compound as a white solid. LC-MS: m/z=323.1 (MH+), tR=0.52 min, Method B. 1H NMR (600 MHz, DMSO-ds): δ 7.96 (d, 2H), 7.63 (m, 1H), 7.60 (t, 1H) 7.50 (m, 3H), 7.06 (d, 1H), 4.68 (s, 2H), 2.67 (s, 3H).