Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1.C(O)(=O)C.Cl>CO>[CH3:21][C:20]([OH:22])([CH3:23])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([N:1]2[CH:26]=[CH:30][CH:29]=[CH:28]2)=[CH:10][CH:9]=3)=[O:12])[CH2:14][CH2:15]1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(O)CC1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(O)CC1CCN(C(=O)c2cc3cc(-n4cccc4)ccc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 127 mg of 1-{1-[(5-amino-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol in 3 mL of methanol were added 90 μl, of 2,5-dimethoxytetrahydrofuran and 1 mL of acetic acid, followed by stirring at 60° C. for 1 day. 1M hydrochloric acid was added to the reaction liquid which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified from ethyl acetate-hexane to obtain 30 mg of 2-methyl-1-(1-{[5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}piperidin-4-yl)propan-2-ol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:23]3[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 76.9 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1,1-dimethylethyl 1-piperazinecarboxylate (0.44 g, 3.4 mmol) and the reaction was carried out by the method of Example 3. Following chromatographic purification, 1.16 g of the title product was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:41])=[C:16]([N:24]([CH2:39][CH3:40])[CH:25]2[CH2:30][CH2:29][CH:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]2)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][OH:23])[CH:19]=1)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][CH:28]1[CH2:27][CH2:26][CH:25]([N:24]([CH2:39][CH3:40])[C:16]2[C:15]([CH3:41])=[C:14]([CH:19]=[C:18]([O:20][CH2:21][CH2:22][OH:23])[CH:17]=2)[C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[CH2:30][CH2:29]1
Reactant: CCN(c1cc(OCCO)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cc(OCCO)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of tert-butyl (4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(2-hydroxyethoxy)-2-methylphenyl)-(ethyl)-amino)cyclohexyl)carbamate (0.80 g, 1.40 mmol) in DCM (5 mL) was added TFA (2 mL) and the reaction mixture was stirred at rt for 1 h. After completion of reaction, the solvent was removed under reduced pressure and saturated NaHCO3 solution was added. Extraction was carried out using 10% MeOH/DCM; the combined organic layers were washed with water and brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to give the title compound (0.5 g, 76%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)=O)=CC=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.CCOCC>[N:25]([CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN=[N+]=[N-]
Temperature: 70 °C
Yield: 90.6 %

Procedure:
(S)-2-[[[(4-Methylphenyl)sulfonyl]oxy]methyl]-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3.55 g, 10 mmol, see J. Das et al, J. Med Chem, 1992, Vol.35,2610 for preparation) was dissolved in dimethyl sulfoxide (DMSO) (40 mL) and treated with sodium azide (980 mg, 15 mmol). The mixture was heated at 70° C. for 5 hours, then cooled and diluted with ether. After washing with water (3×50 mL), the ether layer was dried (MgSO4) and freed of solvent in vacuo to give title compound as a colorless oil (2.05 g, 91%) which was used without further purification.
Reaction SMILES: Br[C:2]1[C:15]([F:16])=[C:14]([F:17])[C:5]([CH2:6][O:7]C2CCCCO2)=[C:4]([F:18])[C:3]=1[F:19].[CH2:20](Cl)[C:21]#[CH:22]>>[CH2:22]([C:2]1[C:3]([F:19])=[C:4]([F:18])[C:5]([CH2:6][OH:7])=[C:14]([F:17])[C:15]=1[F:16])[C:21]#[CH:20]
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1Br
Reactant: C#CCCl
Product: C#CCc1c(F)c(F)c(CO)c(F)c1F

Procedure:
4-(Prop-2-yn-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol was prepared from 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy)-tetrahydropyran and propargyl chloride, by a two stage procedure similar to that described in Example 4.
Reaction SMILES: [Br:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8]=[C:7]([C:17](O)=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8]=[C:7]([CH2:17][OH:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2c(Br)cccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCC1=Cc2ccccc2Oc2c(Br)cccc21
Yield: 99 %

Procedure:
Preparation analogous to Example 12f) from 6-bromo-dibenz[b,f]oxepine-10-carboxylic acid. Yield: 99% crude, brown oil; TLC (silica gel; hexane/ethyl acetate=7:3; UV): Rf =0.07; 1H-NMR (CDCl3, 200 MHz): 3.54 (s, 2H); 6.70-7.49 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:25])[NH:15][C:16]1[N:17]=[C:18]2[N:22]([CH:23]=1)[CH:21]=[C:20](Br)[S:19]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:25])[NH:15][C:16]1[N:17]=[C:18]2[N:22]([CH:23]=1)[CH:21]=[C:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:19]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1

Procedure:
Compound 15 was synthesized from compound 14 (0.155 mmol) and phenylboronic acid (0.492 mmol), following the procedure as described for compound A1 to give compound 15 as a yellow gum in 38% yield. MS (ESI, EI+) m/z=429 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][O:9]C2C=CC(C3CCN(C4C=CC5N(C(C(F)(F)F)=NN=5)N=4)CC3)=CC=2)=[CH:5][CH:4]=[N:3]1.C([Li])CCC.CN1C=CC=N1.O1CC1>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1CCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: Cn1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CO1
Solvent: ClCCl
Product: Cn1nccc1CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
The 2-(1-methyl-1H-pyrazol-5-yl)ethanol used as starting material was prepared as follows:—n-Butyl lithium (1.6M in hexanes) (1226 mL, 1961.78 mmol) was added dropwise to 1-methyl-1H-pyrazole (153.4 g, 1868.37 mmol) in THF (3000 mL) cooled to −78° C. over a period of 1 hour under nitrogen. The resulting solution was stirred at −60° C. for 30 minutes, then warmed to −10° C. and stirred for a further 40 minutes. A solution of oxirane (210 mL, 4203.82 mmol) in THF (600 mL) was added slowly at −10° C. followed by further THF (1000 mL) and the resulting slurry was stirred at −10° C. for 30 minutes, then at 0° C. for 30 minutes. The mixture was then allowed to gradually warm to room temp under nitrogen and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl solution (2000 ml), the layers separated and the aqueous phase extracted with n-butanol (3×1000 ml). The combined organics were washed with saturated brine (1500 ml), dried over MgSO4, filtered and evaporated to give an oil, which was azeotroped with toluene (1000 ml) to leave an oil with some solid. The oil was dissolved in DCM and the insoluble solid was filtered off and washed with DCM. The filtrate was purified by chromatography using a silica Novasep prep HPLC column, eluting with a gradient of 5-10% methanol in DCM. Pure fractions were evaporated to dryness to afford 2-(1-methyl-1H-pyrazol-5-yl)ethanol (195 g, 83%) as an oil.
Reaction SMILES: [Si]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])(C(C)(C)C)(C)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:38][O:39][CH2:40][CH2:41][NH2:42]>C1(C)C=CC=CC=1>[OH:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:20]([NH:42][CH2:41][CH2:40][O:39][CH3:38])=[O:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Reactant: COCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCCNC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 124.1 %

Procedure:
To a solution of 2-tert-butyldimethylsilyloxy-4-nitroaniline (200 mg, 0.75 mmol) in toluene (5 mL), triphosgene (84 mg, 0.3 mmol) and triethylamine (0.13 mL, 0.9 mmol) were added. The reaction mixture was stirred at 80° C. for 3 hours. Then it was cooled to room temperature and all solvent was evaporated. The residue was dissolved in DMF (1 mL) and 2-methoxyethylamine (56.3 mg, 0.75 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. Chromatography of the resulting liquid on silica gel (50% Ethyl acetate/Hexane) gave desired product (95 mg, 50%). EI-MS m/z 256.2 (M+). mp: 190.0-190.7° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](NC2C(Cl)=CC=CC=2Cl)=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.[C:20]12(C)[C:27](C)(C)C(C[CH2:26]1)C[C:21]2=O.[CH:31]1(C)CCC(C(C)C)C(O)C1>>[OH:10][C:8]([CH:7]([C:5]1[CH:6]=[CH:1][C:2]([CH2:21][CH:20]([CH3:27])[CH3:26])=[CH:3][CH:4]=1)[CH3:31])=[O:9]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CC12CCC(CC1=O)C2(C)C
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 5 %

Procedure:
5% Ibuprofen cream was prepared as described in Example 2. The composition of the emulsion for 5% Diclofenac cream is presented in Table 4. The cream contains approximately 26% of the oil phase with a ratio MCT:Camphor:Menthol of approximately 4.25:1:1.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:25]([OH:27])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])[O-].[Ca+2].C(OCC)(=O)C.O.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C=O>[CH2:40]([O:26][C:25](=[O:27])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction sequence is shown in FIG. 5. Nε-(tert-butoxycarbonyl)-L-lysine (2 g, 8.12 mmol) was dissolved in methanol (40 ml) and water (40 ml), and the pH was adjusted to 8 with triethylamine. A solution of N-(benzyloxycarbonyl-oxy)succinimide in dioxane (2.4 g, 9.7 mmol in 20 ml) was added to the above mixture and the pH was maintained at 8–9 with triethylamine. The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine. Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine was treated with 0.2 M calcium carbonate (4 ml) and the aqueous layer was removed to obtain a white solid. The solid was resuspended in N,N-dimethylformamide(40 ml) and benzyl bromide (1.16 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was worked up with ethyl acetate and water, and the organic layer was dried over magnesium sulphate. The solvent was removed to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester which was purified by silica gel chromatography using 25% hexane in ethyl acetate as a solvent. To Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester (1 g, 2.2 mmol) in methylene chloride (10 ml) was added trifloroacetic acid at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for further 2.5 hr at room temperature. The solvent was removed and the crude product was obtained. Pure Nα-CBZ-L-lysine benzyl ester was obtained by silica gel chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[ClH:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CN2CCN(c3ccccc3)CC2)cc(OC)c1OC
Product: Cl
Reaction time: 8 h
Yield: 45 %

Procedure:
4.32 g of 3,4,5-trimethoxybenzyl chloride and 3.24 g of N-phenyl piperazine is dissolved in 50 ml of dimethyl formamide in the presence of 3.0 g of water-free soda and is boiled for 8 hours under reflux. After sucking off insoluble matter, the filtrate is evaporated to dryness, the residue is dissolved in methanol. Subsequently hydrochloric acid gas is introduced in the solution and the precipitate sucked off. After drying, 3.4 g of N-(3,4,5-trimethoxybenzyl)-N'-phenyl-piperazine hydrochloride is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[NH:19]([C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH2:26][NH:27][C:28](=[O:30])[CH3:29])[C:20]([NH2:22])=[NH:21]>CC#N>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:22]=[C:20]([NH:19][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[CH2:26][NH:27][C:28](=[O:30])[CH3:29])[N:21]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: CC(=O)NCc1cccc(NC(=N)N)c1
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: CC(=O)NCc1cccc(Nc2nccc(-c3sc(C)nc3C)n2)c1

Procedure:
By treatment of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(3-guanidino-benzyl)-acetamide nitrate. Yellow solid. Mp 206-207° C. Anal. RP-HPLC: tR=13.6 min (0-60% MeCN, purity >95%). 1H-NMR (DMSO-D6) δ: 1.99 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.68 (s, 3H, CH3), 4.38 (s, 2H, CH2), 6.94 (d, 1H, J=7.5 Hz, Ph-H), 7.01 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.26 (d, 1H, J=8.0 Hz, Ph-H), 7.56 (d, 1H, J=7.5 Hz, Ph-H), 7.70 (s, 1H, Ph-H), 8.40 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 345.42 [M+H]+ (C18H19N5OS requires 353.44).
Reaction SMILES: [C:1]([C:4]([C@@:6]([C:21](=[O:23])[CH3:22])([C@:8]([C:18](=[O:20])[CH3:19])([C@:10]([C:15](=[O:17])[CH3:16])([C@@H:12]([CH3:14])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C@:15]2([CH3:16])[O:17][C@:4]([C:1](=[O:3])[CH3:2])([OH:5])[C@:6]([C:21](=[O:23])[CH3:22])([OH:7])[C@@:8]([C:18](=[O:20])[CH3:19])([OH:9])[C@@:10]2([C:12](=[O:13])[CH3:14])[OH:11])=[CH:28][CH:27]=1
Reactant: CC(=O)C(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H](C)O
Reactant: COc1ccc(O)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc([C@]2(C)O[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@]2(O)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
D-Fucose (3) (4.95 g, 30.14 mmol) was dissolved in 30 mL of acetic anhydride and 30 mL of pyridine and stirred for 12 h. The solvent was removed in vacuo. Column chromatography (2:1 hexane/EtOAc) yielded 10.15 g (quant.) of 1,2,3,4-tetraacetyl-D-fucose (as a mixture of α-and β-anomer). 1,2,3,4-tetraacetyl-D-fucose (20.0 g, 60.2 mmol) and p-methoxyphenol (MPOH) (10.46 g, 84.3 mmol) were dissolved in 220 mL of dichloromethane and cooled to 0° C. BF3.OEt2 (21.4 g, 19.0 mL, 150.5 mmol) was added and the mixture stirred overnight. The reaction mixture was quenched by addition of saturated NaHCO3 solution, washed 2 times with water, dried over Na2SO4, concentrated and the residue was purified by column chromatography (3:1 hexane/EtOAc) yielding 16.8 g (71%) of 4-methoxyphenyl 1,2,3,4tetraacetyl-α-D-fucose (Only the β-anomer reacts, α-anomer could be recovered). 4-methoxyphenyl 1,2,3,4-tetraacetyl-α-D-fucose (3.90 g, 9.85 mmol) was dissolved in 150 mL of methanol and 6 mL of 0.5 M NaOMe solution were added. The mixture was stirred for 6 h. The solvent was removed in vacuo. Column chromatography (3:1 dichloromethane/methanol) afforded 2.63 g (99%) as a colorless solid: [α]D: +201.6 (c=0.32, CH3OH). 1H NMR (CD3OD, 300 MHz) δ 1.18 (d, J=6.6 Hz, 3H), 3.74 (s, 3H), 3.89 (m, 2H), 4.09 (quart., J=6.0 Hz, 1H), 5.31 (d, J=3.6 Hz, 1H), 6.82 (d, J=9.3 Hz, 2H), 7.04 (d, J=9.3 Hz, 2H). 13C NMR (CD3OD, 75 MHz) 16.3, 55.7, 67.9, 69.5, 71.2, 73.2, 100.0, 115.1, 119.0, 152.2, 156.0. MALDI-HRMS: m/z [M+Na]+ calcd 293.0996, obsd 293.0994.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[NH:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:20]3[CH2:25][CH2:24][C:23]4([C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26]4)[CH2:22][CH2:21]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 42.7 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.420 g, 1.68 mmol) obtained in Example 19, step 2 and spiro[inden-1,4′-piperidine]hydrochloride (0.450 g, 2.02 mmol), the title compound (0.300 g, 43%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[F:27][C:28]1[CH:29]=[C:30]2[C:35](=O)[O:34][C:32](=[O:33])[C:31]2=[CH:37][CH:38]=1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][N:1]2[C:35](=[O:34])[C:30]3=[CH:29][C:28]([F:27])=[CH:38][CH:37]=[C:31]3[C:32]2=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: O=C1OC(=O)c2cc(F)ccc21
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C1c2ccc(F)cc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A suspension of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one (490 mg, 1.4 mmol) and 4-fluorophthalic acid anhydride (233 mg, 1.4 mmol) in xylene (3 mL) was stirred for 30 minutes at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, followed by recrystallization from dichloromethane-hexane to give 436 mg (yield 62%) of the titled compound, m.p. 235°-236° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH4+:13].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 3,5-difluorobenzenesulfonyl chloride (25 g, 0.117 mol) in THF (150 mL) was added 35% aq. NH4OH (120 mL) over 1 h in an ice-bath. After the reaction was complete, it was evaporated in vacuo. To a solution of this residue in water (150 mL) was added 2N HCl (1 mL). After stirring 1 h, the reaction mixture was filtered and dried under high vacuum to give 3,5-difluorobenzenesulfonamide as a light brown solid (19.9 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.49-7.44 (m, 2H), 7.04-6.99 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:10][CH3:11])=[CH:4][C:5]([O:7]CC)=O.[H-].[Na+].[N-:16]=[C:17]=[S:18].[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:11][N:10]1[C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][C:5](=[O:7])[N:16]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]1=[S:18]
Reactant: CCOC(=O)C=C(NC)C(F)(F)F
Reactant: Cc1ccccc1
Reactant: [N-]=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(Cc2ccccc2)c1=S
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
4,4,4-Trifluoro-3-(methylamino)-2-butenoic acid, ethyl ester, (2Z)-(1.43 g) in toluene (25 ml) was slowly added to a stirred suspension of sodium hydride (60%, 0.28 g) in anhydrous N,N-dimethylformamide (25 ml) at −10° C. The solution was stirred for 0.5 hr at this temperature and cooled to −50° C. The above isothiocyanate dissolved in toluene (25 ml) was added drop wise with stirring to the solution, while maintaining the temperature at −50° C. The solution was then allowed to warm to −20° C. and stirred for 2 hr. After neutralization with dilute hydrochloric acid, the solution was partitioned between water and ethyl acetate and the organic layer was evaporated to furnish a crude product. Column chromatography over silica gel (eluent, hexane:ethyl acetate, 90:10) afforded the title compound (2.6 g). 1H NMR, CDCl3, 3.86 (3H, m), 5.74 (2H, s), 6.51 (1H, s), 7.27-7.30 (3H, m), 7.42-7.46 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C=O)C.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C(c1ccccc1)c1c[nH]c2ncc(Br)cc12
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(c1ccccc1)c1c[nH]c2ncc(-c3cccc(O)c3)cc12
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To (5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-phenyl-methanone (50 mg, 0.167 mmol), 3-hydroxyphenyl boronic acid (30 mg, 0.217 mmol), and dichlorobis (triphenylphosphino)palladium (II) (6 mg, 0.0083 mmol) in a Smith process vial was added 1 mL of a 1:1 mixture of acetonitrile, and a 2 M solution of sodium carbonate in water. The reaction was run in a Personal Chemistry® microwave reactor at 150° C. for 1200 s. The mixture was diluted with DMF (ca. 5 mL) and filtered on a silica plug. The filtrate was adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/dichloromethane afforded [5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-phenyl-methanone as a yellow solid (37 mg, 71% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.80 (dd, J=2.0, 7.5 Hz, 1H), 7.10 (t, J=2.0 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 2H), 7.65 (t, J=7.5 Hz, 1H), 7.84 (d, J=7.0 Hz, 2H), 8.14 (s, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 9.65 (broad s, 1H). MS: m/z 315 (M+H+).