Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:5][CH2:1][C:8]1[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:10][CH:11]=[CH:12][C:7]=1[F:6]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)Nc1nccc(F)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(F)c1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
CBr4 (531 mg, 1.6 mmol) was added to a solution of the product of Step B (242 mg, 1 mmol) in THF (3 mL). Then a solution of triphenylphosphine in THF (1 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. The mixture was loaded onto a silica gel column. Elution with (EtOAc:PE=1:3) to afford the title compound (160 mg, 52%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.38-8.35 (m, 1H), 7.09 (s, 1H), 6.90-6.86 (m, 1H), 4.61 (s, 2H), 1.54 (s, 9H) ppm MS: M/e 305 (M+1)+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CO>C1(C)C=CC=CC=1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:20][C:19]2[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Br)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: Brc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The method of Taguchi and Westheimer1 was modified as follows: benzophenone (455 g, 2.50 mol) and 4-bromoaniline (473 g, 2.75 mol) were dissolved in toluene (1.2 L) under argon in a 5 L flask containing activated molecular sieves (5 Å, 1.25 kg). The flask was fitted with a reflux condenser, rubber septum, and pressure outlet. The mixture was heated to gentle reflux and shaken occasionally; an intense yellow color soon developed. After 18 h, heating was discontinued and the solution was cooled to rt. The solution was decanted from the molecular sieves, and the sieves were washed with Et2O until the filtrate was colorless. The combined organic solutions were concentrated in vacuo to give an orange oil. MeOH (ca. 80 mL) and a seed crystal of 1 were added. The product was allowed to crystallize at 0° C. and the precipitate was collected by filtration. The mother liquor was further concentrated, and a second crop of crystals was collected from MeOH. Recrystallization of the combined material from MeOH afforded yellow crystals (760 g, 90%). 1: mp 82-83° C.; 1H NMR (300 Mz, CDCl3) δ 7.75 (dd, J=6.9, 1.6 Hz, 2H), 7.52-7.39 (m, 3H), 7.32-7.23 (m, 5H), 7.11 (dd, J=8.5, 2.0 Hz, 2H), 6.61 (dt, J=8.5, 2.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 168.7, 150.4, 139.5, 136.1, 131.6, 131.0, 129.5, 128.8, 128.3, 128.2, 122.8, 116.3, 103.6;IR(CDCl3) 3058, 3024, 1615, 1478 cm−1; Anal. Calcd for C19H14BrN: C, 67.87; H, 4.20. Found: C, 68.08; H, 4.28.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11]P(=O)(OCC)OCC)=[CH:5][CH:4]=1.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>C1COCC1.O1CCOCCOCCOCCOCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH:11]=[C:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cc2)c1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cc3)c2)CC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Diethyl 3-(4-(trifluoromethyl)phenoxy)benzylphosphonate (1.7 g, 4.4 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.02 mL, 0.10 mmol) were combined in THF (10 mL). Sodium hydride (195 mg, 60% dispersion in mineral oil, 4.9 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (875 mg, 4.9 mmol) in THF (5 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10%, EtOAc:heptane) to afford the title compound (1.75 g, 92% yield) as a thick oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1C=O.[C:15]1([NH2:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:1][O:2][CH:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[N:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc2ccccc2c1C=O
Solvent: c1ccccc1
Product: COC1C=Cc2ccccc2C1=Nc1ccccc1
Yield: 102.2 %

Procedure:
2-Methoxy-1-naphthaldehyde [50.0 gm. 0.27 mole] and phenylamine [25 gm., 0.27 mole] were refluxed with benzene [100 ml] for 4 hours. The benzene was evaporated to an oil, dissolved in chloroform, the chloroform dried over sodium sulfate and evaporated to a green semisolid of the 2-methoxy-1-naphthylidene-phenylamine [68.8 gm., 97% yield].
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]([C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]2[CH3:19])=[N:11][CH:12]=1)([OH:6])[CH3:5].C(N(CC)CC)C.[N+:29]([C:32]1[S:36][C:35]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(Cl)Cl>[N+:29]([C:32]1[S:36][C:35]([S:37]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[N:11]=[CH:12][C:7]([C:4]([OH:6])([CH3:5])[C:3]([F:2])([F:20])[F:21])=[CH:8][N:9]=3)[C@@H:14]([CH3:19])[CH2:15]2)(=[O:39])=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: C[C@H]1CNCCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
The 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol hydrochloride (95 mg, 0.291 mmol) was dissolved in CH2Cl2 (15 mL) was chilled to 0° C. To this solution was added triethylamine (101 μL, 0.727 mmol) followed by 5-nitrothiophene-2-sulfonyl chloride (66.2 mg, 0.291 mmol, Enamine Building Blocks, Kiev, Ukraine). The mixture was warmed slowly to room temperature and stirred for 2 h. Afterwards, the mixture was concentrated onto silica gel and then purified via column chromatography (24 g silica gel, 0 to 10% MeOH in CH2Cl2) to give racemic 2-(2-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (108 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[C:17]([C:19](=O)[NH:20]C(C)(C)C)[CH:16]=[C:15]([C:26](=O)[NH:27]C(C)(C)C)[CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([C:26]#[N:27])[CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1

Procedure:
In another embodiment of the present invention there is provided a process for the preparation of a compound according to formula III wherein R2 is 3,5-dicyano-phenyl which process further comprises (i) contacting sodium 3,5-bis-tert-butylcarbamoyl-phenolate with 2,3,4-trifluoronitrobenzene in an appropriate solvent at temperatures from about −30° C. up to about 40° C. to afford a 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene; and (ii) contacting 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobezene with phosphorus oxychloride or a similar dehydrating agent to afford 3,4-difluoro-2-(3,5-dicyano-phenoxy)nitrobenzene III (R2=3,5-dicyanophenyl). The ether can be convert to IV (R2=3,5-dicyanophenyl) as described below.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C@@:11]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:7]([O:6][P:4]([CH2:9][CH2:10][C@@:11]1([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:15][CH2:14][C@H:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=2)[CH2:12]1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](/C=C/P(=O)(OCC)OCC)(NC(=O)OC(C)(C)C)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCc1ccc([C@H]2CC[C@@](CCP(=O)(OCC)OCC)(NC(=O)OC(C)(C)C)C2)cc1
Yield: 99.3 %

Procedure:
Tert-butyl (1R,3S)-1-((E)-2-(diethoxyphosphoryl)vinyl)-3-(4-octylphenyl)cyclopentylcarbamate (0.237 g, 0.442 mmol) was dissolved in ethanol. Palladium on carbon (0.094 g, 0.088 mmol) was added and the reaction was flushed with hydrogen and hydrogenated at atmospheric pressure for about 72 h. The solution was filtered through a syringe filter and washed through with methanol. Solvent was removed under reduced pressure to provide tert-butyl (1R,3S)-1-(2-(diethoxyphosphoryl)ethyl)-3-(4-octylphenyl)cyclopentylcarbamate (0.236 g, 0.439 mmol, 99% yield) as a colorless oil: LC/MS (method f) Rt=3.60 min.; MS m/z: 538.53 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[NH:18])[C:5]1[CH:6]=[C:7]([CH:13]=[C:14](OC)[N:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].Cl[C:20]1[CH:21]=C(C=C(CC)N=1)C(OCC)=O>>[CH2:1]([O:3][C:4](=[NH:18])[C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([CH2:20][CH3:21])[N:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=N)c1cc(C(=O)OCC)cc(OC)n1
Reactant: CCOC(=O)c1cc(Cl)nc(CC)c1
Product: CCOC(=N)c1cc(C(=O)OCC)cc(CC)n1

Procedure:
The title compound was prepared by a method analogous to Intermediate 17 but using ethyl 2-chloro-6-ethylisonicotinate as the starting material. GCMS analysis of the reaction mixture showed the presence of the desired product. MS (EI+) (M+) 250; GCMS retention time 3.611 minutes (Method O).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:14])[CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:17][C:18]1[C:21](=[O:22])[C:20](=O)[C:19]=1[NH:24][C:25]1[C:26]([OH:36])=[C:27]([CH:33]=[CH:34][CH:35]=1)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])C>CO>[OH:36][C:26]1[C:25]([NH:24][C:19]2[C:18](=[O:17])[C:21](=[O:22])[C:20]=2[NH:14][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([N:30]([CH3:32])[CH3:31])=[O:29]
Reactant: CCOc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2CCOCC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N(C)C)c3O)c(=O)c2=O)C2CCOCC2)o1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94.1 %

Procedure:
644 mg (3.3 mmol, 2 eq) of C-(5-methylfuran-2-yl)-C-(tetrahydropyran-4-yl)methylamine were added to 500 mg (1.64 mmol, 1 eq) of 3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide dissolved under hot conditions in 50 ml of methanol. The reaction medium was stirred at ambient temperature for 21 hours. The methanol was evaporated off and the residue (green oil) was chromatographed on silica gel (column Analogix SF15-40 g, Spot II) eluted with dichloromethane/methanol (gradient). 700 mg of 2-hydroxy-N,N-dimethyl-3-(2-{[(5-methylfuran-2-yl)-(tetrahydropyran-4-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamide were obtained. (M.p.=137-140° C.). Yield=94%. LC/MS: 97.1% [453]
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:5].C(N(CC)CC)C.[C:25](=O)(OC(Cl)(Cl)Cl)[O:26]C(Cl)(Cl)Cl>ClCCl>[I:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][C:25](=[O:26])[N:6]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)CCNC(=O)c1cc(I)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCn1c(=O)[nH]c2ccc(I)cc2c1=O
Temperature: 0 °C
Yield: 237.3 %

Procedure:
4.6 g of 2-amino-5-iodo-N-(2-methoxycarbonylethyl)benzamide were introduced with 2.66 g (26.3 mmol) of triethylamine into 50 ml of dichloromethane and, under nitrogen, 1.21 g (4.1 mmol) of bis(trichloromethyl) carbonate dissolved in 15 ml of dichloromethane were added dropwise. The mixture was refluxed for 2 h and, after cooling, added to ice-water. The aqueous phase was extracted with dichloromethane, and the organic phase was dried and concentrated. 3.64 g (74%) of 6-iodo-3-(2-methoxycarbonylethyl)quinazoline-2,4-dione [RF 0.52 (ethyl acetate/n-heptane, 2:1)] were obtained as a yellowish solid.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:27]([O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:40]2[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:27](=[O:29])[CH3:28])[CH:32]=3)[CH2:42][CH2:41]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Reactant: CC(=O)Oc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(OC(C)=O)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 83 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-acetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]1([CH:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C@H:29]2[CH2:34][CH2:33][C@H:32]([N:8]3[CH2:12][CH2:11][CH:10]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH2:9]3)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN([C@H]2CC[C@H](c3ccccc3)CC2)C1

Procedure:
The title compound, MS: m/e=386.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid and 4-phenylcyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]3[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:23])=[CH:20][CH:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:36][C:37]([F:49])([F:48])[O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:42]3[CH:41]=[CH:40][C:39]([O:38][C:37]([F:36])([F:48])[F:49])=[CH:44][CH:43]=3)=[C:11]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:23])=[CH:34][CH:35]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCc2cc(-c3ccc(Cl)c(Cl)c3)ccc2O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCc2cc(-c3ccc(Cl)c(Cl)c3)ccc2Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
A DCM solution (1 mL) containing the intermediate from Step A (22 mg, 0.043 mmol), copper(II) acetate (8 mg, 0.043 mmol), 4-(trifluoromethoxy)phenyl boronic acid (18 mg, 0.086 mmol), triethylamine (0.03 mL, 0.215 mmol) and 4 Å molecular sieves (small spatula tip) was stirred under an air atmosphere. After stirring overnight the solution was filtered and concentrated to give tert-butyl N-[4-(2-{3′,4′-dichloro-4-[4-(trifluoromethoxy)phenoxy]biphenyl-3-yl}ethyl)benzoyl]-β-alaninate. LCMS1 4.85 min. (M+H)=674. The tert butyl group was cleaved as described in EXAMPLE 1 Step I to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.65 (d, J=8.2 Hz, 2H); 7.59 (d, J=2.2 Hz, 1H); 7.51 (d, J=8.3 Hz, 1H); 7.37-7.34 (m, 3H); 7.24 (d, J=8.3 Hz, 2H); 7.21 (d, J=8.4 Hz, 2H); 6.98-6.95 (m, 4H); 3.79 (q, J=5.9 Hz, 2H); 3.01 (s, 4H); 2.80 (t, J=5.8 Hz, 2H). LCMS1 4.43 min. (M+H)=618.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH2:11][CH3:12])([CH2:9][CH3:10])[NH:3]1>CO>[CH3:13][C:2]1([CH3:1])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH2:9][CH3:10])([CH2:11][CH3:12])[NH:3]1
Reactant: CCC1(CC)CC(=O)CC(C)(C)N1
Solvent: CO
Product: CCC1(CC)CC(O)CC(C)(C)N1
Yield: 99.1 %

Procedure:
To a solution of 15.8 g (0.086 mol) 2,2-dimethyl-6,6diethyl-4-oxopiperidine In 50 ml methanol 2.2 g (0.06 M) sodium borohydride are acided in portions. The temperature is kept below 30° C. After stirring over night methanol is removed under vacuum and the residue is diluted with 20 ml 2N-NaOH. The solution is extracted with ethylacetate. The combined extracts are washed with saturated NaCl solution, dried over MgSO4 and dried under vacuum at 60° C./50 mbar until a constant weight is achieved. 15.8 g (99%) 2,2-dimethyl-6,6-diethyl-4-hydroxypiperidine are obtained as yellowish oil. :
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]2[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1)=[O:5])C.[OH-].[Na+].C(O)C.Cl>O>[C:4]([CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]2[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCc1cc2cccc([N+](=O)[O-])c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCc1cc2cccc([N+](=O)[O-])c2o1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A solution of 2-(3-ethoxycarbonylpropyl)-7-nitrobenzo[b]furan (1.0 g) in a mixture of aqueous 1N-sodium hydroxide (7.2 ml) and ethanol (5 ml) was stirred at 50° C. for 1 hour. The reaction mixture was diluted with water and acidified with 4N-hydrochloric acid. The separated solid was collected, washed with water and dried to give 2-(3-carboxypropyl)-7-nitrobenzo[b]furan (752 mg).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6](=O)[C:7]2[N:8]([CH:10]=[CH:11][CH:12]=2)[CH:9]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:6]1[C:7]2[N:8]([CH:10]=[CH:11][CH:12]=2)[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: CC(C)c1cn2cccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1cn2cccc2c(Cl)n1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
3-isopropylpyrrolo[1,2-a]pyrazin-1(2H)-one from step b (1.6 g, 4.7 mmol) was combined with POCl3 (20 mL) and stirred at 70° C. for 20 minutes. POCl3 was removed under reduced pressure. The residue was taken up in DCM and washed twice with saturated sodium bicarbonate. Afterward the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 5-10% MTBE/hexanes) to provide chloro-3-isopropylpyrrolo[1,2-a]pyrazine (1.09 g, 62% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:32])[CH2:29][C:30]#[N:31])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:29]([C:28]([NH:27][CH2:26][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:32])[C:30]#[N:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N#CCC(=O)NCCCc1ccccc1
Product: CC(C)(C)c1cc(C=C(C#N)C(=O)NCCCc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
M20 was prepared using 3,5-di-t-butyl-4-hydroxybenzaldehyde and N-3-phenyl-n-propyl cyanoacetamide under the similar conditions as descibed for M21 infra.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.[OH-].[Na+]>FC(F)(F)S(O)(=O)=O.O>[CH2:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:16]1[O:18][CH2:17]1
Reactant: CCCCCCCCCCCCO
Reactant: ClCC1CO1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCOCC1CO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 114.3 %

Procedure:
Dodecanol (167.4 g) and 8.1 g of trifluoromethanesulfonic acid were heated to 95° C. while stirring. To the reaction mixture, 166.5 g of epichlorohydrin was added dropwise over 1 hour, followed by stirring for 8 hours. After completion of the reaction, the reaction mixture was cooled to 50° C. Over 1 hour, 75 g of a 48% aqueous solution of sodium hydroxide was added dropwise at a temperature maintained at 50° C. After stirring for 3 hours, 120 mL of water was added to the reaction mixture to cause separation. The water layer thus occurred was removed. The residue was then washed twice with 100 mL of water, whereby 249 g of crude dodecyl glycidyl ether was obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28]CC)=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[N:20]2)=[CH:15][CH:14]=1.COCCN(S(F)(F)[F:42])CCOC.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([OH:28])=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[CH:22][C:21]([CH2:24][F:42])=[N:20]2)=[CH:17][CH:18]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3ccc(CO)n3)cc2)c2cccc(F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cn(Cc2ccc(-n3ccc(CF)n3)cc2)c2cccc(F)c2c1=O
Reaction time: 0.5 h

Procedure:
A solution of ethyl 5-fluoro-1-{4-[3-(hydroxymethyl)-1H-pyrazol-1-yl]benzyl}-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.050 g, 0.119 mmol) in 2 mL of tetrahydrofuran was cooled to −40° C. under nitrogen, and [bis(2-methoxyethyl)-amino]sulfur trifluoride (0.029 g, 0.13 mmol) was added. The reaction mixture was warmed to room temperature and after 4 hours 1 N NaOH (0.50 mL, 0.50 mmol) was added. After 30 minutes, the tetrahydrofuran was removed in vacuo, and 1 mL DMSO and 0.5 mL 40% NaOH were added. After 3 hours, the reaction mixture was acidified with 6 N HCl to pH ˜2, filtered, and purified via reverse phase HPLC to provide the title compound which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 395.9 for M+H+: 1H NMR (400 MHz, d6-DMSO) δ 9.30 (s, 1H), 8.50 (s, 1H), 7.87-7.80 (m, 3H), 7.66 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.40-7.35 (m, 1H), 6.67 (s, 1H), 6.52 (s, 1H), 5.88 (s, 2H), 5.62 (d, J=10.2 Hz, 2H).