Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:41])[C:13]([N:28]3[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[C:14]([F:27])[C:15]=2[NH:19]CC2C=CC=CC=2)[N:10]([CH:42]2[CH2:44][CH2:43]2)[C:9]1=[O:45])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:46])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:41])[C:13]([N:28]3[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:29]3)=[C:14]([F:27])[C:15]=2[NH2:19])[N:10]([CH:42]2[CH2:43][CH2:44]2)[C:9]1=[O:45])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(N)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Yield: 76 %

Procedure:
{7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic acid tert-butyl ester from Example 10 (0.435 g, 0.676 mmol) in tetrahydrofuran (20 mL) is hydrogenated at room temperature and atmospheric pressure over 20% palladium hydroxide on carbon (0.114 g) for 27 hours. The mixture is filtered through Celite, the solid is washed with chloroform, and the combined filtrates concentrated under vacuum. Purification by column chromatography (2:3 ethyl acetate/hexanes) gives {5-amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamic acid tert-butyl ester as a solid (0.284 g). 1H NMR (CDCl3): δ 6.61 (bs, 1H), 5.94 (bs, 2H), 4.82-4.69 (bd, 1H), 4.40-4.21 (m, 1H), 4.00-3.59 (m, 3H), 3.55-3.41 (m, 1H), 3.35-3.21 (m, 1H), 2.32-2.08 (m, 1H), 2.01-1.80 (m, 1H), 1.50 (s, 9H), 1.46 (s, 9H), 1.17-1.01 (m, 2H), 0.77-0.63 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1)=[N+:19]=[N-:20]
Reactant: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(Oc2ccc3[nH]ccc3c2)ncn1

Procedure:
490 mg (2.0 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-indole (WO 03/099771; Stage 163.1) and 260 mg (4.0 mMol) NaN3 in 3 ml DMF are stirred for 3 h at 90° C. Then the reaction mixture is poured into water and extracted three times with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: MS: [M+1]+=253.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=O)[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16]C(N)=O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:11])[NH:16][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(N)=O
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)C(=O)NC2=O
Temperature: 250 °C
Yield: 91.8 %

Procedure:
Equimolar quantities of 4-t-butylphthalic anhydride (150.33 grams, 0.7361 mol) and urea (44.21 grams) were mixed with a thermometer in a 1 liter round bottom flask. The solids were heated slowly with a Meker burner. At 175° C., the reaction became exothermic and had to be cooled with an air gun. When the exotherm subsided, the temperature was increased to 250° C. and maintained at that temperature for 30 minutes. The flask was then cooled and 300 milliters of dimethylformamide was added, after which the solution was filtered by gravity to remove any solids which should not dissolve. Water (1 liter) was added, resulting in precipitation of 137.34 grams (0.6757 mole) of 4-t-butyl-phthalimide, which exhibited a melting point of 136.5° to 140° C. The identity of the 4-t-butyl-phthalimide product was confirmed by IR spectrum.
Reaction SMILES: [O:1]=[C:2]1[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:3]1[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[CH2:29][CH2:28]1.C1OCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:67](Br)[CH:68]=[CH2:69].[Cl-].[NH4+]>C1COCC1>[CH2:69]([C@:3]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[CH2:29][CH2:28]2)[C:2](=[O:1])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:68]=[CH2:67]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1[C@H](c2ccccc2)[C@H](c2ccccc2)OC(=O)[C@H]1C1CCN(C(=O)OCC[Si](C)(C)C)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC[C@]1(C2CCN(C(=O)OCC[Si](C)(C)C)CC2)C(=O)O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1.8 g of tert-butyl (3R,5R,6S)-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-yl]morpholine-4-carboxylate were dissolved in 20 ml of THF. 2.5 ml of 15-crown-5 were added, and the mixture was cooled to −78° C. Then 1.9 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 805 μl of allyl bromide were added dropwise. The mixture was allowed to warm to 0° C. over the course of 6 h, and then the reaction was stopped by adding 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted 3 times with 100 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][C:10]([NH:19]C(=O)C2C=CC=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CO>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][C:10]([NH2:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc(-c2ccccc2)n(Cc2ccccc2)n1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(-c2ccccc2)n(Cc2ccccc2)n1
Temperature: 60 °C
Yield: 45.3 %

Procedure:
The crude N-(1-benzyl-5-phenyl-1H-1,2,4-triazol-3-yl)benzamide was dissolved in 5 ml of MeOH. It was stirred and treated with 5 ml of 6N HCl. It was heated at 60° C. for overnight. It was cooled to rt and added to a stirred 4N NaOH (10 ml) in an ice bath. It was extracted with DCM. The combined DCM layer was dried with MgSO4 and rotavapped. The crude was purified by column chromatography with heptane/EtOAc gradient to yield 1-benzyl-5-phenyl-1H-1,2,4-triazol-3-amine (340 mg, 45.3% for 3 steps). 1H NMR (400 MHz, MeOD) 5.24 (br. s., 2H) 7.13 (br. s., 2H) 7.30 (br. s., 4H) 7.52 (br. s., 6H), LCMS method A, (M+H)+ 251.1, ret T=1.12 min.
Reaction SMILES: Br[C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.C(O)(=O)CS>C1COCC1.O>[OH:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@H:2]1[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12Br
Agent: O=C(O)CS
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of 9α-bromo-11β-hydroxyandrost-4-ene-3,17-dione (III, 2.00 g), thioglycolic acid (2.0 ml) in THF (20 ml) and water (5 ml) is stirred under nitrogen at 20°-25°. A chromous sulfate solution (1.4 M, 5.5 ml) is added and the two-phase system is stirred. After four hours, another 4.5 ml of chromous sulfate solution is added and the mixture stirred overnight. The mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate extracts are washed with water, a diluted sodium hydroxide solution, water and saline. The organic phase is dried over sodium sulfate and concentratd to a solid. The solid is crystallized from benzene-hexane to give a first crop of crystals of the title compound (1.38 g, 83.5% chemical yield) which are measured to be 99% pure as measured by GLC and is identical to an authentic sample.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[N-:15]=[N+:16]=[N-:17].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(=O)CC>[N:15]([CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCO[Si](CCCN=[N+]=[N-])(OCC)OCC
Yield: 80 %

Procedure:
To a solution of 3-chloropropyltriethoxysilane (2.31 g, 9.6 mmol) and tetrabutylamonium iodide (0.020 g, 0.05 mmol) in butanone (25 mL) was added sodium azide (3.120 g, 48 mmol) and the reaction mixture was heated under reflux for 50 h. Filtration over celite was followed by evaporation of the solvent under vacuum. The residue was dissolved in dichloromethane (150 mL) and then washed with water (2 times 20 mL). The organic phase was dried (NaSO4) and evaporated to give the desired product (1.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[N:4][C:5]([F:13])=[C:6]([F:12])[C:7]=1[CH2:8]C(O)=O.[Br:15]Br>ClC1C=CC=CC=1.[Hg]=O>[Br:15][CH2:8][C:7]1[C:6]([F:12])=[C:5]([F:13])[N:4]=[C:3]([F:14])[C:2]=1[Cl:1]
Reactant: BrBr
Reactant: O=C(O)Cc1c(F)c(F)nc(F)c1Cl
Agent: O=[Hg]
Solvent: Clc1ccccc1
Product: Fc1nc(F)c(Cl)c(CBr)c1F
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a 1 L 3-neck flask equipped with addition funnel, was placed chlorobenzene (150 ml). (3-Chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid (19.57 g, 86.77 mmol) and mercury oxide (20 g, 92.34 mmol) were added in this order. The mixture was heated up to 140˜150° C. in an oil bath. Bromine (5.4 ml, 105 mmol) in chlorobenzene (90 ml) was then added dropwise through the addition funnel for 3 hr. After the addition of bromine solution, the reaction mixture was refluxed for further 1 hr. and cooled to room temperature. The mixture was filtered through celite pad and the pad was washed with chlorobenzene. The combined filterate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:15)) to give 17 g (75%) of 4-bromomethyl-3-chloro-2,5,6-trifluoro-pyridine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=2)[C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=2)[C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:32])[CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)NCCO)c2)c2ccc(Cl)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2cccc(C(=O)NCCO)c2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-(2-hydroxyethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing 8% of the corresponding Z isomer, MS (ESI+): m/z=472.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13]O.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCc1c[nH]c2ccc(F)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc2[nH]cc(CCCBr)c2c1
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of 3-(5-fluoro-1H-indol-3-yl)-propan-1-ol (2.15 g, 11.2 mmol), carbon tetrabromide (4.80 g, 14.5 mmol) and triphenylphosphine (4.40 g, 16.7 mmol) in methylene chloride is stirred for 1 h and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane 3/7) to afford the title product as an oil, 1.97 g (69% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: BrCC[CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Br:25][CH2:26][CH2:27][CH2:28]CCBr>>[Br:25][CH2:26][CH2:27][CH2:28][CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCCCBr
Reactant: Cc1c(-c2ccccc2)oc2c(OCCCCBr)cccc2c1=O
Product: Cc1c(-c2ccccc2)oc2c(OCCCCCBr)cccc2c1=O

Procedure:
This compound was prepared by the method described for the preparation of Intermediate XVI, but using 1,5-dibromopentane in place of 1,4-dibromobutane and purifying the crude product by column chromatography on silica gel (elution with dichloromethane:ethyl acetate (99:1). m.p. 75°-76° C., after rinsing with petroleum ether:diethyl ether (30:4).
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>O1CCCC1.[C].[Pd]>[NH2:12][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
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2o1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc2oc(=O)[nH]c2cc1F
Reaction time: 10 h
Yield: 107.7 %

Procedure:
To a solution of 5-fluoro-6-nitro-2(3H)-benzoxazolone (20 g, 0.1 mole) in 300 ml tetrahydrofuran was added 2 g palladium carbon (5%) under nitrogen atmosphere. The mixture was hydrogenated with a Parr shaker for 10 hours at 45 psi. The precipitate which resulted from hydrogenation was redissolved by adding tetrahydrofuran. The catalyst was removed by filtration and the filtrate was concentrated to give 18.1 g of the title compound as a brown solid: m.p. 180°-182° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=2)[CH:18]=[N:17]1.[OH-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(Cl)(Cl)Cl>[C:9]1([CH2:8][CH2:7][O:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[NH:16][N:17]=[CH:18]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCc1ccccc1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: c1ccc(CCOc2ccc3[nH]ncc3c2)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 7.9 %

Procedure:
Potassium carbonate (68 mg, 0.492 mmol), tetrabutylammonium iodide (17 mg, 0.0447 mmol) and phenethyl bromide (0.061 ml, 0.447 mmol) were added to a solution of the 1H-indazol-5-ol (60 mg, 0.447 mmol) obtained in Reference Example 4 in N,N-dimethylformamide (2 ml), and the resulting mixture was heated to 60° C. After 7 hours, chloroform (3 ml) and a 1M-aqueous sodium hydroxide solution (4 ml) were added to the reaction mixture and stirred. After removing the aqueous layer, water (3 ml) was added to the organic layer and stirred. After removing the aqueous layer, the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-(2-phenylethoxy)-1H-indazole (8.4 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=3)=[CH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]([CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:16][CH:15]=3)=[CH:8]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCN(C(=O)OC(C)(C)C)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
According to Scheme 19 Step 4: tert-Butyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenylcarbamate (0.34 mmol 0.14 g) was dissolved in dry THF (4 mL) and the resulting solution was cooled at 0° C. Then, NaH (60% mineral oil; 1.02 mmol, 40.8 mg) was added, the mixture was stirred at 0° C. for 10 minutes, warmed at room temperature and stirred for 30 minutes. After, N,N-dimethylaminoethyl chloride (0.69 mmol) and KI (0.34 mmol, 57.0 mg) were added and the reaction mixture was heated at 90° C. for 16 hours. The resulting suspension was taken up in CH2Cl2, washed with water, washed with brine, filtered off and the filtrate washed with CH2Cl2. The organic solvent was separated, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge (CH2Cl2/MeOH(NH3)sat. 95/5). The product fractions were collected and the solvent was evaporated to yield tert-butyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl(2-(dimethylamino)ethyl)carbamate (87.9 mg)
Reaction SMILES: [CH3:1][P:2]([CH2:7][O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1[N+:27]([O-:29])=[O:28])(=[O:6])[O:3]CC.[OH-].[Na+]>C(O)C>[CH3:1][P:2]([CH2:7][O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1[N+:27]([O-:29])=[O:28])(=[O:3])[OH:6]
Reactant: CCOP(C)(=O)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CP(=O)(O)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To ethyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinate (1.30 g) in ethanol (10 ml) is added 5% aq. sodium hydroxide (20 ml) and the solution is stirred at RT for 20 minutes. The ethanol is evaporated off; the aqueous solution is extracted with ether and the ether layer is discarded. The basic aqueous solution is acidified with dilute HCl and extracted with methylene chloride. The combined organic extracts are washed, dried and evaporated to dryness to give P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinic acid (IX; R is NO2, R1 is CH3, R2 =R6 is H, W=X is O, Y is Cl, Z is CF3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][CH:20]([CH3:39])[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38])O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH3:38])[CH:20]([CH3:39])[CH3:19])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(C)C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl)-propan-1-ol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-ethoxy-3-(2-methyl-4-{2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-propionic acid ethyl ester as a mixture of two diastereomeric racemates as light yellow liquid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[CH:21][C:22]2([CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C=C2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Yield: 94.3 %

Procedure:
21.0 g of crude 4-(4-tert-butyl-phenyl)-2-(1-methyl-cyclo-hexylmethylene)-indan-1-one (GC: ˜83% purity) are dissolved in 220 ml of ethyl acetate in a flask with gas inlet and stirrer. 1.5 g of palladium on activated carbon (10 wt-% palladium) are added. The system is evacuated and refilled with argon three times to remove oxygen and then evacuated and refilled with hydrogen three times. The stirrer is started and the reaction mixture is vigorously stirred to help the diffusion of hydrogen gas into the liquid reaction mixture. The hydrogen uptake is monitored and stirring is continued until the hydrogen uptake ceases. Filtering the crude reaction mixture over a paper filter and removing the solvent in a vacuum leaves crude 4-(4-tert-butyl-phenyl)-2-((1-methylcyclohexyl)methyl)-indan-1-one (yield 19.9 g, GC: ˜86% purity). The obtained crude product was used without further purification for the subsequent reduction/elimination-sequence.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CP(CCP(C)C)C.CC[O:22]CC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:22])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Cl)c1
Reactant: CCOCC
Agent: CP(C)CCP(C)C
Product: COC(=O)c1cc(O)cc(Cl)c1
Yield: 72 %

Procedure:
The general process was applied to methyl 3-chlorobenzoate (171 mg, 1.0 mmol). The borylation step was carried out neat with HBPin (200 mg, 1.55 mmol) and dmpe (3.0 mg, 0.02 mmol, 2 mol %) at 150° C. for 3 hours. The oxidation step was then performed as described above, after which the crude material was dissolved in ether and passed through a plug of silica gel (pentane/ether 2:1). Evaporation of solvent gave 134 mg phenol 5 (72%) with trace water. Sublimation at 85° C. under 0.06 mm Hg afforded analytically pure 5 as a white solid; mp 133-135° C. (lit. 138-139). 1H NMR (300 MHz, acetone-d6): δ 9.2 (brs, 1 H), 7.43 (t, J=1.7 Hz, 1 H), 7.40 (dd, J=2.2, 1.7 Hz, 1 H), 7.10 (t, J=2.2 Hz, 1 H), 3.87 (s, 3 H); 13C NMR (75 MHz, acetone-d6): δ 165.9, 159.3, 135.3, 133.8, 121.0, 120.6, 115.7, 52.7; IR (neat): 3335, 1690, 1591, 1431, 1350, 1242, 768 cm−1; LRMS: m/e 186 (M+), 155, 127, 99. Anal. Calcd for C8H7ClO3: C, 51.50; H, 3.78. Found C, 51.78; H, 3.73. For a previous preparation see Takahashi et al., Heterocycles 23: 1483-1491 (1985) (three steps from 3,5-dichlorobenzoic acid, 65% overall yield).