Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>CN(C)C=O>[CH3:39][O:38][C:36](=[O:37])[CH2:35][N:2]1[CH:3]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:1]1
Reactant: COC(=O)CBr
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.70 g, 1.80 mmol) in dimethylformamide (14 ml) was added ceasium carbonate (2 g) followed by methyl bromoacetate (255 μl, 2.70 mmol). The mixture was stirred for 18 hours at room temperature, and partitioned between ethyl acetate and water. The aqueous phase was extracted with three portions of ethyl acetate, and the combined organic phases dried over magnesium sulfate and concentrated in vacuo to provide a yellow solid. No further purification was required. Yield: 0.51 g, 61%; LCMS method: basic, RT: 3.77 min, MI: 462 [M+1].
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11]C)=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].B(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].Cl>ClCCl.CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[C:10]([OH:11])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)c(O)c1O
Reaction time: 2 h

Procedure:
An anhydrous dichloromethane (500 mL) solution of 2,3,4-trimethoxy-benzaldehyde (6a, 19.6 g, 100 mmol) under argon at ambient temperature was stirred for 10 min and boron trichloride (100 mL, 100 mmol, 1 eq, 1.0 M soln in dichloromethane) was added. After 2 hours, the second equivalent of boron trichloride (100 mL, 100 mmol; 1 eq; 1.0 M solution in dichloromethane) was added. The dark reaction mixture was stirred for 24 hours, and then slowly poured into 10% sodium bicarbonate (aq) (40 g/360 mL). The resulting solution was acidified with concentrated hydrochloric acid to pH 1. The dichloromethane layer was separated, and the aqueous layer was extracted with ethyl acetate (4×100 mL) and dried. Evaporation of solvent in vacuo gave a brown oil, which was absorbed onto silica gel and subjected to flash column chromatography (50:50:1 hexane-ethyl acetate-acetic acid) to afford a yellow solid. Recrystallization from ethyl acetate-hexane gave yellow needles (12.4 g; 74%): m.p. 115-116° C. [lit. 116-117° C. (Pettit et al, 1987)]; Rf0.40 (1:1, hexane-ethyl acetate); EIMS m/z 168 (100%, M+), 125 (25%), 122 (40%), 79 (20%), 52 (20%). Anal. Calcd. for C8H8O4: C, 57.14; H, 4.80. Found: C, 57.23; H. 4.79.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=3[CH:22]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[O:29]=[S:26]1(=[O:30])[CH2:27][CH2:28][N:23]([C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]4)=[CH:22][C:15]=3[CH:16]=2)=[O:21])[CH2:24][CH2:25]1
Reactant: CC(C)N1CCC(Oc2ccc3oc(C(=O)O)cc3c2)CC1
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3oc(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Yield: 72.3 %

Procedure:
In a flask were mixed together the above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzofuran-2-carboxylic acid (1.25 g, 3.92 mmol, calculated as 73%), thiomorpholine 1,1-dioxide (0.636 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (2.081 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (1.60 mL) in 24 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) and trituration in hexane/AcOEt=7/3 yielded 1.192 g of the title compound as off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Br:21][C:22]1[C:27]([F:28])=[CH:26][C:25](O)=[CH:24][C:23]=1[F:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Br:21][C:22]1[C:27]([F:28])=[CH:26][C:25]([O:20][CH2:19][CH2:18][C@@H:16]2[CH2:17][C@@H:15]2[CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=3)[CH2:10][CH2:11]2)=[CH:24][C:23]=1[F:30]
Reactant: Oc1cc(F)c(Br)c(F)c1
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(Br)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
2-((1S,2R)-2-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (1.4 g, 5.05 mmol), 4-bromo-3,5-difluorophenol (1.26 g, 6.06 mmol) and triphenylphosphine (1.98 g, 7.57 mmol) were dissolved in dichloromethane (25 ml). The mixture was stirred at RT under N2 for 5 min and diisopropyl azodicarboxylate (1.53 g, 7.57 mmol) added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with 0.5 N NaOH (50 ml), brine, dried over sodium sulfate and the volatiles removed in vacuo. The residue was purified by silica gel column chromatography (50 g SNAP, 10˜40% EtOAc in hexane) to afford 1.86 g (79%) of the titled compound. LC/MS (m/z): 469 (M+H)+. Rf was 0.3 @ 30% EtOAc in hexanes (blue spot on CAM stain)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([CH2:20]O)=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[N:16]=2)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(N(S(F)(F)[F:33])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([CH2:20][F:33])=[C:18]([C:22]([F:24])([F:25])[F:23])[N:17]([CH3:26])[N:16]=2)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2CO)c(F)cc1Cl
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2CF)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.5 g 2-chloro-4-fluoro-5-[4-(hydroxymethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester in 50ml methylene chloride was added 5 mL of diethyl aminosulfurtrifluoride and the solution stirred overnight at room temperature. The reaction mixture was poured onto ice water and the organic layer washed with brine, dried over anhydrous magnesium sulfate, filtered and the concd in vacuo to give 2-chloro-4-fluoro-5-[4-(fluoromethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester as a tan solid: mp 74° C.; 1HNMR (CDCl3) δ8.02 (d, 1H, J=8.0), 7.30 (d, 1H, J=9.6), 5.29 (d, 2H, J=48.0), 5.26 (m, 1H, J=6.0), 4.09 (s, 3H), 1.37 (d, 6H, J=6.4).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:20][C:19]([O:21]C)=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.Cl.O>O1CCOCC1>[Cl:1][C:2]1[C:3]2[S:20][C:19](=[O:21])[NH:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1
Reactant: COc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Temperature: 40 °C
Yield: 72.8 %

Procedure:
The product from example 31 step (b) (2.0 g) was dissolved in dioxan (150 ml) followed by addition of concentrated hydrochloric acid (1 ml) and water (1 ml) and the whole heated at 40° C. for 67 hours. The mixture was evaporated to dryness and purified by column chromatography (silica-dichloromethane) to give a white solid (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]2[C:10](B(O)O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[N:7]=1.Br[C:29]1[CH:38]=[C:37]([F:39])[C:32]2[N:33]=[C:34]([CH3:36])[O:35][C:31]=2[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O.Cl[Pd]Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]2[C:10]([C:29]3[CH:38]=[C:37]([F:39])[C:32]4[N:33]=[C:34]([CH3:36])[O:35][C:31]=4[CH:30]=3)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(B(O)O)c2c(OC3CCCC3)nc(Cl)nc21
Reactant: Cc1nc2c(F)cc(Br)cc2o1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(F)cc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
(2-Chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid (1 equiv), 6-bromo-4-fluoro-2-methylbenzo[d]oxazole (1.1 equiv), sodium carbonate (3 equiv) and [1,1′-Bisdiphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (0.1 equiv) were suspended in 1,4-dioxane/water, flushed with nitrogen, and stirred at 90° C. for 2 h. The reaction mixture was purified by silica gel chromatography (0 to 60% ethyl acetate in hexane) to give the title compound (72% yield). MS (ESI) m/z 517.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[OH:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(S)c1
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)c1)c1ccc(Sc2cccc(O)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide (from Example 26A) (0.356 g, 1.0 mmol), 3-hydroxythiophenol (0.126 g, 1.0 mmol) and cesium carbonate (0.65 g, 2.0 mmol) in N,N-dimethylformamide (5 mL) was heated to 95° C. for 3 hours. After cooling to room temperature the mixture was poured into ice water (20 mL) and the resultant solution acidified with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×10 mL), the combined extracts dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.430 g, 97%).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:8]([O:10][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=C(O)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(OCCC1CCNCC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)acetic acid and t-butyl 4-(2-hydroxyethyl)tetrahydro-pyridine-1(2H)-carboxylate, the title compound was prepared by a method similar to steps 2 and 3 of Referential Example 12.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.CCN(CC)CC.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.O>[CH3:17][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:3]=1)[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2ccccc2)c2[nH]c(-c3ccccn3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole (45 mg, 0.20 mmol) prepared in Step A of Example 1 was dissolved in dichloromethane (10 mL). Et3N (0.56 mL, 0.4 mmol) and benzoyl chloride (0.03 mL, 0.22 mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was diluted with water, extracted with EtOAc, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent EtOAc/n-Hex=1/5) to give the title compound (18 mg, Yield 27%).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:3]=[CH2:4].P(Br)(Br)[Br:15]>>[Br:15][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(CC)CC
Product: CCC(=CCCC(C)=CCBr)CC

Procedure:
Following the procedure of Example 9, 3-methyl-7-ethyl-1,6-nonadien-3-ol and phosphorus tribromide are reacted to form 1-bromo-3-methyl-7-ethyl-2,6-nonadiene.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH:20]4[CH:16]([CH2:17][N:18](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH2:19]4)[CH2:15][CH2:14]3)[CH2:8]2)=[CH:4][CH:3]=1.O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH:20]4[CH:16]([CH2:17][NH:18][CH2:19]4)[CH2:15][CH2:14]3)[CH2:8]2)=[CH:40][CH:41]=1
Reactant: Fc1ccc(C[C@@H]2CCCN(C3CCC4CN(C(c5ccccc5)(c5ccccc5)c5ccccc5)CC43)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1ccc(C[C@@H]2CCCN(C3CCC4CNCC43)C2)cc1
Reaction time: 0.67 h
Yield: 94.7 %

Procedure:
(3aRS,4RS,6aSR)-4-[(3S)-3-(4-fluorobenzyl)piperidin-1-yl]-2-trityloctahydrocyclo-penta[c]pyrrole (500 mg, 918 μmol) was dissolved in trifluoroacetic acid (4 mL) to form a dark orange-yellow solution. Water (5 mL) was added dropwise to form a dense slurry, lighter in color. After 40 minutes, the mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate and extracted with 1.0 N aqueous hydrochloric acid. The aqueous phase was washed with ethyl acetate, and then made strongly basic by the addition of 50% aqueous sodium hydroxide. The resulting mixture was extracted several times with ether, and the combined ether phases were dried over sodium sulfate and concentrated, yielding a gum (263 mg, 95%), which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.08 (m, 2H), 6.95 (m, 2H), 3.14 (m, 1H), 3.0-2.6 (m, 4H), 2.6-2.3 (m, 7H), 2.0-1.2 (m, 9H), 0.93 (m, 1H). Mass spec (CH4-CI) m/z 303.2 (M+H+, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:9][CH:8]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][CH2:4][CH:5]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:11][CH:12]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C(CCCO)Oc2ccc(OC3CCCCO3)cc2)cc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Yield: 100 %

Procedure:
A solution of 4-{4-hydroxy-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenoxy]butyl}benzonitrile (see step (ii) above; 2.37 g, 6.45 mmol) and TEA (1.35 mL, 9.68 mmol) in DCM (10 mL) was cooled to −5° C. Methanesulfonyl chloride (0.65 mL, 8.38 mmol) in DCM (5 mL) was added slowly. After addition was complete, the temperature was maintained below 5° C. for 1 h before DCM and water were added. The organic layer was washed with water, dried (Na2SO4) and then evaporated to yield 2.87 g (100%) of the sub-title compound. This was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C([O-])=O.[K+].NC1C(F)=CC2NC(=O)OC=2C=1.[CH2:31]([S:43]([CH:46]([CH2:50][CH3:51])[C:47](Cl)=[O:48])(=[O:45])=[O:44])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>O.C(OCCC)(=O)C.[Pd].C(O)(C)C>[CH2:31]([S:43]([CH:46]([CH2:50][CH3:51])[C:47]([NH:12][C:3]1[C:2]([F:1])=[CH:11][C:6]2[NH:7][C:8](=[O:10])[O:9][C:5]=2[CH:4]=1)=[O:48])(=[O:45])=[O:44])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCS(=O)(=O)C(CC)C(=O)Cl
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2o1
Agent: [Pd]
Agent: Nc1cc2oc(=O)[nH]c2cc1F
Agent: O=C[O-]
Solvent: CC(C)O
Solvent: O
Solvent: CCCOC(C)=O
Product: CCCCCCCCCCCCS(=O)(=O)C(CC)C(=O)Nc1cc2oc(=O)[nH]c2cc1F
Reaction time: 4 h
Yield: 79.1 %

Procedure:
In a 250-ml flask, place 9.9 g (0.05 m) of 5-fluoro-6-nitro-benzoxazol-2-one (2a), 40 ml of isopropyl alcohol and 20 ml of propyl acetate, and 0.4 g 5% Pd/C with 1.5 ml of water. Add 16.8 g (0.2 m) of potassium formate in 20 ml of water, and stir the mixture vigorously at 55°-60° C. for 4 hrs. Keep strictly inert nitrogen atmosphere throughout the reaction. Take a TLC to confirm completeness of reaction. Cool the reaction mixture containing 6-amino-5-fluoro-benzoxazol-2-one (3a, X=F) to 40° C. under nitrogen, and add 40 ml of propyl acetate and a solution of 18.8 g (0.05 m×1.05 @95%) of 2-dodecylsulfonyl-butyryl chloride (R′COZ; R′=1-dodecylsulfonylpropyl and Z=Cl) in 60 ml of propyl acetate keeping the temperature at 40°-45° C. over 15 min. Stir the reaction mixture at 40° C. for 30 min. Add 60 ml of water and filter off catalyst and wash it with 60 ml of propyl acetate and 60 ml of water. Separate propyl acetate solution, wash with 120 ml of 1N HCl, and concentrate under a reduced pressure to a thick slurry. Cool the slurry in an ice-water bath for 2 hrs. Collect solid, wash with chilled propyl acetate and heptane, and dry in a vacuum oven to give 18.6 g (79%) of 6-(2-dodecylsulfonylbutyryl)amino-5-fluoro-benzoxazol-2-one (Formula I, Y=X=F and R′=1-dodecylsulfonylpropyl) as off-white solids.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1.I[Si](C)(C)C.CO>C(#N)C.C(OCC)(=O)C>[CH:18]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[NH:14][N:13]=1)=[CH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C(=C/c1n[nH]c2ccc(OCc3ccccc3)cc12)\c1ccccc1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: Oc1ccc2[nH]nc(C=Cc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A solution of 652 mg of 5-benzyloxy-3-((E)-styryl)-1H-indazole in 60 ml of acetonitrile is stirred under argon. 1.13 ml of iodotrimethylsilane are added dropwise under an inert atmosphere. The suspension is stirred at approximately 50° C. for 3 hours and then at ambient temperature overnight. The medium is heated to around 50° C. and then 1.2 ml of iodotrimethylsilane are added. After stirring for 3 hours, 0.8 ml of iodotrimethylsilane is added. After stirring for approximately 4 hours, the medium is treated with 10 ml of methanol and stirred at ambient temperature for about fifteen minutes. The suspension is filtered through a paper filter and the filtrate is concentrated under vacuum in a rotary evaporator. The reaction crude is taken up in 50 ml of ethyl acetate and the organic phase is washed with 2×50 ml of a sodium thiosulfate solution, 2×50 ml of a saturated sodium bicarbonate solution, and 50 ml of a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and then concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on silica (Varian 20 g cartridge), eluent: ethyl acetate/cyclohexane gradient 5:95 to 35:65 to obtain 265.4 mg of 3-styryl-1H-indazol-5-ol.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[CH:11]([F:25])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Si:35](OS(C(F)(F)F)(=O)=O)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>ClCCl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:11]([F:25])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a solution of 2-{[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}-1-phenylethanol (8.46 g, 24.6 mmol) in dichloromethane (100 mL) at 0° C. was added diisopropylethylamine (17.1 mL, 98.8 mmol) and TBSOTf (13.0 mL, 49.4 mmol). The reaction mixture was stirred for 5 min and then poured into water. The layers were separated and the aqueous extracted with dichloromethane (3×). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (5% ethyl acetate in hexanes) gave (2-{[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}-1-phenylethoxy)(tert-butyl)dimethylsilane (11.3 g, 100% yield) as a clear oil.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c(C)c1
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc(-n2c(CF)nc3ccc([N+](=O)[O-])cc3c2=O)c(C)c1
Yield: 68.6 %

Procedure:
4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2,4-dimethylaniline are added to a mixture of 30 ml of acetic acid and 3.5 g of boron trifluoride etherate, and the mixture is stirred under heating at 100° to 105° C. for 30 minutes. The mixture is cooled and concentrated under reduced pressure to remove acetic acid. 50 ml of water are added to the residue, and the mixture is neutralized with potassium carbonate. The mixture is extracted with chloroform, and the extract is washed with water and dried. The chloroform solution is concentrated under reduced pressure to remove solvent. Isopropanol is added to the residue, and crystalline precipitates are collected by filtration. The thus-obtained crystals (3.0 g, M.p. 198°-200° C.) are recrystallized from a mixture of dimethylformamide and ethanol (1:2). 2.6 g of 2-fluoromethyl-3-(2,4-dimethylphenyl)-6-nitro-4(3H)-quinazolinone are obtained as colorless prisms.