Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 210 mg, 68%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-methylphenyl)boronic acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow oil (yield 210 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:4]=1[C:5]#[N:6]>C(O)C.O.NN.[Ni]>[CH3:1][O:2][C:3]1[C:4]([CH2:5][NH2:6])=[C:7]([C:12]([F:15])([F:13])[F:14])[CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: COc1nc(C)cc(C(F)(F)F)c1C#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1nc(C)cc(C(F)(F)F)c1CN
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a solution of 2-methoxy-6-methyl-4-(trifluoromethyl)nicotinonitrile (0.6 g, 2.7 mmol) in ethanol (50 mL) was added the suspension of raney-Ni in water (1 mL) and hydrazine (5 mL). After stirring at 60° C. for 3 hours, the mixture was filtered and concentrated to give a residue. The residue was purified by chromatography (dichloromethane/methanol=10:1) to give (2-methoxy-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methanamine (0.47 g, 77%) and used directly in next step without further purification. LRMS (M+H) m/z: calcd 220.08. found 220.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[CH2:49][OH:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[CH:49]=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Yield: 65.8 %

Procedure:
The solution of alcohol 100 (600 mg, 0.85 mmol) and Dess-Martin periodinane (540 mg, 1.27 mmol) in CH2Cl2 (4.2 mL) was stirred at room temperature for 2 h. The reaction mixture was filtered off the white solid. The filtrate was diluted with CH2Cl2 and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography provided the desired aldehyde 101 (395 mg, 65%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH:3]([NH2:6])[C:4]#[CH:5].[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].C(N(CC)CC)C>ClCCl>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([NH:6][CH:3]([CH:2]([CH3:7])[CH3:1])[C:4]#[CH:5])=[O:13]
Reactant: O=C=NCCCl
Reactant: C#CC(N)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(NC(=O)NCCCl)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 256 mg of 4-methylpent-1-yn-3-amine (Formula 23) in 10 mL of dichloromethane was added 0.5 mL of 2-chloroethyl isocyanate and 0.5 mL of triethylamine. After the mixture was stirred at room temperature for 2 hours, the solvent was removed and column chromatography (40% ethyl acetate/hexane) gave 210 mg of 1-(2-Chloroethyl)-3-(4-methylpent-1-yn-3-yl)urea (Formula 24) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.95-1.01 (m, 6H), 1.84-1.93 (m, 1H), 2.25-2.26 (m, 1H), 3.51-3.63 (m, 4H), 4.40-4.45 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[C:58]([F:61])([F:60])[F:59].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[C:58]([F:60])([F:59])[F:61]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 mg, 0.226 mmol), HBTU (125 mg, 0.33 mmol), 1-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine dihydrochloride (170 mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.5 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone: MS (ES) [M+H]+ found: 490.4
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.O=P(Cl)(Cl)[Cl:17].C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc2oc(=O)cc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc2oc(=O)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A stirred mixture of 4-hydroxy-6-methoxycoumarin (116 g, 0.603 mole) and POCl3 (462.29 g, 3.015 mole) in toluene is treated dropwise with tri-n-butylamine (250 mL, 1.73 mole) at 25° C., heated at 100°-110° C. and monitored by HPLC analysis. When the reaction is complete, the mixture is cooled to room temperature, poured over ice, stirred mechanically for about 2 hours and filtered. The filtercake is washed with water and toluene, dissolved in methylene chloride and filtered through diatomaceous earth. The methylene chloride filtrate is concentrated and treated with a mixture of dimethylformamide and acetonitrile to afford crystallization. The mixture is filtered to give the title product, 81.7 g, (64% yield) identified by HPLC analysis.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:7][C:6]=1Br.CCCCCC.C([Li])CCC.CN([CH:31]=[O:32])C>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](=[CH:7][C:8]([CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=1)[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: COCOCc1ccc(OCOC)c(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COCOCc1ccc(OCOC)c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-4-methoxymethoxymethylphenol methoxymethyl ether (11.18 g) in diethyl ether (400 ml) was cooled to -78° C. To the solution was added dropwise a 1.6M n-butyl lithium hexane solution (28 ml) under argon atmosphere. The mixture was stirred for one hour while maintaining the temperature, to which was added dropwise DMF (5 ml), followed by raising the temperature up to room temperature and stirring overnight. The reaction mixture was subjected to extraction with the addition of water and ethyl acetate. The organic layer was washed (a saturated aqueous saline solution) and dried (anhydrous magnesium sulfate). Then, the solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-methoxymethoxymethyl salicylaldehyde methoxymethyl ether (7.23 g) (Compound B-23). The physical properties are shown in Table 7.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11](COCC[Si](C)(C)C)[N:12]=[C:13]([I:14])[C:8]2=[CH:7][N:6]=1.Cl>CO>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([I:14])[C:8]2=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cnc(Oc3ccc(F)cc3F)nc21
Agent: Cl
Solvent: CO
Product: Fc1ccc(Oc2ncc3c(I)n[nH]c3n2)c(F)c1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
6-(2,4-Difluoro-phenoxy)-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (89 mg) was dissolved in 3 mL of MeOH. Aqueous HCl (2 mL, 18.5%) was added, and the mixture was heated to reflux for four hours. The reaction mixture was cooled to room temperature, transferred to a stoppered flask, and heated to 90° C. for w hours. The reaction mixture was evaporated under reduced pressure and the residue was taken up in 12 mL of EtOAc, made basic with 25 mL of 5 N NaOH, wahsed with water, saturated brine, dried over MgSO4, filtered, and evaporated under reduced pressure to yield 26 mg of 6-(2,4-Difluoro-phenoxy)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=373.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I:11]Cl.C(OCC)(=O)C>C(#N)C>[I:11][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: ClI
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.9 %

Procedure:
To a solution of 4-nitroaniline (27.6 g, 0.2 mol) in 200 mL of dry acetonitrile was added a solution of ICl (31.0 g, 0.19 mol) in 50 mL of acetonitrile and the mixture was stirred at room temperature for 18 h. The reaction mixture was then poured into ethyl acetate, washed (20% aq. Na2S2O3, brine), dried (Na2SO4) and evaporated to give a brown solid. Chromatography (SiO2 /CH2Cl2 -hexane, 6:4 to 7:3) afforded the title compound (18.0 g, 36%) as a yellow solid, mp 104°-106° C.: IR (neat) 3480, 3380, 1610, 1300 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ8.38 (d, J=2.6 Hz, 1H), 7.97 (dd, J=9.0, 2.6 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H), 6.73 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[C:16]3[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]3)[C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (85% pure—contains 15% 3,3,5,5-tetramethylcyclohexanone) (0.117 g, 0.25 mmoL), 4-(methanesulphonyl)benzeneboronic acid (0.165 g, 0.82 mmoL), tetrakis(triphenylphosphine)palladium (0) (0.026 g, 0.023 mmoL), 2 M Na2CO3 (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 3.5 h. The oil bath was removed and the reaction mixture was allowed to cool at RT. The reaction mixture was transferred to a separatory funnel and partitioned between H2O and EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel using a hexanes:EtOAc gradient (100:0 to 75:25) to give 0.063 g (53%) of compound 163 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 12 H), 1.26 (s, 2 H), 1.93 (s, 4 H), 3.23 (s, 3 H), 6.67 (d, J=8.5 Hz, 2 H), 6.95 (d, J=8.4 Hz, 2 H), 7.25 (d, J=8.2 Hz, 2 H), 7.67 (d, J=8.3 Hz, 2 H), 7.91 (d, J=8.6 Hz, 2 H), 7.95 (d, J=8.6 Hz, 2 H), 9.29 (s, 1 H). HRMS (ESI) Calcd for C30H33O3S: 473.2150 (M−H)−. Found: 473.2168.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CO>C1COCC1>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH:17]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CN1CC=C(C2c3ccccc3CCc3ccccc32)CC1
Temperature: -78 °C
Yield: 93 %

Procedure:
Dissolved 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-methylpiperidine (12 g, 0.042 mol) in 250 mL of dry THF. Cooled to -78° C. under a nitrogen atmosphere. Added n-butyl lithium (18 mL of 2.5M in hexane) dropwise via addition funnel. Maintain temperature at 0° C. for 1 hour then recooled to -78° C. Added 21 mL of dry methanol, and let warm to room temperature. Added saturated NH4Cl, and extracted with THF. Dried combined organic extracts with MgSO4, filtered, and evaporated to give 11.3 g (94% yield) of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-methyl-1,2,5,6-tetrahydropyridine as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:20][CH2:19]1)#[N:17]>C(OCC)(=O)C>[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:9])=[O:26])[CH2:20][CH2:19]1)#[N:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)S(=O)NC1CCN(C#N)CC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)S(=O)(=O)NC1CCN(C#N)CC1
Reaction time: 16 h

Procedure:
Meta-chloroperbenzoic acid (60 mg) was added to the chloroform solution (0.5 mL) containing 1-cyano-4-(tert-butylsulfinyl-amino)piperidine at room temperature, followed by stirring at the same temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate and aqueous saturated sodium chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (58 mg).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:3]1.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:11][C:10]([O:9][C:7]([NH:6][C@H:5]([CH2:4][CH2:3][C:2](=[O:1])[C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:28][CH:29]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])([CH3:13])[CH3:12]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Ic1ccc(OCc2ccccc2)cc1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared (2.9 g, 16%) using a similar procedure as set out earlier in Description 2 starting from 1-(1,1-dimethylethyl) 2-ethyl (2R)-5-oxo-1,2-pyrrolidinedicarboxylate (D14, 10.5 g 40.8 mmol) and 4-iodophenyl phenylmethyl ether (13.34 g, 43 mmol); Rt (HPLC): 6.37 min; MS: (ES/+) 464 m/z: [M+Na+]; C25H31NO6 requires 441; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, 2H); 7.29-7.45 (m, 5H); 6.99 (d, 2H); 5.18 (bs, 1H); 5.12 (s, 2H); 4.29-4.4 (bm, 1H); 4.20 (q, 2H); 2.94-3.16 (m, 2H); 2.22-2.33 (m, 1H); 2.00-2.15 (m, 1H); 1.39 (s, 9H); 1.28 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[N:4]=[N:3][C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:7][CH:6]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Cl)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N2CCOCC2)nn1
Temperature: 116 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
A mixture of 3-chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (150 mg, 0.5 mmol) and morpholine (0.17 mL, 2 mmol) was stirred at 116° C. for 4 h. After extraction with ethyl acetate/water the organic phase was concentrated and chromatographed (SiO2, heptane/ethyl acetate=100:0 to 70:30) to afford the title compound as a white solid (40 mg, 23%). MS: m/e=353.3 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)N1CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.04 g (8.91 mmol) of the compound from Example 21A are dissolved in 69 ml of dry THF, and 9.8 ml (9.8 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF are added. The reaction mixture is stirred at RT for 48 h. The solvent is then removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 200:1→1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[O:33][CH2:34][CH3:35])=[C:3]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1COC1CCCCO1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(C(=O)c2ccccc2)cc1COC1CCCCO1
Yield: 83.5 %

Procedure:
To a stirred and cooled (10° C.) solution of 13.7 parts of intermediate 57, namely [4-amino-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl] phenylmethanone, in 147 parts of pyridine were added dropwise 7.14 parts of ethyl chloroformate. After stirring for 1 hour at 10° C., the reaction mixture was poured into 700 parts of water. The product was extracted with dichloromethane and the extract was washed with water (3×), dried, filtered and evaporated. The residue was co-evaporated with ethanol (3×) and was then crystallized from ethanol. The product was filtered off, washed with ethanol and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 14.05 parts (83.5%) of ethyl [4-benzoyl-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]carbamate; mp. 115.9° C. (interm. 58).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(C(=O)O)s2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of methyl 5-(4-methoxyphenyl)thiophene-2-carboxylate (1.4 g, 5.6 mmol), and 1 M sodium hydroxide (55 mL) in methanol (55 mL) was heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product (1.2 g, 93%) as an off-white solid: ESI MS m/z 325 [C12H10O3S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([CH3:23])([CH3:22])[CH2:12][C@:13]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:14][C:15]#[CH:16])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N1C=CN=C1.[Si:29](Cl)([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31]>CN(C=O)C>[CH3:22][C:11]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:23])[CH2:12][C@:13]([O:21][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])([C:17]([F:19])([F:20])[F:18])[CH2:14][C:15]#[CH:16]
Reactant: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C(=O)O)C(F)(F)F
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CC[C@@](CC(C)(C)c1ccc(F)cc1C(=O)O)(O[Si](CC)(CC)CC)C(F)(F)F
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of 10.6 g (0.032 mol) of 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzoic acid and 17.8 g (0.026 mol) of imidazole in 70 mL of DMF was added 75.6 mL (0.45 mol) of TESCl. The reaction mixture was stirred at 100° C. for 3 days. Volatiles were removed in vacuo, the reaction mixture was cooled to 10° C. with an ice bath, and 1 L of 1 N HCl was added. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added and the mixture was washed with 1 N HCl, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. 200 mL of 1 N HCl is added and stirred for 1 hour. Ethyl acetate was added and the mixture was washed with 1 N HCl, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-((S)-1,1-dimethyl-3-triethylsilanyloxy-3-trifluoromethylhex-5-ynyl)-5-fluorobenzoic acid.