Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H](C)[C@H](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)C(O)=O)C1C=CC=CC=1.N[C@H](C1C=CC(OC[C@H](O)CO)=CC=1)C(N[C@@H]([C@H](C1C=CC=CC=1)C)C(NC1C=CC(I)=CC=1Cl)=O)=O.C(O[C:75](=[O:99])[NH:76][C@H:77]([C:86](=[O:98])[NH:87][C:88]1[CH:93]=[CH:92][C:91]([CH:94]2[CH2:96][CH2:95]2)=[CH:90][C:89]=1[F:97])[CH2:78][C:79]1[CH:84]=[CH:83][C:82]([F:85])=[CH:81][CH:80]=1)(C)(C)C.C(O[C:105]([NH:107][C@H:108]([C:112]1[CH:117]=[CH:116][C:115]([O:118][CH2:119][C@H:120]2COC(C)(C)[O:121]2)=[CH:114][CH:113]=1)C(O)=O)=[O:106])(C)(C)C>NC(C1C=CC(OC(CO)CO)=CC=1)C(N[C@@H](CC1C=CC(F)=CC=1)C(NC1C=CC(C2CC2)=CC=1F)=O)=O>[CH:94]1([C:91]2[CH:92]=[CH:93][C:88]([NH:87][C:86](=[O:98])[C@@H:77]([N:76]3[C:75](=[O:99])[C@@H:108]([C:112]4[CH:113]=[CH:114][C:115]([O:118][CH:119]([CH2:120][OH:121])[CH2:1][OH:8])=[CH:116][CH:117]=4)[NH:107][C:105]3=[O:106])[CH2:78][C:79]3[CH:84]=[CH:83][C:82]([F:85])=[CH:81][CH:80]=3)=[C:89]([F:97])[CH:90]=2)[CH2:96][CH2:95]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1ccc(C2CC2)cc1F
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)C(=O)Nc1ccc(I)cc1Cl
Agent: NC(C(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1ccc(C2CC2)cc1F)c1ccc(OC(CO)CO)cc1
Product: O=C(Nc1ccc(C2CC2)cc1F)[C@H](Cc1ccc(F)cc1)N1C(=O)N[C@H](c2ccc(OC(CO)CO)cc2)C1=O

Procedure:
Prepared by the same method as described in example 3 except that (i) (S)-2-tert-butoxycarbonylamino-3-(4-fluoro-phenyl)-propionic acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1, (ii) (S)-[1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester was converted in to (S)-[1-(4-cyclopropyl-2-fluoro-phenylcarbamoyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester after step 2 and prior to step 3 (using the conditions described below), (iii) (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetic acid (prepared as described below) was used in place of (R)-tert-butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-acetic acid in step 4, and (iv) the diol functionality contained in (S)-2-{2-amino-2-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetylamino}-N-(4-cyclopropyl-2-fluoro-phenyl)-3-(4-fluoro-phenyl)-propionamide was temporarily protected as the bis-trimethylsilyl ether during step 6 by the same method as described in example 114.
Reaction SMILES: Cl[C:2]([F:10])([F:9])[C:3]([O:5]CC=C)=[O:4].[CH3:11][Si](C)(C)Cl.II.[C:18](#N)[CH3:19]>[Zn]>[F:10][C:2]([F:9])([CH2:11][CH:18]=[CH2:19])[C:3]([OH:5])=[O:4]
Reactant: CC#N
Reactant: C[Si](C)(C)Cl
Reactant: C=CCOC(=O)C(F)(F)Cl
Agent: II
Agent: [Zn]
Product: C=CCC(F)(F)C(=O)O
Temperature: 100 °C

Procedure:
100.0 g (0.59 mol) of allyl chlorodifluoroacetate, 42.2 g (0.65 mol) of zinc dust (activated according to Fieser & Fieser), 96.7 g (0.88 mol) of trimethylchlorosilane and 400 ml of absolute acetonitrile are introduced together into a glass autoclave, a spatula tip of iodine is added and the mixture is heated for 48 hours at 100° C. The zinc salt which has precipitated is filtered off, the filtrate is hydrolysed with H2O and rendered basic with 2N NaOH. The dark brown aqueous phase, extracted with pentane, is acidified with half-concentrated HCl, and the product is extracted with ethyl acetate. After the organic phase has been dried over MgSO4 and evaporated in a rotary evaporator (RE), the residue is distilled in vacuo. Yield: 59.4 g (74%) of a colourless oil of boiling point 73°-75° C./15.6 mbar.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:5]=1)(=[O:3])[CH3:2].[Br:21]Br>CC(O)=O.O.C([O-])(O)=O.[Na+]>[C:1]([C:4]1[C:9](=[O:10])[C:8]([Br:21])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 3-acetyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.00 g, 3.54 mmol) in AcOH (3.5 mL) was added Br2 (0.181 mL, 3.54 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and NaHCO3 aqueous solution, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (332 mg, 26% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.57 (3H, s), 7.79-7.91 (2H, m), 8.09-8:17 (1H, m), 8.22 (1H, s), 9.58 (1H, s).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[N+:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[NH:10][CH:11]=1>C(OCC)(=O)C.[Pt]=O>[Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[NH:10][CH:11]=1
Reactant: Clc1c[nH]c(C=[N+]2CCCC2)c1
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Clc1c[nH]c(CN2CCCC2)c1
Product: [O-][Cl+3]([O-])([O-])O
Reaction time: 72 h

Procedure:
A suspension of 114.4 g. (0.404 mole) of the product of Example V in 1 l of ethyl acetate is shaken with 1.2 g of platinum oxide under an initial hydrogen pressure of 48 psi. After being shaken for 72 hours, the reaction mixture is filtered and the filter cake is washed exhaustively with ethyl acetate. The filtrate is evaporated to give 4-chloro- 2-(1-pyrrolidinomethyl)pyrrole perchlorate as a brown oil.
Reaction SMILES: O[CH:2]([CH3:4])[O-:3].[Li+].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N+]([O-])=O)[C:10]=1[C:11]#[N:12])([O-:8])=[O:7].[O-:20]CC>O1CCCC1>[OH:20][CH2:4][CH2:2][O:3][C:13]1[CH:14]=[CH:15][CH:16]=[C:9]([N+:6]([O-:8])=[O:7])[C:10]=1[C:11]#[N:12]
Reactant: CC([O-])O
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(OCCO)cccc1[N+](=O)[O-]

Procedure:
2-(2-Hydroxyethoxy)-6-nitrobenzonitrile is prepared by the dropwise addition of a tetrahydrofuran solution of lithium hydroxyethoxide to a tetrahydrofuran (500 ml.) solution of 2,6-dinitrobenzonitrile (19.3 g.) at reflux. After all the ethoxide is added, the reaction is refluxed for 4 hours, cooled and evaporated to dryness. The solid product is extracted with hot benzene, m.p. 140°-142°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=2)=[CH:4][CH:3]=1.Cl.Cl.NC1C2CCN(CC2)C1.CCN(C(C)C)C(C)C.CS(C)=[O:49]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([OH:49])[N:18]=2)=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3cnccn23)n1
Agent: Cl
Agent: NC1CN2CCC1CC2
Solvent: CCN(C(C)C)C(C)C
Product: Oc1nccc(-c2c(-c3ccc(F)cc3)nc3cnccn23)n1
Yield: 20 %

Procedure:
A solution of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-imidazo[1,2-a]pyrazine (Preparation #4, 0.050 g, 0.14 mmol), 3-aminoquinuclidine dihydrochloride (0.054 g, 0.27 mmol), DIEA (0.047 mL, 0.27 mmol), and DMSO (1 mL) were shaken at about 80° C. for about 24 h. Additional DIEA (0.100 mL) was added to the mixture. The mixture was concentrated in vacuo to remove DMSO. The material was treated with saturated solution of NaHCO3 (30 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was washed sequentially with EtOAc (3×50 mL) and DCM (50 mL). The combined organic layers were dried over MgSO4 and concentrated. The mixture was triturated in EtOAc and filtered to yield the title compound (0.007 g, 20%): LC/MS (Table 1, Method b) Rt=1.3 min; MS m/z: 308.2 (M+H)+.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:11]=1.[OH-].[Na+].ClCCl.[CH2:32](O)[CH2:33][CH3:34]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:34][CH:33]=[CH2:32])[CH:18]=2)[N:11]=1)[CH:2]=[CH2:3]
Reactant: CCCO
Reactant: Oc1cccc(Oc2cccc(Oc3cccc(O)c3)n2)c1
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCOc1cccc(Oc2cccc(Oc3cccc(OCC=C)c3)n2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
59.7 g allyl chloride were added dropwise at 95° C. to a solution of 87.9 g of 2,6-bis-(3-hydroxyphenoxy)-pyridine (prepared according to DE-A 19 34 889 from 2,6-dichloropyridine and 2 moles of resorcinol; colorless crystals of melting point 188° C.) and 26.4 g of sodium hydroxide in 500 ml of n-propanol. The mixture was refluxed for a further 10 hours and then cooled to room temperature, after which 500 ml of dichloromethane were added and the precipitated sodium chloride was filtered off. After the solvent had been distilled off under reduced pressure, 101 g (90%) of product were obtained as a yellowish oil having a viscosity of 60 mPa.s at 50° C.; NMR (300 MHZ, D6-DMSO): 4.56 (d, 4H, allyl), 5.22-5.42 (dd, 4H, allyl), 5.95-6.10 (m, 2H, allyl), 6.60-6.85 (m, 6H, arom.), 7.22 (t, 2H, arom.), 7.82 (t, 1H, arom.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[Li]CCCC.[I:21]I>C1COCC1.CCOC(C)=O>[I:21][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: II
Reactant: CC(C)Oc1cc(Br)cc(OC(C)C)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(I)cc(OC(C)C)c1
Temperature: -78 °C
Yield: 79.2 %

Procedure:
To a solution of 1-bromo-3,5-bis(propan-2-yloxy)benzene (46) (2.0 g, 7.3 mmol) in THF (100 mL), cooled to −78° C., a 1.6 M n-BuLi solution in hexanes (9.16 mL, 14.7 mmol) was added dropwise. The temperature was maintained at −78° C. for 30 min, after which a solution of iodine (3.17 g, 29.3 mmol) in THF (15 mL) was added dropwise. The mixture was warmed to −35° C. and maintained at this temperature for 1.5 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave 1-iodo-3,5-bis(propan-2-yloxy)benzene (47) (1.85 g, 79%) as a viscous orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:27])[CH:21]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)CCc1cccc(N)c1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN(C)C)c1
Yield: 72.8 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (340 mg, 1.20 mmol) was reacted with 3-(2-(dimethylamino)ethyl)aniline (215 mg, 1.31 mmol) to afford the desired product (360 mg, 50%) as a yellow solid: ESI MS m/z 412 [C21H22BrN3O+H]+.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[I:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17].CCN(CC)CC.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][C:38]=2[C:44]([F:47])([F:46])[F:45])[CH2:32][CH2:31]1>C(Cl)CCl>[I:13][C:14]1[CH:15]=[C:16]([NH:17][C:5]([NH:41][C:40]2[CH:42]=[CH:43][C:37]([CH2:36][N:33]3[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]3)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)=[O:11])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(N)cc1I
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I

Procedure:
Triphosgene (1.04 g, 3.5 mmol) and ClCH2CH2Cl (20 ml) were added into a 100 ml round-bottomed flask, and stirred at room temperature until triphosgene was completely dissolved and the system appears colorless and transparent. The reaction system was placed in an ice-salt bath and stirred, 3-iodo-4-methylaniline (1.64 g, 7 mmol) in ClCH2CH2Cl solution (20 ml) was slowly added dropwise, and the system appears yellow milky. After the addition was complete, the mixture was stirred at room temperature for 4 hours. Et3N (1.43 g, 14 mmol) was added and stirred at room temperature for 0.5 hour. 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline (1.87 g, 7 mmol) was added and stirred at room temperature for 16 hours. The volatiles were removed by distillation under reduced pressure, and the residue was extracted with ethyl acetate (30 ml×3) and H2O (30 ml). The organic phases were combined, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography, to give a yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:27]=[CH:26][C:25]=2[CH3:36])[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:27]=[CH:26][C:25]=2[CH3:36])[CH2:12]1
Reactant: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(=O)(=O)C3CC3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a suspension of 60% sodium hydride (560 mg, 14 mmol) in N,N-dimethylformamide (5 mL) was added cyclopropanesulfonic acid amide (1.33 g, 14 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A24. A solution of 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (800 mg, 2 mmol) and 1,1′-carbonyldiimidazole (690 mg, 4 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B24. Solution B24 was added to Solution A24 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (90 mg, 9%) as a white solid: MS (ESI) M+1=484.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].C(=O)=O.CC(C)=O>C(OCC)C.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([F:14])[CH:9]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cc(Br)ccc1Br
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A solution of n-butyllithium (n-BuLi, 2.5 Molar (M) in hexanes; 900 microliters (μL), 2.2 millimoles (mmol), 1.1 equivalents (equiv)) was added to a stirred solution of 1,4-dibromo-2-fluorobenzene (500 milligrams (mg), 2.0 mmol, 1.0 equiv) in diethyl ether (Et2O; 10 milliliters (mL)) at −78° C. The resulting pale yellow solution was stirred at −78° C. for 2 hours (h). Chlorotrimethylsilane (TMSCl; 300 μL, 2.4 mmol, 1.2 equiv) was added, and the resulting pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and was stirred for 72 h. The reaction mixture was diluted with water (H2O; 50 mL) and was extracted with dichloromethane (CH2Cl2; 3×50 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a pale yellow oil (350 mg, 71%): IR (thin film) 3068 (w), 2955 (m), 2927 (m), 2855 (w), 1598 (w), 1567 (w) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.49 (m, 3H), 0.30 (s, 9H).
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[CH3:27][NH2:28]>C1COCC1.CCO>[CH3:27][NH:28][CH2:6][CH:7]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)CCCCC1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CNCC(CC1(C)CCCCC1)NC(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propyl methanesulfonate in 16 mL of THF, and 10 mL of 33% wt. methylamine in EtOH was heated at 70° C. for 3 h. After cooling to rt, the reaction mixture was evaporated under reduced pressure. The crude benzyl 1-(methylamino)-3-(1-methylcyclohexyl)propan-2-ylcarbamate was used directly in the next step without further purification. MS ESI +ve m/z 319 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8](O)[CH2:9][OH:10].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[O:10]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[O:7][CH2:8][CH2:9]1
Reactant: OCCO
Reactant: O=C1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: C1CC2(CCO1)OCCO2
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of tetrahydro-4-pyranone (10 g, 99.9 mmol), ethylene glycol (20 mL, 150 mmol) and catalytic toluene sulfonic acid was refluxed in benzene (120 mL) for 5 h. After cooling to room temp, the benzene layer was decanted from the dark oil in the bottom of the flask and was concentrated. The resulting oil was taken up in methylene chloride and shaken in a separatory funnel. The CH2Cl2 layer was decanted from the insoluble oil. The CH2Cl2 layer was concentrated to give the title compound as a pale yellow oil (11.62 g, 81% yield). 1H-NMR (300 MHz, CDCl3) δ: 3.91 (4H, s), 3.71 (4H, t, J=5.5 Hz), 1.68 (4H, t, J=5.7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([N:16]2[CH:17]=[C:13]([C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[C:18]([F:21])([F:19])[F:20])[N:14]=[CH:15]2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 44 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (900 mg, 3.0 mmol), using methyl 4-fluorobenzoate instead of 4-fluoroacetophenone, was converted to the title compound (580 mg, 44%) which was obtained as a white solid. MS: m/e=432.3 [M+H]+.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)=[O:6].Cl>>[CH3:12][C:9]1([CH3:13])[O:8][C@@H:7]([C:5]([OH:6])=[O:4])[CH2:11][O:10]1
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC1(C)OC[C@H](C(=O)O)O1
Reaction time: 3 h
Yield: 79 %

Procedure:
To a 2 N aqueous solution of potassium hydroxide was added (R)-(+)-2,2-dimethyl-1,3-dioxolan-4-carboxylic acid methyl ester (1.00 g, 6.24 mmol), followed by stirring under ice cooling conditions for 3 hours. After neutralization with hydrochloric acid, the solution was salted out and extracted with ethyl acetate (50 ml) to yield (R)-(+)-2,2-dimethyl-1,3-dioxolan-4-carboxylic acid as colorless amorphous powders (0.72 g). To a solution of the compound obtained in Reference Example 29 (0.572 g, 1.0 mmol) in dichloromethane (5 ml) were added diisopropylethylamine (1.04 g, 8 mmol) and the (R)-(+)-2,2-dimethyl-1,3-dioxo-lane-4-carboxylic acid obtained (0.292 g, 2 mmol), followed by stirring under ice cooling conditions. To this solution was added benzotriazol-1-yloxytrisdimethylaminophosphonium hexafluorophosphate (BOP reagent) (0.885 g, 2 mmol). After stirring under ice cooling conditions for 1 hour, the solution was further stirred at room temperature for 4 days. The reaction mixture was concentrated to dryness under reduced pressure, and then the obtained residue was partitioned between water (50 ml) and chloroform (50 ml). The water layer was again extracted with chloroform (10 ml). The combined extracts were washed with saline, and dried (MgSO4), the solvent was distilled off under reduced pressure. The obtained residue was chromatographed on silica gel to yield colorless amorphous powders (0.5 g),which was then dissolved in trifluoroacetic acid (10 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and treated with alkali, after which it was partitioned between chloroform (50 ml) and water (50 ml), and then the water layer was again extracted with chloroform (10 ml). The combined extracts were washed with saline, and dried (MgSO4), the solvent was distilled off under reduced pressure. The obtained residue was chromatographed on silica gel to yield 0.5 g of colorless amorphous powders (76%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[N:19]=[CH:20][CH:21]=2)[N:16]([CH3:25])[CH:15]=1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[N:19]=[CH:20][CH:21]=2)[N:16]([CH3:25])[CH:15]=1
Reactant: [H][H]
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.5 %

Procedure:
A mixture of Example 2C (0.165 g, 0.401 mmol) and 10% palladium on carbon (0.043 g, 0.040 mmol) in ethyl acetate (10 mL) was treated with a balloon of hydrogen gas. The reaction mixture was stirred for 10 hours at ambient temperature. The solid was removed by filtration, and the filtrate was concentrated to give the title compound (0.152 g, 0.399 mmol, 99% yield).