Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN=C([C:10]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3N(N)[C:14]=2[CH:13]=[CH:12][C:11]=1[CH2:26][C:27]1C=CC=CC=1)C1C=CC=CC=1.[ClH:33].N1CCC(=O)CC1.S(=O)(=O)(O)O.[NH3:46]>O.C(O)C>[ClH:33].[CH:27]1[N:46]2[C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[CH:18]=[CH:19][C:20]3=[C:10]2[C:11](=[CH:12][CH:13]=[CH:14]3)[CH:26]=1
Reactant: N
Reactant: NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N
Agent: Cl
Agent: O=C1CCNCC1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: C1=Cc2cccc3ccn(c23)-c2ccccc21
Reaction time: 0.67 h

Procedure:
A mixture of 24.6 g of N-aminoiminodibenzyl (5-amino-10,11-dihydro-5H-dibenz[b,f]azepine) and 14.8 g of 4-piperidone hydrochloride in 250 ml. ethanol was heated on a steam bath for 15 minutes 1,2,3,4,4cooled; 8,9,14a-octahydropyridoof 20 g. indoloconcentrated sulfuric acid in 250 ml. ethanol was added. The resulting mixture was reheated on the steam bath for an additional 40 minutes; the solution which formed was cooled, basified with ammonia, and diluted with 1 liter of water. The crude, semisolid material which separated was taken up in ether, and the aqueous mother liquors were extracted with additional portions of ether. The combined ethereal extracts were concentrated to 500 ml. and treated, under an atmosphere of nitrogen and with vigorous stirring, with 50 ml. of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and C (dec). 1N hydrochloric acid, and dried in vacuo at 100° to yield 1,2,3,8,9-hexahydropyrido[4',3':2,3]=indolo[1,7ab][1]benzazepine hydrochloride, m.p. 309°, a salt only very slightly soluble in water. Dissolving the above salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystallizing it from benzene regenerated the free 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine, m.p. 134°-136° C.
Reaction SMILES: [C:1](=[O:3])=[O:2].CC(C)=O.[Si]([N:15]1[C@@H:18]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([CH2:39]O)[C:16]1=[O:41])(C(C)(C)C)(C)C.[Li]CCCC>O1CCCC1>[CH:1]([O:3][CH2:39][C@H:17]1[C@H:18]([S:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:15][C:16]1=[O:41])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CO)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=COC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.42 h
Yield: 60 %

Procedure:
To a cold (dry ice-acetone bath, -78° C.) solution of trans 1-(t-butyldimethylsilyl)-3-hydroxymethyl-4-tritylthio-2-azetidinone (4.89 g, 10 mmol) in tetrahydrofuran (15 ml) was added dropwise 1.6 M n-BuLi (8.2 mmol). The red solution was stirred in a cold bath for 25 min and then treated dropwise with a solution of paranitrobenzylchloroformate (2.6 g, 12 mmol). Stirring was continued for 2 h. The reaction mixture was partitioned between ammonium chloride and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2×10 ml). The organic layers were combined and washed with brine, dried (MgSO4), and evaporated in vacuo. The residual oil was chromatographed on a silica gel column (70 g). Elution with benzene gave the title compound 4.0 g (60%) as an amorphous solid. ir νmax (CDCl3) 1750, 1610 cm-1 1 Hmr (CDCl3) δ: 8.40 (2H, d, J=9), 7.45 (17H, m), 5.22 (2H, s, benzyl), 4.4 (1H, d, J=1.5, H-4), 4.05 (1H, dd, J=14, J=4.5, H-1'), 3.28 (1H, m, H-3), 3.18 (1H, dd, J=14, J=4, H=1'), 0.95 (9H, s, t-Bu) and 0.32 ppm (6H, s, CH3).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>CS(C)=O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:9]([N:11]([CH2:12][CH3:13])[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH3:10]
Reactant: CCNCC
Reactant: O=Cc1ccc(Br)o1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: CS(C)=O
Product: CCN(CC)c1ccc(C=O)o1
Yield: 85 %

Procedure:
5-Bromofuraldehyde was dissolved in dimethylsulfoxide (DMSO) and 1-2 drops of Aliquart 336 (tricaprylylmethylammonium chloride, produced by Aldrich Co.) was added to the solution. 10 Equivalents diethylamine was added to the mixture and refluxed for 4 days. The remaining diethylamine was removed from the reaction mixture and subjected to extraction and column chromatography to obtain 5-diethylamino-2-furaldehyde with a yield of 85%.
Reaction SMILES: C(OC([C:6]1[S:7][C:8]([NH:11][C:12](=[O:43])[C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH:39]4[CH2:41][CH2:40]4)[CH2:31][CH2:30]3)=[O:28])=[CH:15][C:14]=2[Cl:42])=[N:9][N:10]=1)=O)C.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:42][C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[C:27]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH:39]3[CH2:40][CH2:41]3)[CH2:31][CH2:30]2)=[O:28])[C:17]([Cl:19])=[CH:18][C:13]=1[C:12]([NH:11][C:8]1[S:7][CH:6]=[N:10][N:9]=1)=[O:43]
Reactant: CCOC(=O)c1nnc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1nncs1)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 0.10 g (0.16 mmol) 5-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (Example 47) in 1 mL dioxane were added 1 mL water and 0.008 g (0.19 mmol) lithiumhydroxide monohydrate. The resulting suspension was stirred for 2 hours at room temperature and then at 80° C. for 5.5 hours. Another 0.001 g (0.024 mmol) lithiumhydroxide monohydrate was added and the reaction mixture was heated for another 1.5 hours at 80° C. After stirring at room temperature for 64 hours the reaction mixture was poured on 1M aqueous hydrochloric acid and ethyl acetate and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in N,N-dimethylformamide, filtered over a syringe microfilter and purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 0.030 g (33%) of the product as a light yellow solid. MS (ESI): m/z=567.08 [M+H]+.
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:10][CH2:9]1.Cl[S:26](O)(=[O:28])=[O:27]>ClCCl>[NH2:14][CH:11]1[CH2:10][CH2:9][N:8]([S:26]([NH:3][CH3:6])(=[O:28])=[O:27])[CH2:13][CH2:12]1
Reactant: O=S(=O)(O)Cl
Reactant: CCN(CC)CC
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Solvent: ClCCl
Product: CNS(=O)(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (1.5 mL) was added to a dichloromethane (30 mL) solution of Benzyl piperidin-4-ylcarbamate (580 mg) at 0° C. followed by the dropwise addition of chlorosulfonic acid (290 μL; TCI), the resulting mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. Benzene (32 mL) and phosphorus pentachloride (0.7 g; WAKO) were added to this residue and the resulting mixture was stirred at 80° C. for 1.5 hours. The reaction mixture solution was cooled to room temperature followed by the addition of 1 N aqueous sodium hydroxide solution (10 mL), the resulting mixture was extracted with dichloromethane, the organic layer was dried, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; hexane/ethyl acetate). 30 mg of this purified compound was dissolved in dichloromethane (0.4 mL) followed by the addition of 3,5-lutidine (0.4 mL; WAKO) and methylamine (2 M, 70 μL; Ald) and the resulting mixture was stirred at room temperature for 24 hours. 1 N hydrochloric acid (2 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with dichloromethane, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The title compound was obtained from this residue according to the method described in Step c of Reference Example N-14.
Reaction SMILES: S(O[C@H:6]1[C@@H:10]([CH2:11][O:12][C:13]([O:15][CH3:16])=[O:14])[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C)C=O>[N:26]([C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13]([O:15][CH3:16])=[O:14])[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A mixture of 1-[2-deoxy-3-O-mesyl-5-O-methoxycarbonyl-β-D-threopentofuranosyl]-thymine (5.0 g, 13.2 mmoles) from Example A13 and sodium azide (1.07 g, 16.5 mmoles) in dimethylformamide (40 mL) was heated at 85°-90° C. for 4 h. The suspension was cooled to ambient temperature poured into 300 mL of water and the aqueous solution extracted with 3×100 mL portions of ethyl acetate. The combined organic extracts were washed with 2×100 mL portions of water and concentrated by rotary evaporation affording 3.88 g (90.2%) of 3'-azido-3'-deoxy-5'-O-(methoxycarbonyl)thymidine as a colorless oil: 1H NMR (CDCl3) δ1.91 (d, J=1.15 Hz, 3H, C-5-CH3), 2.30-2.49 (m, 2H, C-2'H), 3.83 (s, 3H, CO2CH3), 3.97-4.44 (m, 4H, C-3'H, C-4'H and C-5'H), 6.21 (t, J=6.26 Hz, 1H, C-1'H), 7.29 (q, J=1.15 Hz, 1H, C-6H) and 8.75 (broad, 1H, NH); 13C NMR (CDCl3) δ12.42, 37.57, 55.28, 60.04, 66.39, 81.56, 84.94, 111.38, 135.28, 150.45, 155.18 and 164.03; TLC, Rf =0.78, silica gel, CHCl3 :CH3OH/90:10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[O:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2([OH:27])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C2(O)CCOCC2)cc1
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of tert-butyl(4-bromophenyl)carbamate (1.5 g) in tetrahydrofuran (30 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 7.2 mL) at −78° C. under nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hr. Dihydro-2H-pyran-4(3H)-one (0.58 g) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (590 mg).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4ccccc4)ccc32)n1)c1ccccc1
Yield: 52.9 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and benzoyl chloride (14 mg 0.10 mmol) furnished the product (23 mg, 53%) after chromatography.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3](O)=O.[NH2:14][C:15]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.Cl.[NH2:48]CCC(OCC)=O>N1C=CC=CC=1>[Cl:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:16]2[C:15]=1[N:14]=[C:3]([C:2]([F:13])([F:1])[C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[N:48]=[C:17]2[OH:18]
Reactant: CCOC(=O)CCN
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: O=C(O)C(F)(F)c1ncc(F)cn1
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: Oc1nc(C(F)(F)c2ncc(F)cn2)nc2c(Cl)cccc12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetic acid (700 mg, 3.64 mmol) and 2-amino-3-chlorobenzoic acid (625 mg, 3.64 mmol) in pyridine (10 mL) was added triphenyl phosphite (1.05 mL, 4 mmol) and the mixture heated in a microwave synthesizer at 150° C. for 10 min. The mixture was allowed to cool to rt and then ethyl 3-aminopropanoate hydrochloride (615 mg, 4 mmol) was added. The mixture was heated in a microwave synthesizer at 190° C. for 4 min, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and 4 N HCl, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added THF (10 mL) followed by sodium ethoxide (21% in EtOH, 1 mL) and the mixture was stirred at 65° C. for 0.5 h. An additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added and the mixture was stirred at 60° C. for 30 min. The mixture was allowed to cool to rt, and then partitioned between EtOAc and 4 N HCl. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with hexanes and Et2O, and the solid was collected by filtration to afford 8-chloro-2-(difluoro(5-fluoropyrimidin-2-yl)methyl)quinazolin-4-ol (420 mg, 35%) as a tan solid. LC-MS (ESI) m/z 327 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O>CO.C(O)=O>[O:13]([C:3]1[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1/[N:1]=[CH:20]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N)c(O)c(C(C)(C)C)c1
Reactant: O=Cc1ccccn1
Solvent: CO
Solvent: O=CO
Product: Cc1cc(/N=C/c2ccccn2)c(Oc2ccccc2)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a slurry of 2-amino-4-methyl-6-tertbutylphenol (0.70 g, 3.90 mmol) in 5 mL methanol, a methanol solution of pyridine-2-carbaldehyde (0.418 g, 3.90 mmol) was slowly added, forming a dark orange solution. Two drops formic acid were added, quickly forming a yellow precipitate. This was stirred for 2 hr, then collected on a frit, washed with cold methanol and dried under vacuum to yield 0.72 g of 12 (69%).
Reaction SMILES: [CH2:1]([O:3][NH2:4])[CH3:2].Cl.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:20])[S:12](=[O:19])(=[O:18])[CH2:13][C:14](=O)[C:15]=2[N:16]=1>CCO.C([O-])([O-])=O.[K+].[K+]>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:20])[S:12](=[O:18])(=[O:19])[CH2:13][C:14](=[N:4][O:3][CH2:1][CH3:2])[C:15]=2[N:16]=1
Reactant: CCON
Reactant: CN1c2ccc(Br)nc2C(=O)CS1(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCON=C1CS(=O)(=O)N(C)c2ccc(Br)nc21
Reaction time: 0.33 h

Procedure:
To a suspension of EtONH2.HCl (171 mg, 2.06 mmol) in EtOH (5 ml) was added K2CO3 (288 mg, 2.06 mmol) and stirring was continued for 20 min at ambient temperature. A solution of 6-bromo-1-methyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-one (500 mg, 1.72 mmol) in EtOH (5 ml) was added and stirring was continued for 12 h affording a milky suspension. Since the conversion was not complete, the same amount of EtONH2.HCl in EtOH and K2CO3 were separately mixed and added to the reaction mixture affording after 60 min full conversion. The mixture was concentrated under reduced pressure followed by addition of water and ethyl acetate then the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate/heptane, gradient, afforded 6-bromo-N-ethoxy-1-methyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-imine as a yellow solid and a single isomer.
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C[Al](C)C.[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20](OCC)=[O:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:2][C:1]([NH:10][C:20]([C:16]1[S:15][CH:19]=[CH:18][N:17]=1)=[O:21])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)c1nccs1
Reactant: CC(C)(N)c1ccccc1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(NC(=O)c1nccs1)c1ccccc1
Yield: 67.1 %

Procedure:
7.13 ml (50.0 mmol) of cumylamine and 156 ml of toluene are placed in a 1-liter three-necked flask with stirring and under an inert atmosphere. 24.8 ml (49.6 mmol) of trimethylaluminium are then added dropwise, and white fumes are evolved. After waiting until the medium has clarified, a solution of 3.9 g (24.8 mmol) of ethyl 2-thiazolecarboxylate (2) in 195 ml of toluene is added. The mixture is stirred for 15 minutes and then refluxed. After heating for 15 hours, the reaction medium is poured into 300 ml of 1M citric acid solution diluted with 200 ml of water and the whole is filtered through Celite®. The Celite® is washed with 100 ml of ethyl acetate and the aqueous phase is extracted with twice 100 ml of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, and after evaporating under reduced pressure, the residue is purified by flash chromatography (msilica=200 g; eluent: dichloromethane). 4.1 g of N-(1-methyl-1-phenylethyl)thiazole-2-carboxamide are obtained in the form of a brick-red solid. Rf(dichloromethane)=0.4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])([O:19][CH2:20][CH3:21])[CH2:15][CH:14]=1)=O)([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([O:8][CH2:9][CH2:10][NH:12][C:13]2[CH:14]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])([O:19][CH2:20][CH3:21])[CH2:17][CH:18]=2)[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1([N+](=O)[O-])C=CC(NC(=O)COc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=CC1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC1([N+](=O)[O-])C=CC(NCCOc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=CC1

Procedure:
1.92 g (4.5 mmole) of 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-N-(4-nitrophenetyl)acetamide (synthesis intermediate of compound 47) is introduced into 80 ml of anhydrous THF in a flask, under an argon atmosphere. A solution of 13.45 ml (13.45 mmole) of BH3 in THF is added to the reaction mixture and the mixture is agitated while heating at reflux for 4 hours 30 minutes. At the end of the reaction, 10 ml of MeOH is added and heating is maintained for a further 30 minutes. The reaction mixture is then concentrated under vacuum, the residue is taken up in 30 ml of a MeOH/HCl 3N mixture (2/1) and the mixture is taken to reflux for another hour. The reaction mixture is returned to 22° C., diluted with 50 ml of CH2Cl2 and 2M aqueous soda is added until a basic pH is obtained. After decantation, the organic phase is washed successively with 20 ml of water and 20 ml of brine, dried over sodium sulphate, filtered and concentrated under vacuum. The expected product is purified by chromatography on a silica column (eluent: CH2Cl2/EtOH: 25/1). Pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:6]2=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[CH:13]=[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=[CH:10][C:9]=1[NH:8]2.[OH2:28].C[N+]1([O-])CC[O:33]CC1.OS([O-])=O.[Na+]>C(O)(C)(C)C.O1CCCC1.O.CC(O)(C)C.[Os](=O)(=O)(=O)=O>[OH:28][CH:23]1[C:24]([CH3:27])([CH3:26])[O:25][C:5]2[C:6](=[C:7]3[C:16](=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15](=[O:17])[C:14]2[CH:13]=[C:12]4[CH:18]=[CH:19][CH:20]=[CH:21][C:11]4=[CH:10][C:9]=2[NH:8]3)[C:22]1=[O:33]
Reactant: COc1cc2c(c3[nH]c4cc5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1cc2c(c3[nH]c4cc5ccccc5cc4c(=O)c13)C(=O)C(O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1.33 mmol of the compound obtained in Step 2 in 30 ml of a 10/3/1 mixture of tert-butanol/tetrahydrofuran/water there are added osmium tetroxide in the form of a 2.5% solution in 0.67 ml of 2-methyl-2-propanol and 1.35 mmol of 4-methylmorpholine-N-oxide monohydrate. After stirring for two days at ambient temperature, NaHSO3 solution is added. After stirring for one hour, the reaction mixture is extracted with dichloromethane. The organic phase is dried, filtered and then evaporated under reduced pressure. Chromatography of the residue over silica gel (dichloromethane/methanol: 98/2) allows the expected product to be isolated.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH:11]([C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]2)[C:14]=1[Cl:30])[CH3:12])(=O)C.O>O1CCCC1>[C:26]([C@@H:23]1[CH2:22][CH2:21][C@H:20]([NH:19][C:15]2[C:14]([Cl:30])=[C:13]([CH:11]([OH:10])[CH3:12])[N:18]=[CH:17][N:16]=2)[CH2:25][CH2:24]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(=O)OC(C)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Reaction time: 8 h

Procedure:
1.5 g (40 mmol) of lithium aluminum hydride were placed in 100 ml of dry tetrahydrofuran, and a solution of 14 g (40 mmol) of 6-(1-acetoxyethyl)-4-(cis-4-tert-butylcyclohexylamino)-5-chloropyrimidine (Example 30) in 50 ml of dry tetrahydrofuran was added dropwise at a temperature of 20° to 30° C. The mixture was then heated at reflux for 2 hours. After cooling, 5 ml of water were added carefully dropwise and, after standing overnight, the mixture was filtered with suction to remove the inorganic material. The filtrate was concentrated and the residue was chromatographed on silica gel (ethyl acetate/methanol 9:1) to give 6.0 g (48.1% of theory) of a colorless oil.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O)(=[O:10])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(=O)ON=NOC(=O)OCC)C>C1COCC1>[CH:1]1([O:7][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:8](=[O:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(=O)Nc1ccccc1O
Reactant: OC1C=CCCC1
Agent: CCOC(=O)ON=NOC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1OC1C=CCCC1
Yield: 19.4 %

Procedure:
2-Cyclohexenol (491 mg, 0.49 ml, 5.00 mmol, 1.0 equiv.), 2-acetamidophenol (756 mg, 5.00 mmol, 1.0 equiv.) and triphenylphosphine (1.44 g, 5.50 mmol, 1.1 equiv.) were dissolved in THF (10 ml) and kept at ambient temperature by a water bath. After dropwise addition of diethyl azodicarbonic acid (871 mg, 0.78 ml, 5.00 mmol, 1.0 equiv.), dissolved in THF (3 ml), the reaction mixture was stirred over night. Extractive work-up and flash chromatography on silica gel (heptane/tertbutyl(methyl)ether=1:1) afforded 224 mg (19%) the title compound as a yellow oil.