Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[OH-].[Na+].[CH3:21]I.O>CS(C)=O>[CH3:21][N:7]1[C:6]2[CH:17]=[C:2]([CH3:1])[C:3]([CH3:18])=[CH:4][C:5]=2[NH:11][C:10]2[N:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]1=[O:16]
Reactant: Cc1cc2c(cc1C)Nc1ncccc1C(=O)N2
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(cc1C)N(C)C(=O)c1cccnc1N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4.55 g (0.019mol) of 6,11-dihydro-8,9-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one in 40 ml of dimethylsulfoxide was added 3.0 ml of a 30% NaOH solution (0.022 mol). After two hours at room temperature 5.0 ml (0.08 mol) of methyl iodide was added and the mixture stirred at room temperature overnight. It was then poured into water, the resulting precipitate collected, washed, dried and crystallized from ethanol to yield 3.3 g (69% of theory) of a crystallized solid melting at 206°-209° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[CH3:26].N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[CH3:26])(=[O:5])=[O:4]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C#N)cc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride was dropwise added, under ice-cooling, to a mixture of 4-hydroxy-3,5-dimethylbenzonitrile, pyridine and dichloromethane, followed by stirring at room temperature for 2 hours to obtain 4-cyano-2,6-dimethylphenyl trifluoromethanesulfonate. In an atmosphere of nitrogen, a mixture of 4-cyano-2,6-dimethylphenyl trifluoromethanesulfonate, (3-formylphenyl)boronic acid, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred at room temperature for 6 hours to obtain 3′-formyl-2,6-dimethylbiphenyl-4-carbonitrile.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]O)=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:13]([F:39])[CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][F:7])=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:13]([F:39])[CH:12]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCF
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
DAST (0.16 gram, 1 mmol) was added slowly to a cooled solution (−78° C.) of Compound 29a (0.047 gram, 0.1 mmol) in dichloromethane (2 ml) and the resulting mixture was allowed to warm to room temperature and was thereafter stirred for 12 hours. The reaction mixture was then poured to a saturated solution of sodium bicarbonate), diluted with water, extracted thrice with dichloromethane, washed with brine, and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded Compound 35a (0.036 gram, 78% yield) having a purity of 94%, as determined by HPLC. The compound was used in the following procedures without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[O:22]=[O:23]>>[O:22]([C@:4]12[CH2:3][C@@H:2]([OH:1])[CH2:19][CH2:18][C@:17]1([CH3:20])[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]3)[CH:6]=[CH:5]2)[OH:23]
Reactant: O=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@@]4(OO)C[C@@H](O)CC[C@]34C)[C@@H]1CCC2=O

Procedure:
3β-Hyroxyandrost-5-en-17-one (DHEA) 1 reacts with singlet oxygen to yield 5α-hydroperoxy-3β-hydroxyandrost-6-en-17one 2. This hydroperoxide undergoes a rearrangement when in chloroform solution to yield 7α-hydroperoxy-3β-hydroxyandrost-5-en-17-one, 3. Treatment of the hydroperoxide with zinc and acetic acid yields 3β,7α-dihydroxy-androst-5-en-17-one, 4. ##STR43##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:16]3[CH2:17][C@H:18]([CH2:23][C:24]([O:26]C)=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=3[CH:14]=2)[CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1.CO.Cl>O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:29]=[CH:28][C:16]3[CH2:17][C@H:18]([CH2:23][C:24]([OH:26])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=3[CH:14]=2)[CH:3]=1
Reactant: COC(=O)C[C@H]1Cc2ccc(OCCCNc3cc(N)ccn3)cc2CNC1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1ccnc(NCCCOc2ccc3c(c2)CNC(=O)[C@@H](CC(=O)O)C3)c1

Procedure:
According to the procedure of Example 1(c), except substituting methyl (R)-8-[3-[(4-amino-2-pyridyl)amino]-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound was prepared as an off-white solid: [α]D23+74.97° (c 1.45, MeOH); MS (ES) m/e 385.4 (M+H)+. Anal. Calcd for C20H24N4O4. HCl.1.5 H2O: C, 53.63; H, 6.30; N, 12.50. Found: C, 53.87; H, 6.13; N, 12.42.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.C([Li])(C)(C)C.C1C[O:24]CC1>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([CH2:6][C:7]3([CH2:10][CH2:9][CH2:8]3)[C:11]2=[O:24])=[CH:4][CH:3]=1
Reactant: N#CC1(Cc2ccc(Br)cc2I)CCC1
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Product: O=C1c2cc(Br)ccc2CC12CCC2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A dried flask charged with 1-(4-bromo-2-iodobenzyl)cyclobutanecarbonitrile (Intermediate 37, 2.60 g, 6.91 mmol), was dissolved in dry THF (100 mL) under an argon atmosphere. The resulting mixture was cooled to −78° C. and then was tert-butyllithium (1.7 M in pentane, 8.13 mL, 13.83 mmol), added dropwise. The reaction was stirred for 1.5 h at −78° C. and then the reaction was quenched with MeOH (0.5 mL), followed by aq. hydrochloric acid (2M, 10 mL). The resulting solution was concentrated to remove the organic solvent and then partitioned between DCM and water. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/EtOAc20:1-15:1-10:1) to afford the title compound (1.1 g, 63% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.97-2.13 (m, 3 H), 2.13-2.24 (m, 1 H), 2.45-2.60 (m, 2 H), 3.24 (s, 2 H), 7.31 (d, 1 H), 7.67 (dd, 1 H), 7.88 (d, 1 H); GC MS (EI) m/z 250 M+.
Reaction SMILES: [N:1](=[C:3]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1)[OH:2].Cl>C1COCC1.CCO>[NH:1]([CH:3]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1)[OH:2]
Reactant: ON=C1CCn2c1cc1ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: ONC1CCn2c1cc1ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of the oxime from Step 1 (2.5 g, 13.4 mmol) in THF (30 mL) and EtOH (30 mL), at 0° C. there was added pyridine-borane complex (3.12 g, 33.6 mmol) and then, slowly, 12N aqueous HCl (3.9 mL, 47 mmol). The mixture was stirred at 0° C. for 15 minutes, then at r.t. for 20 hours. The solvents were evaporated and the residue dissolved in H2O (100 mL) and extracted with EtOAc (2×20 mL). The aqueous fraction was then brought to pH 8 with 2.5N aqueous NaOH and the precipitate filtered to afford the title compound as a white solid, m.p.: 159°-161° C.
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].S(C)C.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:7][CH2:8][CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]1=[O:12])([O:3][CH3:4])=[O:2]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Reactant: Br[Mg]c1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCC(c2ccccc2)CC1=O
Yield: 71 %

Procedure:
The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexen-1-one (X) prepared by the process of Example 1, Step (c) (61.1 mmol, 12.0 g), CuBr.Me2S (6.11 mmol, 1.256 g) and Me2S (12.3 ml) were stirred in 85 ml of dry THF at -40° C. under nitrogen and treated with 61.1 mmol (20.4 ml of 3M in THF), of PhMgBr added dropwise over 30 minutes. The reaction was then quenched with 250 ml of 1M HCl (aq.) and extracted with 4×100 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 11.87 g (43.3 mmol, 71%) of product. The two diastereomers were separated by preparative HPLC on a Prep 500A using a brand of silica gel available from Waters Associates, Milford, Ma., affording 4.8 g of each isomer, designated "less polar isomer" and "more polar isomer."
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Br:18][C:19]1[CH:23]=[C:22]([Cl:24])[S:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[Br:18][C:19]1[CH:23]=[C:22]([Cl:24])[S:21][C:20]=1[S:25]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][C:6]3[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=3)[C:10]=2[N:11]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3sc(Cl)cc3Br)nc1-2

Procedure:
The title compound was prepared 7-methoxy-4,5-dihydronaphtho(1,2-D)(1,3)thiazol-2-amine hydrobromide (85 mg) and 3-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (17.8 mg) with purity >80%: MS (pos) m/z 491.3, 493.3.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[N:26]([Si](C)(C)C)=[N+:27]=[N-:28].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:54]>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:28][N:27]=[N:26][N:22]=4)=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[ClH:54]
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nnn[nH]2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
In an 4-mL was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile (16 mg, 0.043 mmol), azidotrimethylsilane (80 mg, 1.44 mmol) and tetrabutylammonium fluoride trihydrate (20 mg, 0.057 mmol). The mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was dissolved in dichloromethane (2 ml) and 2N HCl (aq.) (1 ml) was added. The precipitate was collected by filtration and washed with water (5 ml) followed dichloromethane (5 ml). After dried, the title compound was obtained as a solid (13 mg, 71% yield, HCl salt, it is regioisomers). MW/HCl=448.41. 1H NMR (DMSO-D6, 360 MHz) δ 8.0 (s, brs, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.27 (d, J=3.6 Hz, 1H), 4.32 (s, 2H), 2.74 (q, J=6.8 Hz, 2H), 2.50 (s, 3H), 1.11 (t, J=6.8 Hz, 2H). MS: ESI+, m/z 412 [M+H]+. LCMS: 98.6%.
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])C.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25]([NH:27][NH2:28])=O.C(O)CCC>C1(C)C=CC=CC=1>[CH:5]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)=[N:27][N:28]=1)([CH3:7])[CH3:6]
Reactant: CCSC(=Nc1ccccc1)C(C)C
Reactant: NNC(=O)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: CC(C)c1nnc(-c2ccc3ccccc3c2)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
First, 5.7 g of N-[1-(ethylsulfanyl)isobutylidene]aniline, 4.4 g of 2-naphthohydrazide, and 40 mL of 1-butanol were put in a 100 mL three-neck flask, and heated and stirred at 120° C. for 20 hours to be reacted. After the reaction, 1-butanol was distilled off to give a brown oily substance. Toluene was added to this oily substance, whereby a solid was precipitated, and then filtrated to give the solid. The resulting solid was recrystallized from toluene, so that 2.7 g of 3-isopropyl-5-(2-naphthyl)-4-phenyl-4H-1,2,4-triazole (abbreviation: HiPrntz) was prepared as a white solid with a yield of 37%. The synthetic scheme of Step 1 is shown by (a-13). As described above, the objective compound of Example 14 has a favorable yield.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][CH2:19]O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CCN(S(F)(F)[F:27])CC.ClCCl>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][CH2:19][F:27])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2CCC(OCCCO)CC2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC1CCC(C2CCC(OCCCF)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
A mixture of 2.75 g (9.8 mmol) of 4-(4-propylcyclohexyl)-(3-hydroxypropyloxy)cyclohexane obtained in Example 4, 3.14 g (19.6 mmol) of DAST, and 25 ml of dichloromethane was stirred for 5 hours at a room temperature. The reaction product was put in 40 ml of an ice water and extracted with 40 ml of toluene. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The magnesium sulfate was separated, the solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to a silica gel column chromatography (eluate: toluene) to obtain 1.87 g of a crude 4-(4-propylcyclohexyl)-(3-fluoropropyloxy) cyclohexane. This product was recrystallized twice from 6 ml of ethanol in a freezer to obtain 1.60 g (yield 58%) of 4-(4-propylcyclohexyl)-(3-fluoropropyloxy)cyclohexane. Several kinds of spectra well supported its structure.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[C:30]#[CH:31]>O1CCCC1.[Cu]I>[CH2:13]([NH:12][C:10]([C:6]1[S:5][C:4]([N:1]2[CH:31]=[C:30]([C:29]([O:33][CH2:34][CH3:35])=[O:32])[N:3]=[N:2]2)=[N:8][C:7]=1[CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CC(=O)OCC
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 2-azido-N-benzyl-4-methylthiazole-5-carboxamide (1.00 g, 3.67 mmol) in tetrahydrofuran (30 mL) was added copper(I) iodide (0.70 g, 3.67 mmol), N,N-diisopropylethylamine (1.28 mL, 7.32 mmol) and ethyl propiolate (0.45 g, 4.58 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:1) to afford the title compound as a white solid in 61% yield (0.83 g): 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 7.36-7.26 (m, 5H), 6.17 (br s, 1H), 4.63 (d, J=6.0 Hz, 2H), 4.47 (q, J=6.0 Hz, 2H), 2.70 (s, 3H), 1.42 (t, J=6.0 Hz, 3H); MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+].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.O>[F:18][C:19]1[C:24]([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
5-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.15 g), (2-fluoropyridin-3-yl)boronic acid (2.83 g), sodium hydrogencarbonate (2.53 g) and tetrakis(triphenylphosphine)palladium (870 mg) were added to a degassed mixture of 1,2-dimethoxyethane (80 mL) and water (20 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a colorless oil (yield 2.25 g, 68%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH:1]1([O:7][N:9]2[C:13](=[O:14])[C:12]3[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A solution of triphenylphosine (15.53 g, 59.2 mmol), cyclohexanol (6.25 mL, 59.2mmol), and N-hydroxypthalimide (9.66 g, 59.2 mmol) in anhydrous tetrahydrofuran (500 mL) under Argon was treated dropwise over approximately 20 minutes with a solution of di-tert-butyl azodicarboxylate (15.00 g, 65.14 mmol) in tetrahydrofuran (100 mL) with a water bath to control the exotherm. After the reddish color had dissipated, a mixture of di-tert-butyl azodicarboxylate (3.00 g, 13.0 mmol) and triphenylphosine (3.11 g, 11.8 mmol) in anhydrous tetrahydrofuran (50 mL) was added to the reaction mixture and allowed to stir overnight at ambient temperature. After evaporation in vacuo, the residue was treated with trifluoroacetic acid (100 mL) and stirred for 20 minutes. The reaction was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified twice by flash silica gel chromatography eluting with hexane : ethyl acetate (4:1 and 9:1). Pure fractions were concentrated in vacuo to a solid and dried under high vacuum to provide 2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione as a solid (10.90 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=1[Cl:25])[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:27])=[C:19]([Cl:25])[CH:20]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2Cl)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)c(Cl)c2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (3′-chloro-4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1C=C[C:11]([O:14]C)=[C:10](OC)[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].O1C=CC=C1C(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[O:14][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccco2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)furane was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.5 g, 10 mmol) and 2-furoyl chloride (1.1 mL, 10 mmol) with a reaction time of 2 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 4% ethyl acetate/methylene chloride) to afford 1.69 g (78%) of the product as a white solid: mp 112–114° C.; 1H NMR (CDCl3) δ 7.78–7.66 (m, 2H), 7.59–7.52 (m, 1H), 7.26–7.17 (m, 1H), 6.96–6.90(m, 1H), 6.63–6.55 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H); 13C NMR (CDCl3) δ 180.9, 153.0, 152.5, 148.9, 146.5, 129.8, 124.0, 119.6, 112.0, 111.7, 110.0, 56.0, 55.9; Anal. Calcd for C13H12O4. Theoretical: C, 67.23; H, 5.21. Found: C, 67.09; H, 5.21.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[CH3:16][O:17][P:18]([O-:21])[O:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]([P:18]([O:19][CH3:20])([O:17][CH3:16])=[O:21])[OH:3])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COP([O-])OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COP(=O)(OC)C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a mixture of 4.32 g of p-nitrobenzyl glyoxalate and 2.0 ml of dimethylphosphite in 25 ml of benzene is added a catalytic amount of p-toluenesulfonic acid. The reaction is heated at reflux temperature for 1.5 hours. The formed water is removed using a Dean-Stark trap. After cooling, the solvent is removed in vacuo and the resulting crystals are slurried in ethyl acetate and collected to give 3.48 g of the desired product.