Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([O:8][CH3:13])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ncc(O)cc1Cl
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ncc(OC)cc1Cl
Temperature: 55 °C
Yield: 71.2 %

Procedure:
In a 1-L flask, methyl 3-chloro-5-hydroxypicolinate (Afferchem, 25.00 g, 133 mmol) and cesium carbonate (87 g, 267 mmol) were suspended in DMF (200 mL) and iodomethane (41.7 mL, 666 mmol) was added dropwise. A water-cooled condenser was attached, and the reaction vessel was heated in a 55° C. oil bath. After 3 h the reaction was concentrated under reduced pressure. The residue was taken up in 1.2 L of 80% EtOAc-hexane and 500 mL brine. The mixture was filtered through Celite. The filtrate was transferred into a separation funnel. The organic layer was separated, washed with brine (100 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 30% to 40% EtOAc-hexane, affording the title compound (19.1 g) as a tan solid. MS m/z=202 (M+H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[N:10]=[N:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH:19]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:25][CH2:20][C:5]1[C:6]2[N:10]=[N:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH:19]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=1
Reactant: C[Si](C)(C)CCOCn1nnc2c(CO)cc(C(F)(F)F)cc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nnc2c(CBr)cc(C(F)(F)F)cc21
Reaction time: 0.5 h

Procedure:
To a solution of (6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)methanol (165 mg, 0.475 mmol) and carbon tetrabromide (236 mg, 0.712 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triphenylphosphine (187 mg, 0.712 mmol). The ice bath was removed and stirring continued at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (4→8% ethyl acetate/hexanes) to give 159 mg (82%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.96 (s, 1H), 7.67 (s, 1H), 6.03 (s, 2H), 5.04 (s, 2H), 3.59 (m, 2H), 0.90 (m, 2H), −0.07 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 145.9, 132.6, 131.6, 130.4 (q, J=33 Hz), 123.7 (q, J=273 Hz), 121.6 (q, J=2.9 Hz), 108.6 (q, J=4.8 Hz), 67.7, 25.9, 17.7, −1.5.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13]Br)=[C:4]([CH2:11]Br)[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8].[NH2:15][C@H:16]([C:20]([OH:22])=[O:21])[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH-].[K+]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]2[C:3]=1[CH2:13][N:15]([CH:16]([CH:17]([CH3:19])[CH3:18])[C:20]([OH:22])=[O:21])[CH2:11]2
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: Fc1c(F)c(F)c(CBr)c(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)C(C(=O)O)N1Cc2c(F)c(F)c(F)c(F)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3,4,5,6-tetrafluoro-1,2-bis(bromomethyl)benzene (3 g, 9 mmol), valine (1 g, 9 mmol), potassium carbonate (2.8 g) and 25 ml THF/HMPT (1:1) is stirred for about 24 hours at RT (the reaction is followed by TLC). The reaction mixture is then diluted with 100 ml aqueous 10% KOH and extracted three times with ether. The aqueous phase is acidified to about pH 3 with aqueous HCl and extracted thoroughly with ether. The organic layer is washed with water, dried and solvent removed under vacuum to give 2-(4,5,6,7-tetrafluoro-2-isoindolinyl)-3-methylbutanoic acid.
Reaction SMILES: [Cl:1]C1C=CC([C:8](=[N:19][NH:20][C:21](OC(C)(C)C)=O)[C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH3:17])[C:13]=3[CH:18]=2)=CC=1.[ClH:28].O>O1CCCC1>[ClH:1].[Cl:28][C:9]1[CH:10]=[CH:11][C:21]([NH:20][NH:19][CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH3:17])[C:13]=3[CH:18]=2)=[CH:13][CH:18]=1
Reactant: Cn1nnc2ccc(C(=NNC(=O)OC(C)(C)C)c3ccc(Cl)cc3)cc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 10 g of intermediate 1-b in 60 ml of tetrahydrofuran under a nitrogen atmosphere were added dropwise over 15 minutes 26 ml of a borane tetrahydrofuran complex in tetrahydrofuran (1M). After stirring for 15 minutes at ±22° C. there were added 13 ml of hydrochloric acid (6N). The whole was heated to reflux and refluxed for 1.5 hours. The mixture was cooled to room temperature and 50 ml of water were added. After stirring for 1 hour, the reaction mixture was filtered. The filtrate was mixed with 75 ml of methylbenzene. The layers were separated and the aqueous layer was basified (pH 7.5-8) with NH4OH. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol by adding 3ml of a mixture of hydrochloric acid in 2-propanol (4.8N). After stirring for 2 hours the product was filtered off, washed with 2-propanol and dried in vacuo at 50° C., yielding 2.1 g of (±)-6-[(4-chlorophenyl)hydrazinomethyl]-1-methyl-1H-benzotriazole monohydrochloride (interm. 2-e).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:20]=[CH:19][C:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=1.[CH2:21]([O:23][C:24]([C:26]1[C@@H:27]2[N:42]([CH3:43])[C@H:31]([CH2:32][C:33]=1OS(C(F)(F)F)(=O)=O)[CH2:30][N:29]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:28]2)=[O:25])[CH3:22].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:23][C:24]([CH:26]1[C:33]([C:7]2[CH:20]=[CH:19][C:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=2)=[CH:32][C@H:31]2[N:42]([CH3:43])[C@@H:27]1[CH2:28][N:29]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:30]2)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)=C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
BuLi (1.6M in hexane, 31.9 mL, 51.0 mmol) was added to a sol. of (4-bromo-phenoxy)-tert-butyl-dimethyl-silane (12.8 g, 44.5 mmol) in THF (150 mL) at −78° C. The mixture was stirred for 60 min at −78° C., and ZnCl2 (1.1M, 50.5 mL, 55.6 mmol) was added. The mixture was allowed to warm to rt, and a sol. of (rac.)-(1R*,5S*)-9-methyl-7-trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (WO 2003/093267; 17.0 g, 37.1 mmol) in THF (10 mL) and Pd(PPh3)4 (1.07 g, 0.927 mmol) were added. The mixture was stirred at 50° C. for 25 min, and was allowed to cool to rt. Aq. sat. NH4Cl was added, and the mixture was extracted with EtOAc (3×). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 6:4) yielded the title compound (15.9 g, 83%). LC-MS: tR=0.95 min, ES+: 517.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[CH2:9]1)=[O:7].[O:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(OCCCl)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.CO>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:48][CH2:47][O:46][CH2:50][CH3:49])[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(C)c(C)c3)C2)cc(OC)c1OC
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOCCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(C)c(C)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine (0.46 g, 0.76 mmol) and tetrahydrofuran (35 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of potassium bis(trimethylsilyl)amide (2.1 mL, 0.5 M in toluene, 1.05 mmol). After 20 minutes, warm to ambient temperature. Add tetrabutylammonium bromide (0.21 g, 0.65 mmol) and 2-chloroethyl ethyl ether (1 mL). Heat to reflux. After 2 days, cool the reaction mixture and dilute with dichloromethane. Extract with water and saturated aqueous solution of sodium chloride. Concentrate the separated organic layer in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 28% methanol/0.7% concentrated aqueous ammonia/ethyl acetate to give the title compound: Rf=0.26 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:19](O)[CH3:20]>>[C:1]([O:7][CH2:19][CH3:20])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCOC(=O)C(C)(C)C
Yield: 77 %

Procedure:
Absolute ethanol (1035 ml) was added to 306 grams of neopentanoic acid (Exxon) in a flask fitted with a heating mantle and a reflux condenser. To this mixture was slowly added 65 ml of concentrated sulfuric acid (Mallinckrodt). The mixture was then heated under reflux for three hours. Heating was discontinued and the hot mixture was extracted with 4 liters of a 10% sodium carbonate solution. The organic layer which separated was collected and dried overnight with magnesium sulfate. It was then filtered and purified by distillation at atmospheric pressure. A low heat was first applied in order to collect a fraction at a temperature of 73° C. consisting principally of ethanol. When the head temperature began to drop, the heat was raised and a second fraction, consisting of ethyl pivalate was collected from 108°-111° C. This pure ethyl pivalate (yield about 77%) was then dried over magnesium sulfate.
Reaction SMILES: BrCC1C=CC2C(=CC=CC=2)C=1.C[O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH:28]([CH2:29][O:30][C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][N:26]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:25][CH:24]2[O:57][CH2:58][C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH:60]=2)=[CH:19][CH:18]=1)=O.[BH4-].[Li+]>>[OH:14][CH2:15][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH:28]([CH2:29][O:30][C:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:27][N:26]([C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[CH2:25][CH:24]2[O:57][CH2:58][C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH:60]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(C2C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)CN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Agent: BrCc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22 (d), from tert-butyl (3RS,4RS,5SR)-1-benzyl-4-(4-bromo-phenyl)-5-hydroxymethyl-piperidin-3-ol [Example 68 (e)] by a palladium catalyzed carbonylation with carbon monoxide in methanol there was obtained methyl (3RS,4RS,5SR)-4-(1-benzyl-3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate, hydrogenolysis of which in the presence of 5% palladium-charcoal at atmospheric pressure in methanol analogously to Example 2 (e) gave methyl 4-(3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate. Subsequent introduction of the BOC group analogously to Example 1 (f) yielded tert-butyl (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylate, from which by reaction with triphenylchloromethane analogously to Example 68 (i) there was obtained tert-butyl (3RS,4RS,5SR)-3-hydroxy-4-(4-methoxycarbonyl-phenyl)-5-trityloxymethyl-piperidine-1-carboxylate. Subsequent alkylation by means of 2-bromomethyl-naphthalene analogously to Example 1 (g) yielded tert-butyl (3RS,4RS,5SR)-4-(4-methoxycarbonyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, reduction of which with lithium borohydride analogously to Example 22 (e) yielded tert-butyl (3RS,4RS,5SR)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate as a colourless foam; MS: 737 (M+NH4)+. Further alkylation with 2-(benzyloxy)-ethyl iodide [Helv.Chim. Acta Vol.71, (1988), 2039] analogously to Example 1 (g) gave tert-butyl (3RS,4RS,5SR)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, from which after cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 629 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]([N:22]1[C:26]([CH:27]=O)=[CH:25][C:24]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([CH2:27][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[CH:25][C:24]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: CC(C)Cc1cc(C=O)n(C(C)(C)C)n1
Product: COc1ccc(N2CCN(CCNCc3cc(CC(C)C)nn3C(C)(C)C)CC2)cc1
Yield: 29.7 %

Procedure:
Compound 41 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 2-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Si:1]([CH:18]([OH:25])[C@H:19]1[O:23][C:22](=[O:24])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si](Cl)(C)(C)C.[C:41]1([Se:47]Br)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.CCOCC>[Si:1]([CH:18]([OH:25])[C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([Se:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@@H]1CCC(=O)O1
Reactant: Br[Se]c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@@H]1C[C@@H]([Se]c2ccccc2)C(=O)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a solution of 4 (5 g, 14.1 mmol) in anhydrous THF (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 15.8 mL, 15.8 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Me3SiCl (1.918 g, 17.65 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After being stirred at room temperature for 30 min, the mixture was cooled to −78° C., and a solution of PhSeBr (5 g, 21.19 mmol) in anhydrous THF (25 mL) was added rapidly. The mixture was diluted with ether (50 mL), washed with water until the color of organic layer changed from dark brown to light yellow, dried (Na2SO4), filtered, and evaporated. The resulting oily residue [containing 3R(α, 5) and 3S(β) isomers; TLC: hexane/EtOAc, 10:1; Rf=0.42 and 0.28, respectively] was purified by flash chromatography on silica gel eluting with hexane/EtOAc (99:1 to 95:5) to give the title compound 5 as a light yellow oil (4.22 g, 59%). 1H NMR (CDCl3) δ 7.69-7.60 (m, 6H, arom.), 7.46-7.30 (m, 9H, arom.), 4.37-4.34 (m, 1H, H-5), 4.12-4.08 (m, 1H, H-3), 3.86-3.82 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.62-3.59 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.73-2.67 (m, 1H, H-4), 2.32-2.28 (m, 1H, H-4), 1.02 (s, 9H, t-Bu).
Reaction SMILES: [CH3:1][N:2](/[CH:4]=[N:5]/[C:6]1[S:7][C:8]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][N:10]=1)[CH3:3].Cl.O1CCOCC1>>[CH3:3][N:2](/[CH:4]=[N:5]/[C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1)[CH3:1]
Reactant: CN(C)/C=N/c1ncc(C(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)/C=N/c1ncc(C(=O)O)s1
Temperature: 75 °C

Procedure:
To tert-butyl 2-{[(1E)-(dimethylamino)methylidene]amino}-1,3-thiazole-5-carboxylate 23-1 (12.3 g, 48.17 mmol) was added 35 mL of 4N HCl/dioxane. This suspension was warmed to 75° C. under nitrogen for 18 hours. The solid was filtered off, washed with dioxane and ethyl ether, and then dried under high vacuum at 45° C. 1H-NMR (DMSO): 8.57 ppm (s, 1H); 8.07 ppm (s, 1H); 3.26 ppm (s, 3H); 3.12 ppm (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:13]([Cl:12])(=[O:15])=[O:14])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
Heat 3-bromo-4-fluorobenzoic acid (6.25 g, 26.2 mmol) in chlorosulfonic acid (15 mL) at 125° C. for 120 h. Cool to room temperature and add dropwise to about 125 mL ice water. Collect the filtered solid as the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.F[C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[C:33]=1[C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:32]4[CH:39]=[CH:38][CH:37]=[C:36]([S:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)[C:33]=4[C:34]#[N:35])=[CH:13][CH:12]=3)[C:3]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(O)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: N#Cc1c(F)cccc1Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5cccc(Sc6ccccn6)c5C#N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (0.300 g, 0.736 mmol) in dimethylformamide (20 mL), was treated with 2-fluoro-6-(2-pyridylsulfanyl)benzonitrile (0.424 g, 1.84 mmol) and potassium carbonate (0.203, 1.47 mmol). The reaction mixture was stirred at 120° C. for 2 h under a nitrogen atmosphere. Ethyl acetate (125 mL) and 1 N sodium hydroxide solution (50 mL) were added to the reaction mixture. The layers were partitioned and the organic layer was washed with 1 N sodium hydroxide solution (300 mL). The organic layer was washed with water and brine (250 mL each), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The solid was triturated with ethyl acetate to yield 0.310 g (68%) of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile. A warm solution of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile (0.310 g, 0.502 mmol) in ethanol was treated with a warm solution maleic acid (0.175 g, 1.503 mmol) in ethanol. A precipitate formed upon cooling and was filtered under a nitrogen atmosphere to give 0.356 g of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile bis-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.47-8.46 (d, 1H, J=4 Hz), 8.26 (s, 1H), 7.79-7.72 (m, 4H), 7.53-7.51 (d, 1H, J=8 Hz), 7.38-7.34 (m, 3H), 7.28-7.24 (m, 2H), 6.14 (s, 4H), 4.85 (m, 1H), 3.60-3.10 (m, 7H), 3.1-2.85 (m, 2H), 2.71-2.67 (m, 2H), 2.32-2.27 (m, 3H), 2.05-1.99 (m, 2H), 1.78-1.71 (m, 4H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.196 min (98%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][C@H:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: C[C@H]1NCCNC1=O
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1C(=O)NCCN1Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and (3R)-3-methyl-2-piperazinone (239 mg, 2.09 mmol, commercially available, for example from Sigma Aldrich, St Louis, USA). The reaction mixture was heated to 120° C. for 20 min.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:14]=[N:13][C:12]([C:15]3[CH:56]=[CH:55][C:18]([CH2:19][C:20]4[N:21]([C:33]5[CH:34]=[C:35]([N:39]6[S:43](=[O:45])(=[O:44])[N:42](COCC[Si](C)(C)C)[C:41](=[O:54])[CH2:40]6)[CH:36]=[CH:37][CH:38]=5)[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=5[Cl:32])[N:24]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([CH2:7][O:8][C:9]2[N:14]=[N:13][C:12]([C:15]3[CH:56]=[CH:55][C:18]([CH2:19][C:20]4[N:21]([C:33]5[CH:34]=[C:35]([N:39]6[S:43](=[O:44])(=[O:45])[NH:42][C:41](=[O:54])[CH2:40]6)[CH:36]=[CH:37][CH:38]=5)[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=5[Cl:32])[N:24]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCC5CCCCC5)nn4)cc3)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCC5CCCCC5)nn4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-[4-(6-Cyclohexylmethoxy-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (17 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{3-[2-[4-(6-cyclohexylmethoxy-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.