Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=4[Cl:47])[C:38]([CH3:48])=[C:37]([OH:49])[C:36]3=[O:50])=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:28]1[C:29]2[CH:34]=[C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=4[Cl:47])[C:38]([CH3:48])=[C:37]([O:49][CH3:3])[C:36]3=[O:50])[CH:32]=[CH:31][C:30]=2[N:26]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(c2cccc(Cl)c2Cl)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (9.0 g,160.71 mmol in water), diazald (24 g, 112.02 mmol), ethylene glycol/Et2O (2/1 v/v, 140 mL), 1-(1H-benzo[d]imidazol-5-yl)-5-(2,3-dichlorophenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (3 g, 8.04 mmol, 1 eq) and MeOH (50 mL); yield: 1.2 g (38.46%); MS m/z: 388.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.44 (s, 1H), 8.16 (d, 1H), 7.64 (d, 1H), 7.54-7.40 (m, 2H), 7.32-7.18 (m, 3H), 7.08 (t, 1H), 6.31 (s, 1H), 3.96 (s, 3H), 1.73 (s, 3H); HPLC (METHOD [A]): rt 13.75 min (99.4%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[O:6][CH:7]([OH:9])[CH3:8])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[O:6][CH:7]([OH:9])[CH3:8])[CH3:2].[CH3:14][S:15]([O-:17])(=[O:3])=[O:16]
Reactant: CS(=O)(=O)Cl
Agent: CCOc1ccccc1OC(C)O
Solvent: c1ccncc1
Product: CS(=O)(=O)[O-]
Temperature: -2.5 °C
Reaction time: 3.5 h

Procedure:
50.0 g (0.28 mol) o-ethoxyphenoxyethanol and 197 g pyridine are added into a reaction flask, stirred until they are fully dissolved, and then cooled to −5 to 0° C. During stirring, 53.1 g (0.46 mol) methyl sulfonyl chloride is added gradually into the flask at a temperature controlled at −5 to 0° C. After addition, the reaction lasts for 3 to 4 hours at a temperature of 0 to 5° C. After the reaction is complete, the reacting solution is added gradually into 350 ml ice water under stirring at a temperature controlled at 0 to 5° C. to isolate gradually white solids, which are then filtered, and the filter cake is rinsed three times with 150 ml water until there is no smell of pyridine, and then dried to obtain 61.9 g title compound. Yield: 85.0%; purity: 99.83% (HPLC).
Reaction SMILES: Br[CH:2]([CH:4]1[O:8][CH2:7][CH2:6][O:5]1)[CH3:3].[OH-].[Na+].[CH3:11][NH2:12]>>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH:2]([NH:12][CH3:11])[CH3:3]
Reactant: CC(Br)C1OCCO1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CNC(C)C1OCCO1
Temperature: 100 °C

Procedure:
2-(1-Bromoethyl)-1,3-dioxolane (60 grams) and 40% aqueous methylamine (160 ml) were charged into a pressure vessel and heated, with agitation, for a period of about 16 hours at a temperature of about 100° C. under autogeneous pressure. At the end of this period, the reaction mixture was cooled to room temperature and 16 grams of NaOH added. The resulting mixture was then extracted with methylene chloride. The extract was dried, then stripped of methylene chloride by use of a rotary evaporator. The residue was distilled to yield the desired product N-[1-(1,3-dioxolan-2-yl)ethyl]methylamine as a fraction boiling at 60° C.-65° C. at about 12 mm Hg pressure.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22](Br)([CH3:24])[CH3:23]>>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][C:22]([O:18][N:13]2[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:12]2([CH3:20])[CH3:19])([CH3:24])[CH3:23])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Br)Br
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: CC(C)(ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C

Procedure:
The title compound is prepared from 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 2,2-dibromopropane according to the procedure of Example 30A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.[CH3:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1.C(Cl)Cl>C(O)CCC>[Cl:18][C:15]1[N:16]=[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)[C:12]([CH3:11])=[CH:13][N:14]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCCCO
Product: Cc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.9 %

Procedure:
3,4-Dichloroaniline (639 mg, 3.94 mmol) and concentrated hydrochloric acid (ca. 12M, 0.2 ml, ca. 2.4 mmol) were sequentially added to a solution of 5-methyl-2,4-dichloropyrimidine (643 mg, 3.94 mmol) in n-butanol (20 ml). The mixture was stirred at ambient temperature for 20 hours, after which time a gelatinous precipitate had fallen out of solution. DCM was added until a solution was obtained, and silica (2.5 g) was added. Volatile material was removed by evaporation and the residue was loaded on a Varian Mega Bond Elut column pre-conditioned with ethyl acetate. The column was eluted with 0-10% methanol solution in ethyl acetate containing 0.5% aqueous ammonia. The appropriate fractions were concentrated, and the residue was triturated with n-butanol (20 ml). The filtrate was evaporated onto silica (2.5 g) and loaded on a Varian Mega Bond Elut column pre-conditioned with isohexane. The column was eluted with 0-50% ethyl acetate solution in isohexane. Concentration of the appropriate fractions gave the product as a white solid (340 mg, 26%). NMR: 2.17 (s, 3H), 7.60 (d, 1H), 7.70 (dd, 1H), 8.00 (d, 1H), 8.11 (s, 1H), 8.97 (s, 1H); MS (MH+): 288.1, 290.1, 292.1.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([CH2:16][C:17]#[C:18][Si](C)(C)C)[C@H:10]1/[CH:23]=[CH:24]/[C@@H:25]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O-].[Na+].[Cl-].[NH4+]>CO>[Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([CH2:16][C:17]#[CH:18])[C@H:10]1/[CH:23]=[CH:24]/[C@@H:25]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:34])[CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H](CC#C[Si](C)(C)C)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: C#CC[C@@H]1[C@@H](CO)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
6.40 g (110 mmoles) of (1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(3-trimethylsilyl-2-propynyl)cyclopentane (31) was taken into a 1-liter eggplant-shaped flask, and dissolved by adding 500 ml of methanol. Then, 106.3 g of a 28% methanol solution of sodium methylate was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution (300 ml) was added, and the mixture was extracted twice with ethyl acetate. The organic layer was successively washed with saturated aqueous potassium hydrogensulfate solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 53.9 g (yield 96%) of (1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(2-propynyl)cyclopentane (32) from eluates obtained with 10% ethyl acetate/n-hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:28][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[N:4][C:5]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:27])=[CH:22][CH:21]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc(F)cc1
Product: CC(NC(=O)c1cc(F)cnc1Oc1ccc(F)cc1)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 2 of Example 1) and [1-(4-bromophenyl)ethyl]amine: 1H-NMR (CDCl3) δ 8.31 (1H, ddd, J=8.2, 3.1, 0.9 Hz), 8.14 (1H, d, J=7.2 Hz), 8.03 (1H, dd, J=3.1, 1.1 Hz), 7.45 (2H, dd, J=7.0, 0.9 Hz), 7.25–7.09 (6H, m), 5.28 (1H, dq, J=7.2, 7.0 Hz), 1.57 (3H, d, J=7.0 Hz); MS (ESI) m/z 433 (M+H)+, 431 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:50])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.C(C(O)=[O:73])(F)(F)F.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([CH3:50])[C:5]2[CH2:11][CH:10]([OH:73])[C:9](=[O:12])[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:18][CH:19]=3)[C:6]=2[N:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(C)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(=O)CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(C)c2c(n1)N(Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(=O)C(O)C2
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
To a cooled (-78° C.) solution of 2,4-dimethyl-8-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (1.57 g, 2.41 mmol) in THF (5 mL) was added 0.5M potassium hexamethyldisilazide in toluene (5.5 mL, 2.75 mmol). After 45 min, a solution of (+)-camphorsulfonyloxaziridine in THF (5 mL) was added. The mixture was allowed to warm to 5° C. over 5 h. Water (2 mL) and CF3CO2H (2 mL) were added and stirring was continued for 1 h. 1N NaOH (30 mL) was added and the mixture was extracted with EtOAc (discarded). The aqueous phase was acidified to pH 4 with 1N HCl and extracted with CHCl3. The extracts were dried MgSO4) and concentrated. Purification by flash chromatography (5-10% MeOH/CHCl3) gave 377 mg of a yellow oil. Crystallization from acetone yielded 234 mg (23%) of product as an off-white solid, mp 154°-156° C.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[O:4]1.[NH2:18][CH2:19][CH2:20][OH:21]>>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C@H:5]2[O:4][C@@H:3]([CH2:2][NH:18][CH2:19][CH2:20][OH:21])[CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: FC(F)(F)c1cccc([C@@H]2CC[C@H](CBr)O2)c1
Product: OCCNC[C@H]1CC[C@@H](c2cccc(C(F)(F)F)c2)O1

Procedure:
2-[({cis-5-[3-(Trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)amino]ethanol was prepared via reaction of cis-2-(bromomethyl)-5-[3-(trifluoromethyl)phenyl]tetrahydrofuran (see H. Ebel et al., PCT Int. Appl., 2010070032, Jun. 24, 2010) with 2-aminoethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=O.C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[C:3]([O:13][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OCc2ccccc2F)c1Cl
Yield: 113.5 %

Procedure:
A solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 3.2 g (0.02 mole) 2-fluorobenzoyl chloride, and 2.0 g (0.02 mole) triethylamine in 100 ml diethyl ether was refluxed for 17 hours. After removal of triethylamine hydrochloride by filtration, the filtrate was concentrated in-vacuo to leave 8.4 g of residue, which, after recrystallization from ligroin, gave 4.6 g (59% yield) of pure product; m.p. 101° C.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[SH:19].[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:8][C:6]1[CH:7]=[C:2]([S:19][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][N:13]=2)[CH:3]=[C:4]([CH3:12])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: Sc1cnccn1
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Sc2cnccn2)cc1C
Yield: 25 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (4-2, 3.20 g, 11.7 mmol), pyrazine-2-thiol (11-1, 1.96 g, 17.5 mmol), copper(I) oxide (83.5 mg, 0.6 mmol), and potassium hydroxide (1.64 g, 29.2 mmol) in DMF (9.6 mL) and H2O (2.4 mL) was heated at reflux for 24 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×50 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)ethanone (11-3, 755.2 mg) as yellow oil in 25% yield: 1H NMR (500 MHz, CDCl3) δ 8.47 (s, 1 H), 8.27 (s, 1 H), 8.22 (s, 1 H), 7.28 (s, 2 H), 2.51 (s, 3 H), 2.28 (s, 6 H); ESI-MS: m/z 259.3 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.C([Sn](CCCCC)(CCCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC.[Li+].[Cl-]>[Cu]I.O1CCOCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: CCCCC[Sn](CCCC)(CCCCC)c1ccccn1
Reactant: Ic1n[nH]c2cnc(-c3cccnc3)cc12
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: c1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)nc1
Temperature: 140 °C
Yield: 10.9 %

Procedure:
To a microwave tube was added 3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4 (120 mg, 0.37 mmol), 2-(butyldipentylstannyl)pyridine (168 mg, 0.45 mmol), Pd(PPh)3 (12 mg, 0.015 mmol), LiCl (48 mg, 1.14 mmol), CuI (12 mg, 0.06 mmol) and 1,4-dioxane (0.3 mL). The tube was flushed with nitrogen for 2 minutes and heated in a Biotage microwave at 140° C. for 15 minutes. The solvent was distilled off and the crude product was purified via reverse phase combiflash eluting with 10% to 80% CH3CN in aqueous 0.5% NH4OH solution to afford 204 as a pale red solid (11 mg, 11%). 1H NMR (400 MHz, DMSO) 1H NMR (500 MHz, DMSO) δ 14.0 (s, 1H), 9.30 (s, 1H), 9.25 (s, 1H), 8.97 (s, 1H), 8.81 (d, J=4.0 Hz, 1H), 8.62-8.61 (m, 1H), 8.45 (d, J=8.5 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.97-7.94 (m, 1H), 7.55-7.53 (m, 1H), 7.45-7.43 (m, 1H). ESI MS m/z=274 (M+1)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]3)=[CH:26][CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CO>[NH2:15][C:4]1[N:3]=[C:2]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]3)=[CH:26][CH:25]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)nc(N)n2)CC1
Temperature: 110 °C
Yield: 74.9 %

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.10 g, 0.44 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.16 g, 0.44 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (1:1) complex (0.02 g, 0.02 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in 1,4-dioxane (3 mL), and water (1 mL) was heated at 110° C. overnight. After cooled to r.t., the mixture was diluted with MeOH, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 10% MeOH in dichloromethane (DCM) to afford the desired product (0.14 g, yield: 75%). Analytic LCMS (M+H)+: m/z=425.4.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH3:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccccc1F)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
A mixture of methyl 4-(1-(2-fluorophenoxy)ethyl)benzoate (0.45 g, 1.6 mmol), lithium hydroxide monohydrate (0.57 g, 13.6 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was turned to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 4-(1-(2-fluorophenoxy)ethyl)benzoic acid (0.31 g, 74%).
Reaction SMILES: [CH2:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:6][CH:7]1[CH2:9][O:8]1)[C:4]#[N:5])[CH3:2].[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[CH2:1]([C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4](=[NH:5])[O:8][CH:7]([CH2:9][NH:19][CH:16]([CH3:18])[CH3:17])[CH2:6]1)[CH3:2]
Reactant: CCC(C#N)(CC1CO1)c1ccccc1
Reactant: CC(C)N
Solvent: CCO
Product: CCC1(c2ccccc2)CC(CNC(C)C)OC1=N

Procedure:
A solution of α-ethyl-α-phenyloxiranepropanenitrile and isopropylamine in ethanol is placed in a pressure bottle and heated overnight in a steam bath. After cooling, the bottle is opened and the solvent removed in vacuo. Solvent-solvent extraction by the method described in Example 4 yields the title compound.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](O)(=[O:23])[C:20]([CH3:22])=[CH2:21].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:21][CH:20]1[C:19](=[O:23])[C:9]2[S:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:10]=2[CH2:22]1
Reactant: Cc1ccccc1-c1ccsc1-c1ccccc1
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1ccccc1-c1c(-c2ccccc2)sc2c1CC(C)C2=O
Reaction time: 0.08 h
Yield: 96.4 %

Procedure:
A mixture of 31.8 g of 2-phenyl-3-o-tolyl-thiophene (0.127 mol) and 13.3 ml of methacrylic acid (0.157 mol) was added within 30 minutes at about 80° C. to 500 ml of Eaton's reagent. On completion of the addition, the reaction mixture was stirred for a further 5 minutes and then gradually added to crushed ice. 300 ml of dichloromethane were added to dissolve the reaction product. The organic phase was removed, washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over magnesium sulfate. After removing the solvent, 39 g of product (3) were obtained which, according to GC-MS, constituted a single, isomer and had a purity of 95%.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][C:15](S(C)(=O)=O)=[N:16][C:17]=2[O:19][CH2:20][C@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)[NH:12][N:11]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[OH:40]>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][C:15]([O:40][C:34]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=3[F:32])=[N:16][C:17]=2[O:19][CH2:20][C@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)[NH:12][N:11]=1
Reactant: CC1(C)OC[C@H](COc2nc(S(C)(=O)=O)nc3[nH]nc(-c4ccccc4Cl)c23)O1
Reactant: Oc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Product: CC1(C)OC[C@H](COc2nc(Oc3ccc(F)cc3F)nc3[nH]nc(-c4ccccc4Cl)c23)O1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Powdered KOH (1.0 g) was taken up in 4 mL of 2,4-difluorophenol, and the resulting mixture was heated at 120° C. for 15 minutes. (S)-3-(2-Chloro-phenyl)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methylsulfonyl-1H-pyrazolo[3,4-d]pyrimidine (1.34 g, 0.305 mmol) was added, and the reaction mixture was stirred for one hour at 120° C. The reaction mixture was cooled to room temperature, partitioned between water (100 mL) and 15 EtOAc (300 mL0, and the layers were separated. The organic layer was washed three times with 2N aqueous NaOH, once with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative scale TLC (50% MeOH in methylene chloride to provide 1.395 mg of (S)-3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=489. Mp.=70.1-75.9° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][C:37](=[O:38])[NH2:39])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)O)cc2)c1
Reaction time: 48 h

Procedure:
To a mixture of methyl 4-[3-(2-benzyloxy-5-hydroxyphenyl)propyl]benzoate (510 mg) and potassium carbonate in DMF (10 ml) was added bromoacetamide (384 mg). The reaction was stirred for 48 hours, poured into ethyl acetate (50 ml), washed with 1M HCl (50 ml) and brine (50 ml), dried (magnesium sulphate) filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using ethyl acetate:hexane (75:25) as eluant. There was thus obtained methyl 4-[3-(2-benzyloxy-5-(carbamoylmethoxy)phenyl)propyl]benzoate (200 mg).
Reaction SMILES: OS(O)(=O)=O.[O:6]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:19].[CH3:20][OH:21]>>[CH3:20][O:21][C:18](=[O:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][OH:19]
Reactant: O=C1CCCCCCCCCCCO1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCCCO
Reaction time: 24 h
Yield: 88 %

Procedure:
Concentrated H2SO4 (0.2 mL) was added to a solution of oxacyclotridecan-2-one (850 mg, 4.3 mmol) in 20 mL of methanol and stirred for 1 day. Methanol was removed under reduced pressure and the aqueous residue was extracted with diethyl ether 3 times. The combined organic layers were washed with saturated NaHCO3, saturated NaCl, and then dried over MgSO4. The diethyl ether was removed under reduced pressure to yield 874 mg (88%) of 14c as a white solid. 1H-NMR (400 MHz, CDCl3, δH ppm): 3.65 (3H, s, CO2CH3), 3.63 (2H, t, 3JH—H=6.6 Hz, HO—CH2), 2.29 (2H, t, 3JH—H=7.6 Hz, CH2CO2), 1.50-1.66 (4H, m, 2CH2), 1.22-1.38 (14H, m, 7CH2). HRMS (EI): m/z calcd 231.1955 ([M+H]+, C13H27O3), found 231.1954 [M+H]+.