Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:17]=[C:16]([NH2:18])[NH:15][N:14]=2)=[O:12])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:33])[C:23](=[CH:29]OCC)[C:24](OCC)=[O:25])[CH3:20]>C(O)(=O)C>[CH2:19]([O:21][C:22]([C:23]1[C:24](=[O:25])[N:15]2[N:14]=[C:13]([C:11](=[O:12])[NH:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:17]=[C:16]2[NH:18][CH:29]=1)=[O:33])[CH3:20]
Reactant: Nc1cc(C(=O)NCCc2ccc(Cl)cc2)n[nH]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C(=O)NCCc3ccc(Cl)cc3)nn2c1=O
Temperature: 120 °C
Yield: 35.4 %

Procedure:
To a solution of 5-amino-1H-pyrazole-3-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide (100 mg, 0.4 mmol, 1 eq) in acetic acid (2 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (80 μL, 0.44 mmol, 1.1 eq). The mixture was heated at 120° C. for 16 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol (2×10 mL) to afford the expected compound as white powder (55 mg, 38% yield).
Reaction SMILES: C([O:5][C:6]1[CH:15]=[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH2:19][CH2:18]2)[C:13]2[C:8](=[C:9]([NH:46][CH2:47][CH2:48][O:49][CH3:50])[CH:10]=[C:11]([C:30]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)O)[CH:12]=2)[N:7]=1)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:30]([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[C:11]2[CH:12]=[C:13]3[C:8](=[C:9]([NH:46][CH2:47][CH2:48][O:49][CH3:50])[CH:10]=2)[NH:7][C:6](=[O:5])[CH:15]=[C:14]3[NH:16][CH:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]([F:29])([F:27])[F:28])(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:33][CH:34]=1
Reactant: COCCNc1cc(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(NC3CCN(S(=O)(=O)C(F)(F)F)CC3)cc(OC(C)(C)C)nc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNc1cc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(NC3CCN(S(=O)(=O)C(F)(F)F)CC3)cc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To solution of (2-(tert-butoxy)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl) sulfonyl)piperidin-4-yl)amino)quinolin-6-yl)bis(4-chlorophenyl)methanol (12 mg, 0.0159 mmol) and triethylsilane (0.0152 mL, 0.0953 mmol) in CH2Cl2 (1 mL) was added slowly TFA (0.03 mL, 0.392 mmol). The resulting mixture was stirred for 4 hr at room temperature. The reaction was diluted with CH2Cl2 and washed with Na2CO3 to make the aqueous layer basic. The organics were washed with water, dried over anhydrous Na2SO4 and concentrated. The resulting residue was triturated from Et2O/hexanes (1:3) to yield 6-(bis(4-chlorophenyl)methyl)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=1)[N:29](COCC[Si](C)(C)C)[N:28]=[C:27]2[NH:55][C:56](=[O:60])[CH2:57][CH2:58][CH3:59].C(OCC)(=O)C>O1CCCC1>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][CH:38]=1)[NH:29][N:28]=[C:27]2[NH:55][C:56](=[O:60])[CH2:57][CH2:58][CH3:59]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccco3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccco3)cc12
Yield: 80.5 %

Procedure:
12.4 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.20 g of N-[5-(2-furyl)-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 2×50 cm3 of saturated sodium hydrogen carbonate solution and with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.5 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is dried (90 Pa; 45° C.) to give 750 mg of N-[5-(2-furyl)-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cccnc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyridin-3-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.59 (d, 1H), 7.89 (m, 3H), 7.60 (m, 1H), 7.50 (m, 2H), 7.41 (m, 3H), 7.17 (d, 2H), 7.10 (t, 1H), 6.74 (m, 1H), 6.64 (d, 1H), 6.58 (d, 1H), 4.37 (s, 2H), 4.34 (s, 2H), 4.32 (s, 2H), 1.48 (s, 9H); MS 545 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][NH:12]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])[CH:3]=1.Cl[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:12]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:13]=[C:14]([OH:16])[CH2:15]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:22][CH2:23]2)[CH3:20])[CH:3]=1
Reactant: Clc1cccnc1Cl
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(O)=NN1c1ncccc1Cl)C1CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 87.3 %

Procedure:
1.0 g of N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-5-oxopyrazolidine-3-carboxamide was dissolved in 10 ml of N,N-dimethylformamide, 460 mg of 2,3-dichloropyridine was added and then 350 mg of sodium hydride was added, followed by stirring for about 7 hours at about 70° C. in nitrogen atmosphere, and the reaction liquid was stood to cool. Water was added to the reaction liquid and stirred, followed by extraction with ethyl acetate, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=9/1) to obtain 1.15 g of the desired product.
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccsc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(OCc2ccsc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
To an acetic acid (4.1 mL) and dimethyl sulfoxide (70 mL) solution of 3-(4-((E)-2-nitro-vinyl)-phenoxymethyl)-thiophene (4.1 g, 15.7 mmol) described in Manufacturing Example 77-1-2 was added sodium borohydride (950 mg, 25.1 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (1.93 g, 47%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C1COCC1.CCCCCC>[OH:17][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2C(F)(F)F)CC1
Reaction time: 0.67 h
Yield: 45.2 %

Procedure:
To a solution of 1-bromo-2-(trifluoromethyl)benzene (1.18 g, 5.24 mmol) in THF (20 mL) cooled at −78° C. was dropwise added a 1.60 M solution of n-butyllithium in hexane (3.4 mL). After being stirred for 40 min; a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.0 g, 5.0 mmol) in THF (3 mL) was added and the solution stirred for 1 h at −78° C. The reaction was quenched with saturated ammonium chloride. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated to give 0.78 g of a white solid which was used for the next reaction without purification. MS calculated for C17H22F3NO3: (M+H) 346; found 246.0 (M-Boc+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10].[C:12]([CH2:16][Si:17](Cl)([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[C:12]([CH2:16][Si:17]([O:11][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:10])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C[Si](C)(C)Cl
Reactant: CC(O)c1ccc(F)cc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)CC(C)(C)C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2′,4′-difluoroacetophenone (5 g, 32 mmol) was reacted with sodium borohydride (1.21 g) in THF (20 mL) and methanol (10 mL) for 1 hr. The resultant mixture was evaporated to dryness and partitioned between methylene chloride and water. The organic layer was separated, dried, and evaporated to give 1-(2′,4′-difluorophenyl)-ethanol as a colorless oil (4.86 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 5.15 (q, 1H), 2.0 (s, 1H), 1.5 (d, 3H). 1-(2′,4′-difluorophenyl)-ethanol (5.384 g, 34 mmol), t-butyltrimethylsilyl chloride (6.148 g, 40.8 mmol) and imidazole (5.567 g, 81.8 mmol) in DMF (60 mL) were combined and stirred at rt overnight. The resultant mixture was evaporated to dryness in vacuo, and then the residue was partitioned between methylene chloride and water. The organic layer was separated, dried and evaporated to give 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether as a white solid (6.88 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.45 (q, 1H), 6.75 (m, 1H), 6.62 (m, 1H), 5.05 (q, 1H), 1.32 (d, 3H), 0.88 (s, 9H), 0.05 and 0.01 (each s, each 3H). A 1.6 M solution of n-butyl lithium in hexane (3.75 mL, 6 mmol) was added dropwise to a solution of 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether (1.362 g, 5 mmol) in THF (60 mL) at −50° C. and was stirred at the same temperature for 3 h. The reaction mixture was poured to dry ice; and then was evaporated to dryness. The residue was partitioned between methylene chloride and water, acidified with acetic acid. The organic layer was separated, dried, and evaporated to give 2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoic acid Compound 5A as white solid (1.57 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.70 (q, 1H), 7.00 (t, 1H), 6.00 (br, 1H), 5.15 (q, 1H), 1.40 (d, 3H), 0.90 (s, 9H), 0.12 and 0.05 (each s, each 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.CC1C(O)CC(=[O:23])C=1CC=C.Cl>O1CCCC1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCC1=C(C)C(O)CC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 5 °C
Reaction time: 48 h
Yield: 51.8 %

Procedure:
11.6 g of triethylamine and then 21.9 g of p-toluene sulfonyl chloride were added at -50° C under an inert atmosphere to a mixture of 11.6 g of (R) allethrolone in 100 ml of tetrahydrofuran and the mixture was stirred for 48 hours at 5° C after which it was poured with stirring into aqueous 0.1N hydrochloric acid solution. The aqueous phase was extracted with chloroform and the organic extracts were washed with water, dried and evaporated to dryness. The 29 g of residue was chromatographed over silica gel and was eluted with a 95-5 benzene-ethyl acetate mixture to obtain 6.8 g of p-toluene sulfonate of (R) allethrolone.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].Cl[C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH3:33])([CH3:32])[O:30][C:29]([CH3:35])([CH3:34])[C:27]=2[N:28]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:23]2[N:24]=[CH:25][C:26]3[C:31]([CH3:33])([CH3:32])[O:30][C:29]([CH3:35])([CH3:34])[C:27]=3[N:28]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CC1(C)OC(C)(C)c2nc(Cl)ncc21
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ncc4c(n3)C(C)(C)OC4(C)C)CC2)ccc1OC
Temperature: 25 °C
Yield: 19.3 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in dry DMF (1.5 mL) was added sodium hydride (6.6 mg, 0.15 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt under Ar. After 2 h 2-chloro-5,5,7,7-tetramethyl-5,7-dihydro-furo[3,4-d]pyrimidine (15.5 mg, 0.10 mmol, 1.0 equiv) was added and the mixture heated to 120° C. for 48 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 8.5 mg (12%) of the title compound. MS (ISP): 441.5 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][CH2:14]1>CCOCC>[Br:1][CH2:18][C:17]([C:13]1([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: BrBr
Reactant: CC(=O)C1(c2ccc3ccccc3c2)CCC1
Solvent: CCOCC
Product: O=C(CBr)C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (2.6 ml) was added dropwise over 1 hour at ambient temperature to a stirred solution of 1-[1-(2-naphthyl)cyclobutyl]ethanone (11.25 g) in ether (300 ml). After the addition was complete and the bromine colour had dissipated, the mixture was stirred at ambient temperature for a further 0.5 hour then it was washed with water (100 ml), saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried (MgSO4), and the solvent removed in vacuo to give 2-bromo-1-[1-(2-naphthyl)cyclobutyl]ethanone as an oil which was used without purification.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:19][CH:20]([F:29])[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1>>[F:29][CH:20]([F:19])[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:26][CH:27]=1
Reactant: Nc1ccc(OC(F)F)cn1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1ccc(OC(F)F)cn1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 5-(difluoromethoxy)pyridine-2-amine as the starting materials.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[S:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](OC)=[O:20].[H-].[Na+].O>CN(C=O)C>[OH:20][CH:19]=[C:11]([S:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC=O
Reactant: COC(=O)CSc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=CO)Sc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 15.4 %

Procedure:
Methyl (3-phenylthiophenoxy)acetate (6.60 g) and methyl formate (30.78 g) were dissolved in DMF (30 ml) and added dropwise at 0° C. to sodium hydride (0.83 g, 50% dispersion in oil) in DMF. The reaction mixture was stirred at 0° C. for 45 minutes and then left at room temperature under nitrogen over the weekend. The reaction mixture was then poured into water (300 ml) and washed with diethyl ether (3×150 ml). The aqueous phase was adjusted to pH 7 with hydrochloric acid and then extracted with diethyl ether (3×100 ml). The combined organic extracts were washed successively with water (3×100 ml) and brine (2×75 ml) and then dried. Filtration and evaporation of the solvent under reduced pressure gave methyl 3-hydroxy-2-(3'-phenylthiophenoxy)propenoate (1.13 g) which was used without further purification.
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1.O.[Cl-].[Na+]>CN(C=O)C>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C(C(c2cccc(O)c2)C2CC2)C(=O)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CC(c1cccc(O)c1)C1CC1
Temperature: 90 °C
Reaction time: 7 h
Yield: 85.8 %

Procedure:
To a solution of 5-(cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (164 g) in DMF (1.64 L) was added water (164 mL), and the mixture was stirred at 90° C. for 7 hr. Water and sodium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was back-extracted with saturated aqueous sodium hydrogen carbonate solution, and hydrochloric acid was added until the aqueous layer became pH 4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (100 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:13][O:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>ClCCl>[CH:14]1([C:10]23[CH2:9][O:8][C:6]([C:5]4[CH:4]=[CH:3][C:2]([I:1])=[CH:19][CH:18]=4)([O:7][CH2:13]2)[O:12][CH2:11]3)[CH2:15][CH2:16][CH2:17]1
Reactant: O=C(OCC1(C2CCC2)COC1)c1ccc(I)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Ic1ccc(C23OCC(C4CCC4)(CO2)CO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a stirred solution of (3-cyclobutyloxetan-3-yl)methyl 4-iodobenzoate (7.42 g, 20 mmol) in dry dichloromethane (80 ml) at -70° C. under nitrogen atmosphere was added boron trifluoride etherate (2 ml). The solution was allowed to warm to room temperature, stirred overnight and then quenched with dry triethylamine (3 ml). The mixture was evaporated to dryness, partitioned between water and dichloromethane and the organic layer was separated, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed on basic alumina. Elution with hexane: dichloromethane (9:1 v/v) gave 4-cyclobutyl-1-(4-iodophenyl)-2,6,7-trioxabicyclo[2.2.2]octane (2.8 g, 38%) as white crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (300 mg; 1.01 mmol), N-methylpiperazine (132 mg; 1.32 mmol) and K2CO3 (168 mg; 1.22 mmol) in DMF (4 ml) are heated to 80° C. for 45 minutes. The reaction mixture was diluted with MeOH, filtered and purified via chromatography (SiO2; CH2Cl2/MeOH/NH3conc 95:5:0.5) to yield the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 7.63 (d, 2H); 7.33 (d, 2H); 3.47 (s, 1H); 2.34 (bs, 8H); 2.16 (s, 3H); 1.30 (s, 12H). MS (m/z) ES+: 317 (MH+).
Reaction SMILES: [Br:1][CH:2]1[CH2:28][O:27][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:15])[N:10]=[CH:9]3)=[C:4]2[CH:3]1O.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([CH:3]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:15])[N:10]=[CH:9]3)[O:27][CH2:28][CH:2]1[Br:1])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)C(O)C(Br)CO3)NC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](Cn1ncc2ccc3c(c21)C(N=[N+]=[N-])C(Br)CO3)NC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of the product from Step A (0.31 g, 0.67 mmol) and sodium azide (0.65 g, 10 mmol) in dimethylsulfoxide (20 mL) was heated at 80° C. for 3 h, cooled to room temperature, and extracted with ethyl acetate. The combined extracts were dried and concentrated to a residue which was purified by chromatography (silica, 30% ethyl acetate in hexane) to give an oil (0.26 g, 68%): LC/MS (+APCI) m/z 423 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CCCO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CCCBr)c1
Reaction time: 15 h
Yield: 75.1 %

Procedure:
Compound 16-1 (2.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.58 g) and N-bromosuccinimide (2.40 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.07 g) as a pale-yellow oil.