Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][C:3]=1[CH3:25].[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:30]4[CH:29]=[N:28][C:27]([NH2:26])=[CH:32][CH:31]=4)[CH:19]=3)[N:9]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1Cl
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(N)nc4)c3)n2)ccc1Cl

Procedure:
The title compound was prepared from 4-(4-chloro-3-methyl-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.43) (0.19 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.16 g, 72%). MS (ISP) 442.3 [(M+H)+]; mp 207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-].P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cc(Cl)n1
Temperature: 25 °C

Procedure:
2-Chloro-4-nitro-6-methyl-pyridine 1-oxide (6.2 g, 0.033 mol) was dissolved in chloroform (100 ml), phosphorus trichloride was added (22.6 g, 0.165 mol) and the mixture was heated under reflux for 2 days. The mixture was cooled to room temperature, poured into icewater and the mixture was neutralized with solid potassium carbonate. The phases were separated, the aqueous phase was extracted three times with chloroform, the combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure after which 5.326 g of a brown oil was obtained (0.031 mol, 94%) which was used directly in the next step.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C(O)C.C1(C)C=CC=CC=1>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:27])[CH2:26][C:6](=[O:8])[C:5]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][CH:24]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(C(C)(C)C)cc1
Yield: 100 %

Procedure:
To a cooled solution, <5° C., of sodium ethoxide (4.4 g, 64.6 mmol) in ethanol, diethyl oxalate (7.71 mL, 56.7 mmol) in toluene (150 mL) was added. The reaction mixture was stirred for 30 min, before the addition of 1-(4-tert-butylphenyl)ethanone (56.7 mmol, 10 g) dropwise in toluene (20 mL) (via pressurised dropping funnel). The reaction mixture was stirred overnight to room temperature and then evaporated to low volume. Acetic acid was added and the resultant precipitate was filtered and washed with heptane to obtain ethyl 4-(4-tert-butylphenyl)-2,4-dioxobutanoate (15.68 g, 56.7 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=2.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=2
Reactant: COC(=O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate (160 mg, 500 μmol) and 1N NaOH (1.5 mL) in ethanol (25 mL) was heated at 80° C. for 18 h. The solution was cooled to ambient temperature, diluted with ethyl acetate, acidified with conc. HCl, and the layers separated. The aqueous phase was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered, and the solvent was removed under reduced pressure to afford 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid. MS (m/z) 304.0 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:27][C:12]([C@@H:9]3[CH2:10][CH2:11][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 97.2 %

Procedure:
2.00 g 1-Tert.butoxycarbonyl-azetidin-2(S)-carboxylic acid, 1.70 g 1-amino-6-aminomethyl-isoquinolin, 3.50 g TBTU were dissolved in 40 mL DMF. 3.55 mL N-methylmorpholine was added slowly with stirring. The solution was applied to a reversed-phase chromatography column (lenght 100 mm, diameter 14 mm, Merck Lichroprep RP-18, 15-25 μ). Elution was started with 25 mL of methanol/water containing 0.3% acetic acid (10 90), then a linear gradient to pure methanol over a period of 75 mL was applied followed by 50 mL of pure methanol. Fraktions of 5 mL each were sampled. The solvent was evaporated to give 3.4 g of the tile compound. MS: 357
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH:32]([C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)CB(O)O)([CH3:34])[CH3:33]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:43]2[CH:42]=[CH:37][CH:36]=[C:35]([CH:32]([CH3:34])[CH3:33])[CH:44]=2)[CH:24]=1
Reactant: CC(C)c1cccc(CB(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1cccc(-c2cc(F)ccc2OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 3-isopropylbenzylboronic acid (30 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a white solid. (34 mg, 62%). MS m/e 449.30 (M+H+)
Reaction SMILES: [CH2:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9](O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20]>>[CH:4]1[C:3]2[CH2:2][CH2:1][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:9]([CH2:18][C:19]([OH:21])=[O:20])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CC(=O)O
Reactant: OC1c2ccccc2CCc2ccccc21
Product: O=C(O)CC1c2ccccc2CCc2ccccc21
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A round-bottom flask, equipped with a distillation apparatus, is charged with dibenzosuberol (25.0 g, 0.119 mol) and malonic acid (61.9 g, 0.595 mol). The mixture is heated in an 160° C. oil bath. The solids melt. Gas bubbles form and water and acetic acid are distilled through the condenser. After 30 minutes, the mixture is cooled to room temperature and dissolved in ethyl acetate. The organic solution is washed with brine and dried (magnesium sulfate). The solvent is removed in vacuo to give an off white solid, which is recrystallized from hexane-ethyl acetate/1:1 to yield the title compound as white crystals, 28.8 g; mp 164°-165° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:31]([C:2]1[CH:3]=[C:4]([CH2:5][N:6]2[C:10]([CH3:11])=[N:9][C:8]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=4)[N:13]=3)=[N:7]2)[CH:28]=[CH:29][CH:30]=1)=[CH2:32]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 110 °C

Procedure:
To a mixture of 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 11, Step 1; 200 mg, 0.42 mmol), tributyl(vinyl)stannane (159 mg, 0.50 mmol) and K2CO3 (174 mg, 1.26 mmol) in 1,4-dioxane (5 mL), was added Pd(PPh4)3 (28 mg, 0.025 mmol). The reaction mixture was heated in a sealed vial at 110° C. under inert atmosphere for 12 h, cooled to RT, diluted with H2O (30 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by prep-HPLC to give the title compound as a white solid; MS (ES+) C21H16F3N5O2 requires: 427. found: 428 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ 8.22 (d, J=9 Hz, 2H), 7.61 (d, J=9 Hz, 2H), 7.48 (d, J=7 Hz, 1H), 7.43 (s, 1H), 7.38 (m, 1H), 7.21 (d, J=7 Hz, 1H), 6.76 (m, 1H), 5.87 (d, J=17.5 Hz, 1H), 5.57 (s, 2H), 5.31 (d, J=11.5 Hz, 1H), 2.60 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7](Cl)=[O:8])=[O:4].[NH2:15][CH2:16][C:17](=[O:19])[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[O:19]=[C:17]([CH3:18])[CH2:16][NH:15][C:7]([CH:6]1[CH2:10][CH2:11][CH2:12][N:5]1[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])=[O:8]
Reactant: CC(=O)CN
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CNC(=O)C1CCCN1C(=O)C(F)(F)F

Procedure:
A solution of (S)-N-(trifluoroacetyl)prolyl chloride (Aldrich) 1 equiv. in DCM is treated with 1-amino-propan-2-one (1.5 equiv.) in pyridine at rt for 5 hours. After usual work up, it provides 1-trifluoroacetyl-pyrrolidine-2-carboxylic acid (2-oxo-propyl)-amide.
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:21][CH3:22])[CH:14]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][N:5]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:21][CH3:22])[CH:14]=2)[C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: COc1cc(F)ccc1C#N
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(OC)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (203 mg), 4-fluoro-2-methoxybenzonitrile (151 mg) and lithium carbonate (163 mg), the title compound was obtained as colorless oil (yield: 22 mg, yield: 7.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[N+:19]([C:15]1[C:16]([NH2:18])=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[N:22]=[CH:23][N:24]=[C:4]3[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=3)[N:7]=2)=[CH:13][CH:14]=1)([O-:21])=[O:20]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Product: Nc1nc(NCCNc2nc(-c3ccc(C(F)(F)F)cc3)cc3ncnn23)ccc1[N+](=O)[O-]

Procedure:
In analogy to the procedure described for Example 94, 2.3 mg (4% of theory) of the product are obtained as solid starting from 50 mg (0.133 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo-[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 55A) by coupling with 25.2 mg (0.13 mmol) of [4-(trifluoromethyl)phenyl]boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 2.5 °C
Yield: 44.3 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask was placed a solution of 3-aminobutanoic acid (100 g, 969.75 mmol, 1.00 equiv) in water (1000 mL), followed by the addition of potassium hydroxide (136 g, 2.42 mol, 2.50 equiv) in several batches. To this was added benzyl chloroformate (247 g, 1.45 mol, 1.50 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred at 25° C. for 5 h. The reaction progress was monitored by LCMS. The resulting solution was extracted with 3×250 mL of dichloromethane and the aqueous layers were combined. The pH value of the water phase was adjusted to 3 with hydrogen chloride (2 mol/L). The precipitates were collected by filtration and dried to afford 102 g (44%) of 3-[[(benzyloxy)carbonyl]amino]butanoic acid as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:31][CH2:30][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([N:24]5[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25]5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[ClH:32].[CH3:29][C:27]1[CH:26]=[N:25][N:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[C@H:15]([N:13]2[CH2:14][C:11]4([CH2:30][CH2:31][NH:8][CH2:9][CH2:10]4)[CH2:12]2)[CH2:16][CH2:17]3)[CH:28]=1
Reactant: Cc1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)c1
Reaction time: 3 h

Procedure:
To a solution of 2-[(R)-5-(4-methyl-pyrazol-1-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (8-1a, 239 mg, 0.57 mmol) in MeOH (5 mL) was added 9 mL of 4N HCl in dioxane solution. The reaction was stirred for 3 hours. The reaction was concentrated and the residue was coevaporated with diethylether (3×) to afford 2-((R)-5-(4-methyl-1H-pyrazol-1-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride as a white solid (8-1b, 135 mg, 61%). This material was used without further purification in the next reaction. MS (ES+) 322.9 (M+H)+. 1H NMR (DMSO-d6) δ 1.89-2.20 (m, 7H), 2.28-2.48 (m, 2H), 2.84-3.14 (m, 4H), 3.28-3.46 (m, 1H), 3.84-4.03 (m, 3H), 4.19-4.33 (m, 2H), 4.83-4.98 (m, 1H), 7.54 (s, 1H), 7.66 (s, 2H), 7.74-7.79 (m, 1H), 8.28 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=2)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([C:23]2[N:22]=[CH:21][C:20]([O:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:28])=[O:27])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:25][CH:24]=2)=[CH:33][CH:32]=1
Reactant: CCCCC(Oc1ccc(Cl)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCCCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 62 starting from 3-{4-[1-(6-chloro-pyridin-3-yloxy)-pentyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 499.2 [M−H]−; Isomer 2 MS: 499.2 [M−H]−.
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[C:9]1([CH:15](O)[C:16]([CH3:18])=[CH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)CC>CO>[CH3:17]/[C:16](=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH2:18][CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: COC(C)(OC)OC
Reactant: C=C(C)C(O)c1ccccc1
Solvent: CCC(=O)O
Solvent: CO
Product: COC(=O)CC/C(C)=C/c1ccccc1
Yield: 20.9 %

Procedure:
Trimethyl orthoacetate (186 g, 1.52 mol) and 1-phenyl-2-methyl-2-propen-1-ol (90% pure from Alfa Aesar, 25 g, 0.152 mol) were heated in the presence of propionic acid (0.2 ml) in an oil bath at 145° C. for 4 hours. The methanol formed during the reaction was distilled. The excess orthoacetate was then removed under vacuum and the residue was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1 to 8:1) followed by bulb-to-bulb distillation (67° C./0.001 mbar). 6.5 g (yield=21%) of the desired product were obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[ClH:25]>C(O)C>[ClH:15].[ClH:25].[CH3:13][CH:12]([CH3:14])[CH2:11][CH:2]([NH:1][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: ClCCCN1CCCCC1
Reactant: CC(C)CC(N)C(O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)CC(NCCCN1CCCCC1)C(O)c1ccccc1
Yield: 72 %

Procedure:
A mixture of (1RS,2SR)-2-amino-4-methyl-1-phenylpentane-1-ol (40.6 g, 210 mmol) and 1-(3-chloropropyl)piperidine (34.0 g, 210 mmol) was melted together at 50° to 70° C. in a nitrogen atmosphere. The mixture was then heated on an oil bath of 110° to 120° C. for 3 hours. After being cooled, the reaction mixture was dissolved with heating in ethanol (750 ml), followed by addition of concentrated hydrochloric acid (17 ml). The mixture was cooled and precipitated crystals were collected by filtration. The crystals were agian suspended in ethanol (1,200 ml) and heated under reflux for one hour. The mixture was cooled and the resulting crystals were collected by filtration, washed and then dried to obtain 58.8 g of the intended compound as white crystals [yield: 72%, m.p.: 268°-270° C. (decomposed)].
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([O:16]C(C)(C)C)=[O:15]>C(Cl)Cl>[Cl:8][C:9]1[C:10]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
Trifluoroacetic acid (1.04 mL, 14 mmol) was added to a mixture of tert-butyl 5-chloro-4-(3,4-dichlorophenylthio)-2-fluorobenzoate (571 mg, 1.40 mmol) in DCM (10 mL) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated to dryness to give the title compound as a white solid (492 mg, 100%). No further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[NH:13][N:14]=[CH:15][C:7]=12.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:13]1[C:8]2=[N:9][C:10]([NH2:12])=[N:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[C:7]2[CH:15]=[N:14]1
Reactant: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2cnn(Cc3ccccc3F)c2n1
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (219 mg, 1 mmol) in DMF (2 mL) at 0° C. was treated with NaH (40 mg, 60%, 1 mmol), stirred for 20 min, treated with 2-fluorobenzyl bromide (120 μL, 1 mmol), stirred at room temperature for 1 h, quenched with water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:4) to give the title compound (250 mg, 76%) as a cream solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:18][C:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=C>>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8]([CH3:10])([CH3:9])[CH2:11][C:19]2([CH3:18])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C=C(C)CC(C)(C)C
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CC(C)(C)CC1(C)CC(C)(C)c2ccc(O)cc21

Procedure:
57 g (0.25 mol) of 2,2-bis-(4-hydroxyphenyl)-propane, 10 g of an acid-activated fuller's earth and 84 g (0.75 mol) of diisobutylene are stirred in an autoclave for 8 hours at around 150° C. The catalyst is then filtered off and the reaction mixture subjected to fractional distillation, giving 25.2 g (44% of the theoretical) of 5-hydroxy-1,1,3-trimethyl-3-neopentyl indane.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O.[C:11]1(C)[CH:16]=[CH:15][C:14]([S:17](O)(=O)=O)=[CH:13][CH:12]=1.C1(S)C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5]([S:17][C:14]2[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)CCC(=O)CC1
Agent: Sc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC=C(Sc2ccccc2)CC1

Procedure:
A stirred solution of 4,4-dimethylcyclohexanone (1 g.), p-toluene sulphonic acid monohydrate (23 mg.) and thiophenol (0.81 ml.) in toluene (24 ml.) was heated at reflux for 9 hours with azeotropic removal of water using a Dean and Stark apparatus. The mixture was cooled, diluted with toluene (25 ml.) and extracted with saturated sodium bicarbonate solution (2×10 ml.), washed with water (3×10 ml.) and dried (MgSO4). Evaporation of the solvent gave (4,4-dimethylcyclohex-1-enyl)phenylsulphide as an oil (1.66 g.); NMR (CDCl3,90 MHz): 0.94 (6H,s), 1.45 (2H,t), 1.98 (2H,m), 2.18 (2H,m), 6.02 (1H,m) and 7.3 (5H,m).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[N+](C1C=CC(C([O:17][C@H:18]2[CH2:21][C@H:20]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]2)=O)=CC=1)([O-])=O>CO>[C:26]([O:25][C:23](=[O:24])[NH:22][C@H:20]1[CH2:21][C@H:18]([OH:17])[CH2:19]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Temperature: 100 °C
Yield: 46.3 %

Procedure:
To a mixture of potassium carbonate (5.24 mL, 87 mmol) and water (100 mL) and MeOH (400 mL), was added trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate (17.1 g, 50.8 mmol). The resulting mixture was heated to 100° C. for 2 h, cooled, and filtered. The filtrate was evaporated under vacuum to give the desired product tert-butyl(trans-3-hydroxycyclobutyl)carbamate (4.4 g, 23.50 mmol, 46.2% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.73 (br. s., 1 H), 4.39-4.58 (m, 1 H), 4.22 (br. s., 1 H), 2.10-2.48 (m, 5 H), 1.44 (s, 9 H).