Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[S:39][CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:38]3[S:39][CH:40]=[C:36]([F:35])[CH:37]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)cs2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(F)cs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
To a 30 mL sealed cap glass vessel containing tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol) and 2-(4-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.599 mmol) dissolved in DME and water (4:1) was added tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.399 mmol) and potassium phosphate, tribasic (212 mg, 1 mmol). The cap was sealed, and the reaction mixture was heated at 85° C. for 1 hour and then cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, and solvent removed via rotary evaporation to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(4-fluorothiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the resulting mixture was stirred at room temperature for 1 hour to give crude product, which was purified via preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to minimal volume, and lyophilized to give a TFA salt of the title compound (86 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (d, J=9.60 Hz, 1H), 2.03-2.18 (m, 1H), 3.53-3.68 (m, 1H), 3.75 (d, J=11.62 Hz, 1H), 3.85 (br s, 1H), 4.01 (d, J=12.38 Hz, 2H), 4.32 (td, J=8.53, 4.17 Hz, 1H), 4.45 (s, 2H), 7.32 (t, J=1.64 Hz, 1H), 7.40 (d, J=5.31 Hz, 1H), 7.95 (br s, 3H), 8.65 (s, 1H), 8.98 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C16H16F2N4O2S, 367. found, 367.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][OH:20])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][O:20][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Product: N#Cc1ccc(N(CCOc2ccc(C=O)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxybenzaldehyde, then used directly for the step below, step B.
Reaction SMILES: [Na].CS([O:6][CH2:7][C:8]1[C:17]2[C@@H:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[O:19][C:20]3([CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:16]=2[C:15]2[C@@H:14]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:13][C:12]([CH3:45])([CH3:44])[CH2:11][C:10]=2[N:9]=1)(=O)=O.[CH3:46]O>C(OCC)C>[Si:37]([O:36][C@H:14]1[CH2:13][C:12]([CH3:45])([CH3:44])[CH2:11][C:10]2[N:9]=[C:8]([CH2:7][O:6][CH3:46])[C:17]3[C@@H:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[O:19][C:20]4([CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:16]=3[C:15]1=2)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CC1(C)Cc2nc(COS(C)(=O)=O)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Reactant: CO
Agent: [Na]
Solvent: CCOCC
Product: COCc1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
20 mg Sodium are dissolved in 3 ml methanol cooled to 0° C. and treated dropwise with a solution of 57 mg ((3R,95)-9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-4-yl)methyl methanesulfonate in 0.5 ml methanol. After stirring for 12 hours at room temperature the mixture is diluted with diethylether, washed with saturated aqueous ammonium chloride and dried with magnesium sulphate. The solvents are evaporated in vacuo. The product is directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:24]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:25]([NH2:27])=[O:26])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:21][OH:22])[NH2:20])=[CH:15][C:14]=2[F:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34](#N)C.C(OCC)(OCC)OCC.FC(F)(F)C(O)=O>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[CH:34][O:22][N:21]=3)=[CH:15][C:14]=2[F:23])[C@H:24]([CH2:28][CH2:29][C:30]([F:32])([F:33])[F:31])[C:25]([NH2:27])=[O:26])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(C(N)=NO)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(OCC)OCC
Product: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(-c2ncon2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 45 °C
Yield: 90 %

Procedure:
(R)-2-(4-Chloro-N-(2-fluoro-4-(N′-hydroxycarbamimidoyl)benzyl)-phenylsulfonamido)-5,5,5-trifluoropentanamide (246 g) was charged to a reactor followed by dry acetonitrile (509 mL), triethyl orthoformate (120 mL), and trifluoroacetic acid (7 mL). The solution was heated to 40-50° C. until the reaction was complete by HPLC (<0.15 relative AP starting material). Methanol (1.48 L) was charged in one portion, followed by water (1.034 L), keeping the batch at 45-50° C. The batch was then cooled to 15-20° C. and filtered. The cake was washed with 2:6:5 MeCN:MeOH:water and tray dried under vacuum at 50-60° C., giving the title compound as a white solid (228 g, 90% yield). 1H NMR, (CDCl3, 300 MHz) δ: 1.40-1.58 (m, 1 H) 1.75-1.90 (m, 1 H) 1.92-2.07 (m, 1 H) 2.10 -2.26 (m, 1 H) 4.37 (dd, J=8.67, 6.22 Hz, 1 H) 4.48 (d, J=15.64 Hz, 1 H) 4.64 (d, J=15.82 Hz, 1 H) 5.54 (s, 1 H) 6.33 (s, 1 H) 7.44-7.54 (m, 2 H) 7.62 (t, J=7.72 Hz, 1 H) 7.68-7.76 (m, 3 H) 7.85 (dd, J=7.91, 1.51 Hz, 1H) 8.76 (s, 1 H). 13C NMR, (DMSO-d6, 75 MHz) δ: 170.34, 167.75, 165.80, 159.64 (d, J=244.5 Hz, 1C), 138.19, 137.64, 131.25 (d, J=3.75 Hz, 1C), 129.31, 129.23, 129.05 (d, J=14.25 Hz, 1C), 126.74 (q, J=274.5 Hz, 1C), 126.91, 126.80, 123.12 (d, J=3.75 Hz, 1C), 113.7 (d, J=24.0 Hz, 1 C), 57.92, 41.38 (d, J=4.5 Hz, 1 C), 30.04 (d, J=30.0 Hz, 1C), 22.90. 19F NMR, (CDCl3, 282 MHz) δ: −116.3, −66.5. IR (KBr): 3454, 334, 3286, 2952, 1705, 1432, 1325, 1260, 1167, 1084, 828 cm−1.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH2:19][C:20](O)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:12][C:13]1([CH2:19][C:20]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][CH:2]=[N:1]3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(CC(=O)O)CCCCC1
Reactant: Nc1cccc2ncccc12
Product: CC1(CC(=O)Nc2cccc3ncccc23)CCCCC1
Yield: 17.8 %

Procedure:
Prepared according to the method of example 18, using 5-quinolinamine (230 mg) and 1-methyl-cyclohexaneacetic acid (250 mg). Purification (SiO2, methanol:dichloromethane 1:9 as eluant) followed by recrystallisation from methanol/ethyl acetate gave the title compound as a colourless solid (80 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:5][CH2:4][N:3]1[C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN1C(=O)[C@@](C)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1CNCCN1C(=O)[C@@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (R)-[(2S)-2-methyl-4-(2-nitrobenzenesulphonyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (Example 26; 19.71 g) in anhydrous DMF (60 ml) was added thiophenol (5.5 ml) followed by anhydrous potassium carbonate (18.7 g). The reaction mixture was allowed to stir at ambient temperature under argon for 4 hours, filtered and washed with DCM (2×300 ml). The filtrate was acidified with HCl (2 M, 250 ml) and the organic phase was separated and discarded. The aqueous phase was adjusted to pH 8 with 2 M NaOH and extracted into EtOAc (5×300 ml). The organic layers were combined, dried and concentrated to give a pale yellow gum which slowly crystallized (4.88 g). NMR (DMSO-d6, 100° C.): 1.21 (d, 3H), 1.54 (s, 3H), 2.49-2.55 (m, 1H), 2.65-2.75 (m, 3H), 2.82-2.91 (m, 2H), 2.97-3.01 (m, 1H), 4.31 (d, 1H), 4.60 (s, 1H); m/z (+ve ESP): 241 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1cncnc1
Product: Cc1c2n(c3c(-c4cncnc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (32 mg, 41%), MS (ISP) m/z=313.5 [(M+H)+], mp 306° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][Si:24]([CH3:39])([CH3:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](B(O)O)=[CH:27][CH:26]=1.[CH3:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([C:51]2[C:52]3[C:57]([CH:58]=[C:59]4[C:64]=2[CH:63]=[CH:62][CH:61]=[CH:60]4)=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:43][CH:42]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.O1CCOCC1>[CH3:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([C:51]2[C:64]3[C:59]([C:58]([C:28]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]([Si:24]([CH3:39])([CH3:38])[CH3:23])=[CH:26][CH:27]=4)=[C:57]4[C:52]=2[CH:53]=[CH:54][CH:55]=[CH:56]4)=[CH:60][CH:61]=[CH:62][CH:63]=3)=[CH:43][CH:42]=1
Reactant: C[Si](C)(C)c1ccc(B(O)O)c2ccccc12
Reactant: Cc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2c3ccccc3c(-c3ccc([Si](C)(C)C)c4ccccc34)c3ccccc23)c2ccccc12

Procedure:
1.78 g (5.6 mmol) of tri-o-tolylphosphine and 0.2 g (0.9 mmol) of palladium acetate are added to a vigorously stirred, degassed suspension of 22.8 g (93.3 mmol) of 4-trimethylsilyinaphth-1-ylboronic acid, 37.4 g (93.3 mmol) of 9-(4-methylnaphth-1-yl)anthracene and 90 g (230 mmol) of tripotassium phosphate in a mixture of 575 ml of water, 100 ml of dioxane and 860 ml of toluene, and the mixture is refluxed for 60 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated aqueous sodium chloride solution and subsequently dried over magnesium sulfate. After the desiccant has been filtered off, the organic phase is evaporated to dryness under reduced pressure in a rotary evaporator. The grey residue obtained in this way is recrystallised from dioxane. The deposited crystals are filtered off with suction, washed with 50 ml of ethanol and subsequently dried under reduced pressure; yield: 38 g, 79% of theory; purity: 99.9% according to HPLC.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)([O-:18])=[O:17]>C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(OCc2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a suspension of potassium t-butoxide (5.7 g, 51 mmol) in THF (200 mL) was added 4-methoxyphenol (6.3 g, 51 mmol). After 10 min, 2-nitrobenzyl bromide (10 g, 46 mmol) was added. After 48 h, the reaction was concentrated and the residue was dissolved in ethyl acetate, washed with 1 N citric acid (2×), brine, satd aq NaHCO3 (2×), water, and brine. The organic layer was MgSO4 dried, concentrated, triturated with ether, filtered and vacuum dried to give the title compound as an off-white solid (8.4 g, 71%); MS(FD): 259.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:23])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][N:5]=[C:4]([CH:24]=[N:25][OH:26])[N:3]=1.C1C(=O)N(Cl)C(=O)C1.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[C:36]#[CH:37].CCN(CC)CC>CN(C=O)C.O>[C:11]1([CH:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]([NH:8][C:7]2[C:2]([OH:1])=[N:3][C:4]([C:24]3[CH:37]=[C:36]([C:35]([O:39][CH2:40][CH3:41])=[O:38])[O:26][N:25]=3)=[N:5][CH:6]=2)=[O:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CC(=O)OCC
Reactant: O=C(Nc1cnc(C=NO)nc1O)C(c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ncc(NC(=O)C(c3ccccc3)c3ccccc3)c(O)n2)no1
Temperature: 60 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of step A product, 3-2-a, (0.85 g, 2.4 mmol) in DMF (15 mL), was added NCS (0.42 g, 3.15 mmol) at room temperature. The reaction mixture was heated at 60° C. for 1 h. The reaction mixture was cooled to 0° C. and ethyl propiolate (0.67 g, 6.8 mmol) was added. Then Et3N (0.3 g, 3 mmol) in DMF (5 mL) was added dropwise over 20 min. The reaction mixture was slowly allowed to warm to room temperature and stirred for overnight. The mixture was diluted with water (50 mL) and extracted with EA (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuum. The residue was purified by column chromatography with the eluent (PE:EA=2:1) to afford 3-2 (150 mg, 14%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ10.04 (s, 1H), 8.9 (s, 1H), 7.68 (s, 1H), 7.35-7.26 (m, 11H), 5.76 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H). LC-MS: (M+H)+ 445.
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])([O-:4])(=[O:3])=[O:2].[Na+:8].[CH:9]1([C:15](O)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.S(C1C=CC(C)=CC=1)(O)(=O)=O>C(OCC)C>[CH:9]1([C:15]([O:7][CH2:6][CH2:5][S:1]([O-:4])(=[O:3])=[O:2])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Na+:8]
Reactant: O=C(O)C1CCCCC1
Reactant: O=S(=O)([O-])CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOCC
Product: O=C(OCCS(=O)(=O)[O-])C1CCCCC1
Temperature: 200 °C
Yield: 91 %

Procedure:
A mixture of 3.0 g (20 mmol) of sodium isethionate, 7.7 g (60 mmol) of cyclohexanecarboxylic acid, and 0.38 g (2 mmol) of tosylic acid was heated at 200° C. for 20 hours. Diethyl ether was added to the reaction solution, yielding 4.7 g of sodium 2-cyclohexanecarbonyloxyethanesulfonate. A 1.4-g portion of the sodium salt was combined with 23 g (10 mmol) of an aqueous solution of triphenylsulfonium chloride prepared in Synthesis Example 1-1 and 30 g of methylene chloride, followed by stirring for 12 hours at room temperature. At the end of stirring, the organic layer was taken out, washed with water, and concentrated in vacuum. Methyl isobutyl ketone was added to the concentrate, which was concentrated in vacuum again while distilling off the residual water. Diethyl ether was added to the residue, followed by decantation and purification by column chromatography. There was obtained the target compound, triphenylsulfonium 2-cyclohexanecarbonyloxyethanesulfonate. Colorless oily matter, 1.7 g, yield 66% as calculated from the sodium salt. The compound, designated PAG-4, has the following structure.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)#N.C(O)(=[O:21])C>N1C=CC=CC=1.O.[Ni]>[CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)=[O:21]
Reactant: CCOC(=O)/C=C/c1n[nH]c2cc(C#N)ccc12
Reactant: CC(=O)O
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/c1n[nH]c2cc(C=O)ccc12
Temperature: 55 °C
Yield: 65 %

Procedure:
To a solution of (E)-ethyl 3-(6-cyano-1H-indazol-3-yl)acrylate (723 mg, 3 mmol) in pyridine (10 mL) was added acetic acid (3 mL), followed by a solution of NaH2PO2 (1.056 g, 12 mmol) in H2O (3 mL). The resulting mixture was stirred for 0.5 min at rt before Raney-Nickel 2400 (slurry in H2O, 0.6 mL) was added in one portion. The resulting mixture was heated at 55° C. (oil temp.) for 1 h before cooling to rt. H2O (30 mL) was added and the mixture was extracted with EtOAc (50 mL×2). Combined extracts were washed with H2O (20 mL), 2 M HCl (20 mL), H2O (20 mL×2), brine (15 mL) and dried (Na2SO4). Removal of solvent gave an orange red oil which solidified upon standing O/N under high vacuum. It was then triturated with H2O (30 mL) and suction filtered, rinsed with H2O, dried to give the title compound (476 mg, 65%) as an orange red solid. 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, 1H, NH), 10.14 (s, 1H, CHO), 8.30 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 7.92 (d, J=16.4 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.22 (q, J=6.8 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H); MS ESI 245.0 [M+H]+, calcd for [C13H12N2O3+H]+ 245.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][C:23]([OH:25])=O)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C([Si](C)(C)[O:31][C@H:32]1[C@@H:37]([O:38][Si](C(C)(C)C)(C)C)[CH2:36][CH2:35][NH:34][CH2:33]1)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][C:23]([N:34]3[CH2:35][CH2:36][CH:37]([OH:38])[CH:32]([OH:31])[CH2:33]3)=[O:25])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC[C@H]1O[Si](C)(C)C(C)(C)C
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC(=O)N2CCC(O)C(O)C2)CC1
Yield: 95 %

Procedure:
In analogy to the procedure described in Example 1,3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionic acid (intermediate 5) and (cis)-(rac)-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine (intermediate 9) gave the titled compound in 95% yield as a white solid. MS: 712.5 (MH+, 2Cl).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([O:18][C@@H:19]4[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:28]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:20]4[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:61][CH2:62][O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.[I-].[Na+]>CC(C)=O>[CH2:64]([O:63][CH2:62][CH2:61][N:15]1[C:11]2=[N:12][CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:10]2[C:17]([O:18][C@@H:19]2[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:36]([O:37][C:38](=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42])[C@H:28]([O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])[C@H:20]2[O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])=[N:16]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2nn(CCOCc3ccccc3)c3nccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C

Procedure:
To a solution of 4-(2-phenylethyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (98 mg) in acetone (4 mL) were added cesium carbonate (87 mg), benzyl 2-bromoethyl ether (0.032 mL) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (0.11 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=2[O:19][CH3:20])=[CH:30][CH:31]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1ccc(O)cc1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Product: CCCCOc1ccc(OCCCOc2ccc(CC(OC)C(=O)O)cc2OC)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 4-Butoxy-phenol following the Standard Procedure J. MS (ES) for C24H32O7 [M+Na]+: 455.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16](=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To the ice-cooled solution of aniline (3,72 g, 40 mmol) in methylene chloride (300 mL) containing triethylamine (11.2 mL, 80 mmol) was added dropwise methyl 3-chloro-3-oxopropionate (5.37 mL, 50 mmol). The reaction mixture was then stirred at room temperature for 2 hours and washed with saturated aqueous NaHCO3 (2×150 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate-hexane, 1:2) to give the title compound (7.2 g, 93.3%). 1H NMR (400 MHz, CDCl3) δ: 9.17 (brs, 1H), 7.53 (d, 2H), 7.32 (t, 2H), 7.10 (t, 1H), 3.80 (s, 2H).