Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH:23]12[NH:31][CH:27]([CH2:28][O:29][CH2:30]1)[CH2:26][O:25][CH2:24]2.[F-].[K+]>CN(C=O)C.CCOC(C)=O>[CH:27]12[N:31]([C:3]3[C:2]([Br:1])=[CH:21][C:6]([C:7]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=4)=[O:8])=[CH:5][N:4]=3)[CH:23]([CH2:30][O:29][CH2:28]1)[CH2:24][O:25][CH2:26]2
Reactant: C1OCC2COCC1N2
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C3COCC2COC3)c(Br)c1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 55.4 mg, 0.14 mmol) and 3,7-Dioxa-9-aza-bicyclo[3.3.1]nonane (Organic Chemistry (2006), 71(1), 413-415) (24.53 mg, 0.14 mmol) were dissolved in DMF (150 μL). KF (24.4 mg, 0.42 mmol) was added and the RM mixture was stirred at 140° C. for 18 h in a pressure safe vial. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, n-hexane/EtOAc from 20% to 60% EtOAc) to afford the title compound as a white solid. HPLC (Condition 4) tR=5.84 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=490.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[F:40][CH:41]([F:64])[O:42][C:43]1[CH:44]=[CH:45][C:46](B2OC(C)(C)C(C)(C)O2)=[C:47]2[C:52]=1[O:51][C:50]([CH3:54])([CH3:53])[CH:49]=[CH:48]2.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:46]1[CH:45]=[CH:44][C:43]([O:42][CH:41]([F:40])[F:64])=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50]([CH3:54])([CH3:53])[O:51]2
Reactant: CC1(C)C=Cc2c(B3OC(C)(C)C(C)(C)O3)ccc(OC(F)F)c2O1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: CC1(C)C=Cc2c(-c3c(Cl)c4c(=O)[nH]ncc4n3COCC[Si](C)(C)C)ccc(OC(F)F)c2O1
Yield: 69.8 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 189 mg (0.500 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 352 mg (1.00 mmol) of 2-(8-difluoromethoxy-2,2-dimethyl-2H-chromen-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(i) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 183 mg of the title compound was obtained as a pale yellowish foam. (Yield: 70%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:27]=[CH:26][C:17]2[C:18]3[CH:19]=[CH:20][O:21][C:22]=3[CH2:23][CH2:24][O:25][C:16]=2[C:15]=1[C:28]([O:30][CH3:31])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:27]=[CH:26][C:17]2[C:18]3[CH:19]=[CH:20][O:21][C:22]=3[CH2:23][CH2:24][O:25][C:16]=2[C:15]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1OCCc1occc1-2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCCc1occc1-2
Reaction time: 18 h
Yield: 95.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.55 g) was added to a solution of methyl 8-amino-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylate (Intermediate 15, 0.47 g) and pyridine (3 mL) in DCM (5 mL) and the mixture was stirred for 18 hours. The mixture was evaporated to dryness and water and ethyl acetate were added. The organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give methyl 8-(2-bromo-4-fluorobenzenesulfonylamino)-4,5-dihydro-3,6-dioxa-benzo[e]azulene-7-carboxylate (0.86 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[O:18]1.O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:17]([OH:27])=[O:18])=[O:26])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2
Reactant: Cc1ccc(F)c2c1CCCO2
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: Cc1c(C(=O)c2ccccc2C(=O)O)cc(F)c2c1CCCO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An ice cold mixture of 8-fluoro-5-methylchroman (0.955 g, 5.75 mmol) in 1,2-Dichloroethane (DCE) (10 mL) was treated with aluminum chloride (1.532 g, 11.49 mmol) followed by isobenzofuran-1,3-dione (0.809 g, 5.46 mmol). The mixture was allowed to warm to ambient temperature and stirred for 90 minutes. Water was then added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92-2.05 (m, 2 H), 2.34 (s, 3 H), 2.62-2.79 (m, 2 H), 4.15-4.30 (m, 2 H), 6.68 (d, J=11.73 Hz, 1 H), 7.40 (d, J=7.43 Hz, 1 H), 7.51-7.76 (m, 2 H), 7.88 (d, J=7.43 Hz, 1 H), 13.15 (br. s., 1 H); LC/MS (m/z) ES+=315 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[C:25]([CH:28]=1)[C:26]#[N:27]>C(O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][N:31]=4)=[C:25]([CH:28]=3)[C:26]#[N:27])[NH:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Reactant: N#Cc1cc(CCN)ccc1Oc1ccc(C(F)(F)F)cn1
Solvent: CCO
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)c(C#N)c3)nc2=O)cn1
Yield: 35.5 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (50 mg, 0.20 mmol, 1 eq) and 5-(2-Amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)-benzonitrile (80 mg, 0.26 mmol, 1.3 eq) were heated at 130° C. (sealed bottle) in 500 μl of absolute ethanol for 24 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 11 g normal phase silica KP-NH column and DCM/10% MeOH in DCM solvent system (gradient 10-80% of 10% MeOH in DCM in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting oil was triturated with hexane to obtain 5-{2-[5-(2-methyl-pyrimidin-5-ylmethyl)-4-oxo-1,4-dihydro-pyrimidin-2-ylamino]-ethyl}-2-(5-trifluoromethyl-pyridin-2-yloxy)-benzonitrile (36 mg, yield=32.4%, purity=92%) in form of tain coloured powder. MS: [M+H]+=508.40. 1H NMR (300 MHz; CDCl3) δ/ppm 2.64 (s, 3H), 2.94 (t, J=7.23 Hz, 2H), 3.53 (s, 2H), 3.57-3.66 (m, 2H), 7.14-7.23 (m, 2H), 7.51 (d, J=8.37 Hz, 2H), 7.55-7.64 (m, 2H), 7.96 (d, J=8.60 Hz, 1H), 8.34 (s, 1H), 8.50 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].O>CS(C)=O>[N+:14]([C:9]1[CH:8]=[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Temperature: 100 °C
Yield: 64.7 %

Procedure:
28.4 g (0.33 mol, 5.5 eq) of piperazine is dissolved in 50 ml of DMSO. 6.4 ml (60 mmol) of 2-fluoronitrobenzene is added. The mixture is heated at 100° C. for 60 hours. After cooling, the reaction mixture is transferred into 530 ml of water. The precipitate formed is filtered and the filtrate extracted with Et2O. After drying on MgSO4 and concentration under vacuum, the crude product is purified by column chromatography (eluent CH2Cl2/MeOH 9:1) to produce 8.04 g of the expected compound in the form of an orange oil which crystallizes at room temperature (yield: 65%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH:16]3[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:26])([CH3:25])[C:17]3=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:7][CH:6]=2)=[CH:9][C:10]=1[CH:16]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:25])([CH3:26])[C:17]1=[O:27])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: CCc1ccc(-c2ccc(I)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCc1ccc(-c2ccc(C#C[Si](C)(C)C)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 120 °C
Yield: 76.2 %

Procedure:
A mixture of 4-(4′-iodo-4-ethyl-biphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.200 g, 0.42 mmol), trimethylsilylacetylene (0.10 ml, 0.47 mmol), copper(I) iodide (4 mg, 0.023 mmol), bis(triphenylphosphine)palladium(II) chloride (0.016 g, 0.023 mmol), triphenylphosphine (0.022 g, 0.084 mmol) and diethylamine (0.65 ml) in anhydrous N,N-dimethylformamide (0.25 ml) is heated at 120° C. under microwave irradiation for 25 minutes. This mixture is then allowed to cool to room temperature and filtered through diatomaceous earth (additional washing with dichloromethane). The solvent is removed under reduced pressure and the residue is purified by flash column chromatography on silica gel (hexane/ethyl acetate 9:1 to 3:1 ratio) to yield 4-[4-ethyl-4′-(trimethylsilylethynyl)biphenyl-3-yl]-2,2,6,6-tetramethylpyran-3,5-dione (0.143 g) as a white solid which is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([OH:20])[C:10]([C:21]([OH:23])=[O:22])=[N:9]1.C(N(CC)C(C)C)(C)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:20][C:11]1[C:10]([C:21]([OH:23])=[O:22])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid I-6c (572.0 g, 1.64 mol) was combined with 8 liters of methylene chloride to give an off-white suspension. N,N-Diisopropylethylamine (427.9 g, 3.29 mol) was added over 15 minutes while keeping the temperature between 20–25° C. A clear yellow solution resulted. Acetic anhydride (334.5 g, 3.24 mol) was added over 5 minutes keeping the temperature between 20–25° C. The reaction was stirred at room temperature for 16 hours. The crude reaction solution was washed twice with 4 liters portions of 0.5 M citric acid and once with 4 liters of brine. The crude solution was concentrated in vacuo to a total volume of 1 liter. This milky suspension was then added to 4 liters of hexanes causing the desired product to precipitate instantly. The solids were granulated for 30 minutes and then collected by filtration. The filtercake was rinsed with 3 liters of hexanes and then air-dried for 16 hours. The isolated product was then further dried at 60° C. and 8 mm for 2 hours. 4-Acetoxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6d (601.6 g, 94%) was isolated as a powdery, off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:18]2[CH:19]=[CH:20][C:21]([C:2]3[C:3]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=3)=[CH:22][C:17]=2[F:16])=[CH:33][N:34]=1
Reactant: NS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3S(N)(=O)=O)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-bromo-5-(trifluoromethyl)benzenesulfonamide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C17H12F4N4O2S, 412.06; m/z found, 413.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.56-8.53 (d, J=1.4, 2H), 8.43-8.40 (m, 1H), 7.98-7.92 (d, J=7.7, 1H), 7.63-7.58 (d, J=8.0, 1H), 7.58-7.52 (m, 1H), 7.37-7.35 (m, 1H), 7.35-7.32 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH:17]=[O:18])[C:11](=[CH:12][CH2:13][CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:22][C@@H:15]1[C@@:16]2([CH:17]=[O:18])[C:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[O:1][Si:24]([CH3:27])([CH3:26])[CH3:23])=[CH:12][CH2:13][CH2:14]1
Reactant: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C=O
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C)[C@@]4(C)CC[C@@H]3[C@]21C=O

Procedure:
A mixture of 17β-hydroxy-1α-methyl-4-androsten-19-one, trimethylchlorosilane and pyridine is refluxed in benzene for a period of about 18 hours. The suspension is filtered and the benzene removed under vacuum. The resulting oil is eluted from a silica gel chromatograph with benzene and crystallized from hexane to yield 1α-methyl-17β-trimethylsiloxy-4-androsten-19-one.
Reaction SMILES: [OH-:1].[Li+].C[O:4][C:5](=[O:39])[CH:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[N:8]=1.O>O.CO>[OH:1][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:4])=[O:39])=[N:8][C:9]=1[C:13]1[CH:14]=[C:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:16]2=[N:17][CH:18]=1
Reactant: COC(=O)C(O)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)n1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3nc(CC(=O)O)ccc3O)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.4 %

Procedure:
4 N aqueous lithium hydroxide (17 μl, 0.66 mmol) was added to hydroxy-{6-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid methyl ester (286 mg, 0.55 mmol) in water/methanol(3:1) (5 ml) and stirred at room temperature for 3 days. Water was added and the mixture was extracted with ethyl acetate (3×), the combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to give 5-hydroxy-{6-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid (174 mg, 61% yield) as an off white powder. MS: m/z 507.6 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:13])([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH3:5].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:15])=[CH:10][CH:11]=1)([CH3:5])[CH3:13]
Reactant: COC(=O)C(C)(C)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(C)c1ccc(CBr)cc1
Reaction time: 5 h
Yield: 72 %

Procedure:
To a refluxing solution of 2-Methyl-2-p-tolyl-propionic acid methyl ester (892 mg, 4.64 mmol) and N-bromosuccinimide (826 mg, 4.64 mmol) in CCl4 (120 mL) is added 2,2′-Azobisisobutyronitrile (12 mg, 0.073 mmol). After 5 h, the reaction is concentrated and the residue is chromatographed (SiO2 120 g, 5% to 20% EtOAc/Hex) to yield the title compound (906 mg, 72%) 1H NMR (400 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 4.48 (s, 2H), 3.65 (s, 3H), 1.57 (s, 6H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[C:30](F)(F)F)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].COC(C1CN(CC2C=C(C)C3C(=CC=C(O[C@H]4CC[C@H](C(C)(C)C)CC4)C=3)N=2)C1)=O>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH:25]([C:27]([OH:29])=[O:28])[CH2:26]2)[CH:16]=[C:15]3[CH3:30])[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Agent: COC(=O)C1CN(Cc2cc(C)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Product: Cc1cc(CN2CC(C(=O)O)C2)nc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc12

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]azetidine-3-carboxylic acid methyl ester as starting material. ESI-MS(M+H+): 411.30; 1H NMR (400 MHz, METHANOL-d4) Shift 7.97 (d, J=9.29 Hz, 1H), 7.41 (dd, J=2.64, 9.16 Hz, 1H), 7.36 (d, J=2.51 Hz, 1H), 7.27 (s, 1H), 4.73 (s, 2H), 4.45-4.59 (m, 4H), 4.36-4.45 (m, 1H), 3.71-3.86 (m, 1H), 2.69 (s, 3H), 2.28 (d, J=11.29 Hz, 2H), 1.92 (d, J=10.79 Hz, 2H), 1.37-1.52 (m, 2H), 1.19-1.36 (m, 2H), 1.06-1.19 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[O:13][C:12]2[C:7](=[N:8][C:9]([CH3:15])=[CH:10][C:11]=2Cl)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:1]([C:5]1[O:13][C:12]2[C:7](=[N:8][C:9]([CH3:15])=[CH:10][C:11]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2nc(C)cc(Cl)c2o1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCc1cc2nc(C)cc(N3CCCCC3)c2o1
Temperature: 100 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a mixture of 2-butyl-7-chloro-5-methylfurano[3,2-b]pyridine (Example 229 (c)) (329 mg, 1.45 mmol) and piperidine (3 mL, 30.4 mmol) was added a mixture of K2CO3 (0.85 g, 5.8 mmol) in H2O (1 ML). Mixture stirred at 100° C. under N2 for 16 h. After cooling, the reaction mixture was concentrated. The residue was diluted with H2O (70 mL) and Et2O (50 mL). The mixture was transferred to a separatory funnel and the organic solution was collected. The aqueous solution was washed with Et2O (2×40 mL). The organic solutions were combined, washed with H2O (50 mL), saturated NaCl (70 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 50:50 EtOAc:hexanes as elutant to give 310 mg (77%) of 2-butyl-5-methyl-7-piperidylfurano[3,2-b]pyridine as a cream colored solid. This material (310 mg, 1.12 mmol) was dissolved in EtOAc (10 mL) and heated to boiling. To the hot solution was added 1M etheral HCl (1.20 mL, 1.20 mmol). The solution was left to cool to 25° C. The resulting solid was collected by filtration, washed with EtOAc (2×5 mL), Et2O (3×5 mL) and dried under vacuum at 25° C. to give 311 mg (69%) of the title compound as a white colored powder. Mp: 172-173° C. 1H NMR (CDCl3; 400 MHz): δ 0.95 (t, 3, J=7.4), 1.42 (hextet, 2, J=7.3), 1.69 (quintet, 2, J=7.7), 1.79 (br s, 6), 2.71 (s, 3), 2.79 (t, 2, J=7.5), 3.85 (br, 4), 6.29 (s, 1), 7.01 (s, 1), 15.56 (s, 1). MS m/z: 2793 (M+1 for free base). Anal. Calcd for C17H24N2O.HCl.0.5H2O: C, 64.24; H, 8.25; N, 8.82; Cl, 11.15. Found C, 64.42; H, 8.23; N, 8.75; Cl, 11.26.
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:3]=[CH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1>C(O)C.[H][H]>[O:1]=[C:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1
Reactant: CCOC(=O)COc1ccc(C=CC(=O)c2cccnc2)cc1
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)COc1ccc(CCC(=O)c2cccnc2)cc1
Reaction time: 3 h
Yield: 50.3 %

Procedure:
Ethyl 4-[3-oxo-3-(3-pyridyl)-1-propenyl]phenoxyacetate (3.85 g) and 1.15 g of 10% Pd--C were suspended in 300 ml of ethanol, and stirred in hydrogen atmosphere at ambient temperature and pressure for three hours. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with methylene chloride was obtained 1.95 g of ethyl 4-[3-oxo-3-(3-pyridyl)propyl]phenoxyacetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][C:3]=1[C:22](=O)[CH3:23].Cl.O>[Pd].C(O)(=O)C>[CH2:22]([C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:7][C:2]=1[OH:1])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(C(C)=O)c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCc1ccc(O)c(CC)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A mixture of 23 g of 1-(2-hydroxy-5-tetradecylphenyl)ethanone, 5 g of 5% palladium on carbon catalyst, 10 ml of concentrated hydrochloric acid, 100 ml of water and 100 ml of glacial acetic acid was warmed to 50° C. and then hydrogenated in a Parr apparatus for 24 hours. This mixture was filtered, the solvent removed ad the residue dissolved in ether. The ether solution was washed with water, then a small amount of dilute aqueous sodium bicarbonate and dried. The residue was purified by HPLC, giving 16 g of the desired compound, mp 45.5°-46.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18](=[O:26])(=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:13]3[N:12]=[CH:11][C:10]=2[C:27](OCC)=[O:28])=[C:4]([CH3:32])[CH:3]=1.Cl.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH:19][CH2:20][C:21]([F:22])([F:23])[F:24])(=[O:25])=[O:26])=[C:13]3[N:12]=[CH:11][C:10]=2[C:27]([N:44]2[CH2:45][CH2:46][CH:41]([C:38]3[CH:37]=[CH:36][C:35]([F:34])=[CH:40][CH:39]=3)[CH2:42][CH2:43]2)=[O:28])=[C:4]([CH3:32])[CH:3]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NCC(F)(F)F)cnn2c1Nc1ccc(F)cc1C
Agent: Cl
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccc(F)cc3)CC2)cnc2c(S(=O)(=O)NCC(F)(F)F)cnn12
Yield: 15.4 %

Procedure:
Using ethyl 7-(4-fluoro-2-methylphenylamino)-3-[N-(2,2,2-trifluoroethyl)sulfamoyl]pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.142 g, 0.298 mmol) obtained in step 1 and 4-(4-fluorophenyl)piperidine hydrochloride (0.072 g, 0.335 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.028 g, 21%) was obtained.