Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][S:18][C:12]3=[N:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][S:18][C:12]3=[N:11][C:10]=2[CH3:19])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(O)cc1
Yield: 65.5 %

Procedure:
Intermediate 9 (4.8 g, 17.726 mmol) was treated with HBr (35 ml) and acetic acid (35 ml) at room temperature and the reaction mixture was then heated to reflux overnight for 15.0 g. After completion of the reaction, the mixture was concentrated and basified with NaHCO3 and extracted with ethyl acetate. Combined organic layer was washed with water, brine, dried over anhydrous Na2SO4 purified using 5% CH3OH in chloroform to afford 3.0 g of the desired compound; 1H NMR (300 MHz, DMSO-d6) δ 2.17 (s, 3H), 6.76-6.79 (m, 2H), 7.05-7.08 (m, 2H), 7.48 (d, J=4.8 Hz, 1H), 7.96 (d, J=5.1 Hz, 1H), 9.47 (s, 1H); ESI-MS (m/z) 259.50 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:12]([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1)[CH2:22][CH2:23]C.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(CCO)=CC=CC=1.O>[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[N:12]([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=3[CH:20]=2)=[CH:33][CH:34]=1)[CH2:22][CH3:23]
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Reactant: CCCN1CCCC(C(=O)OC)=Cc2cc(Br)ccc21
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3CCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
Under argon atmosphere, a mixture of methyl 8-bromo-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (1.5 g), 4-(2-butoxyethoxy)phenyl boric acid (1.29 g) and potassium carbonate (1.23 g) in toluene-ethanol-water (45-4.5-4.5 ml) was stirred at room temperature for 1 hour. To the reaction system was added tetrakis-(triphenylphosphine)palladium (0.26 g) was added, and the mixture was refluxed for 4 hours. After cooling to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated to purify by column chromatography (ethyl acetate:hexane=1:49→1:19→1:9) to give methyl 8-[4-(2-propoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (1.10 g) as a yellow oily material.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[OH-].[NH4+:18]>CO>[NH2:18][C@@H:1]1[C@@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: [NH4+]
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Agent: [OH-]
Solvent: CO
Product: N[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 20.7 g (94.4 mmol) of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate in 80 mL of methanol was added 80 mL of ammonium hydroxide. The reaction mixture was stirred at 60° C. overnight. The concentration of the reaction mixture under reduced pressure gave an oil residue (22.3 g, 94.4 mmol), which was used directly for the next N-Boc-protection reaction. MS (M+H)+ 237.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20]C1C=CC=CC=1NC1C=CC=CC=1.N1C=CC=CC=1C=O>>[CH3:19][O:20][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[N:8]1[N:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:9]1
Reactant: COc1ccccc1Nc1ccccc1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: COc1ccccc1-n1nnc(-c2ccccn2)n1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 2-methoxyphenylaniline (36.9 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(2-methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:39])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][C:24]=4[F:38])[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:41]1[N:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C@:10]1([CH3:39])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:41]5[N:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=5)=[CH:25][C:24]=4[F:38])[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC1(C)OB(c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)OC1(C)C
Reactant: Cc1ccc(Cl)nn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)nn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
The compound (600 mg, 1.05 mmol) obtained in Example 89-1), 3-chloro-6-methylpyridazine (161 mg, 1.26 mmol), tris(dibenzylideneacetone)dipalladium (96 mg, 0.10 mmol), tricyclohexylphosphine (29 mg, 0.10 mmol), and tripotassium phosphate (458 mg, 2.09 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL), and the mixture was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, then diluted with methylene chloride (200 mL), and separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol:ethyl acetate=0:100 to 20:80) to obtain the title compound (366 mg, 65%) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH:26]C=O)[CH:6]=[C:7]([CH2:15][P:16]([O:22]C(C)C)([O:18]C(C)C)=[O:17])[CH2:8][CH2:9][CH2:10][O:11]C(=O)C)[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH2:26])[CH:6]=[C:7]([CH2:15][P:16]([OH:18])([OH:22])=[O:17])[CH2:8][CH2:9][CH2:10][OH:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(CCCO)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane, and 5.1 ml (39.5 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 25 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 25 ml of ethanol, and a mixture of 25 ml of propylene oxide and 25 ml of ethanol is added dropwise. A suspension forms, which is stirred for one hour at room temperature and for one hour in an ice bath and is then filtered with suction. Drying yields 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester having a melting point of 210° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
To a mixture of 2-(3-chlorophenyl)acetic acid (11.4 g, 66.7 mmol) in 150 mL of THF was added LiAlH4 (3.04 g, 80.0 mmol) portionwise at 0° C. The resulting mixture was warmed to room temperature and stirred for 2 hours under N2 atmosphere. Then 2 N NaOH (30 mL) was added dropwise and extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to provide the crude product which was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=50:1-10:1) to obtain 4.96 g of the title compound as a colorless oil. Yield: 55%.
Reaction SMILES: [F:1][C:2](I)([F:31])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].[CH2:33]([Sn](CCCC)(CCCC)CCCC)[CH:34]=[CH2:35].CC(N=NC(C#N)(C)C)(C#N)C>CCCCCC>[F:1][C:2]([F:31])([CH2:35][CH:34]=[CH2:33])[C:3]([F:30])([F:29])[C:4]([F:28])([F:27])[C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Product: C=CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 97 %

Procedure:
In a typical procedure for reverse fluorous solid phase extraction in the studies of FIG. 4, a perfluoroalkyl iodide such as perfluorodecyl iodide (RfI, 323 mg, 0.5 mmol), allyltributyltin (330 mg, 1 mmol), AIBN (9 mg, 0.05 mmol) and hexane (5 ml) were placed in a flask under an argon atmosphere and the mixture was refluxed for 5 h. After removal of the volatile components by evaporation, the mixture was submitted to separation by reverse fluorous solid phase extraction. A short column was packed with regular silica gel (6.0 g) using FC-72/Et2O (2/1) as the solvent. The crude reaction mixture was then loaded onto this column and eluted with 20 ml of FC-72/Et2O (2/1) to give 3-(perfluorodecyl)prop-1-ene in 97% yield (271 mg). After similar reactions and separations, the allylated products 2a-d, 3a-d and 4a-d were isolated in yields ranging from 69-93%. The nuclear magnetic resonance (NMR) spectra of these products were clean, and gas chromatography (GC) or high pressure liquid chromatography (HPLC) purities exceeded 90% in all cases. The purity of the products was determined by GC in the case of R═H or R═Me and HPLC (Nova Pak® Silica, UV detection at 254 nm) in the case of R═Ph.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Li+]>C(O)C.O>[C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A mixture of N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (860 mg, 2.43 mmol), lithium hydroxide (233 mg, 9.70 mmol) in ethanol (20 mL) and water (5 mL) is heated to reflux for 1 hour before cooling to room temperature. The mixture is concentrated, dissolved in water and acidified with 10% hydrochloric acid. The solid is collected by filtration and washed with water, methanol and dried to give N-[3-carboxy-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (760 mg); ESI-MS (m/z): 327.0 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:16][C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCC(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
5-[1-(t-Butoxy)formamido]valeric acid is coupled with 5-aminosalicyclic acid to give 5-[5-(1-t-butoxyformamido)valeramido]salicylic acid, m.p. 181° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:18][C:19](=[O:37])[C@@H:20]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:21]C(OC(C)(C)C)=O)[CH:9]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:18][C:19](=[O:37])[C@@H:20]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH2:21])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)Nc1cnc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCc1ccccc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of N-tert-butoxycarbonyl-D-homophenylalanine 3-quinolylamide (A, 114 mg) in dichloromethane (2 mL) at 0° C. After stirring at 0° C. for 5 min and at room temperature for 40 min, the reaction mixture was evaporated and coevaporated three times with toluene and diethyl ether in vacuo to afford the title compound (151 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:27]=[O:28].O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:27]=[O:28])[C:12]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (3, 3.83 g, 14.5 mmol) in 148 mL of tetrahydrofuran. The solution was chilled to −78° C. and n-butyllithium (1.60 M in hexane, 19.1 mL, 30.0 mmol) was added over 30 minutes followed by the addition of 1.12 mL of N,N-dimethylformamide. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from ether to give the desired compound (4, 3.0 g, 71%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]2[C:9]([C:11]3[C:30]([C:31](=[O:32])[C:5]2=[CH:4][C:3]=1[OH:36])=[C:29]([OH:33])[C:14]1[C:15]2[C:20]([CH2:21][CH2:22][C:13]=1[C:12]=3[O:34][CH3:35])=[CH:19][C:18]1[CH:23](O)[O:24][C:25](=O)[C:17]=1[C:16]=2[OH:28])=[O:10].[C:37]1([NH:43][NH2:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)(=O)C>[C:37]1([N:43]2[C:25](=[O:24])[C:17]3[C:16]([OH:28])=[C:15]4[C:14]5[C:13]([CH2:22][CH2:21][C:20]4=[CH:19][C:18]=3[CH:23]=[N:44]2)=[C:12]([O:34][CH3:35])[C:11]2[C:9](=[O:10])[C:6]3[C:5](=[CH:4][C:3]([OH:36])=[C:2]([CH3:1])[C:7]=3[OH:8])[C:31](=[O:32])[C:30]=2[C:29]=5[OH:33])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1c2c(c(O)c3c1C(=O)c1c(cc(O)c(C)c1O)C3=O)-c1c(cc3c(c1O)C(=O)OC3O)CC2
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: COc1c2c(c(O)c3c1C(=O)c1c(cc(O)c(C)c1O)C3=O)-c1c(cc3cnn(-c4ccccc4)c(=O)c3c1O)CC2
Reaction time: 12 h
Yield: 83 %

Procedure:
A 5% mixture of madurahydroxylactone in glacial acetic acid is mixed with 2 mole equivalents of phenylhydrazine and boiled under reflux for 30 min. The reaction mixture is then left to stand at room temperature for about 12 hours. The red solid which has crystallized out is filtered off with suction, washed with glacial acetic acid and dried. The crude product is extracted with tetrahydrofuran (THF) in a Soxhlet. On cooling, the product crystallizes out and is filtered off with suction and dried. The yield is about 83% of theory.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[C:11]#[N:12])=[O:5])C.[H-].[Na+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1.[OH-].[Na+]>CN(C=O)C>[Cl:30][C:27]1[S:26][C:25]([C:23]2[O:22][N:21]=[C:20]([CH2:19][N:7]3[C:6]([C:4]([OH:3])=[O:5])=[C:10]([C:11]#[N:12])[C:9]([CH2:13][CH2:14][CH3:15])=[N:8]3)[CH:24]=2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCCc1n[nH]c(C(=O)OCC)c1C#N
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCc1nn(Cc2cc(-c3ccc(Cl)s3)on2)c(C(=O)O)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
112 mg (0.5 mmol) of 4-cyano-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester was dissolved in 2 ml of DMF and 23.8 mg (0.6 mmol) of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature the solution was cooled to −70° C. and 166 mg (0.6 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added. The reaction was stirred at room temperature for 3 h. The reaction solution was treated with 1 ml of 2N aqueous NaOH for 16h at room temperature. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[OH-].[Na+].[CH:30](OC)(OC)OC>FC(F)(F)C(O)=O.O1CCCC1>[CH3:30][NH:13][C:10]1[CH:11]=[N:12][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COC(OC)OC
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CNc1cnc(N2CCOCC2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of 2.24 g (8.3 mmol) 6-morpholin-4-yl-4-o-tolyl-pyridin-3-ylamine in 17 ml trimethyl orthoformate and 3 drops trifluoroacetic acid was heated for 2 h at 130° C. The reaction mixture was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 5 ml tetrahydrofuran and was added dropwise under ice cooling to 630 mg (16.6 mmol) lithium aluminum hydride in 20 ml tetrahydrofuran. The reaction mixture was stirred for 1 h at room temperature, cooled to 0° C. again and acidified (pH 1-2) by addition of 28% hydrochloric acid solution. After stirring for 5 min, 28% sodium hydroxide solution was added to reach pH 10. The solution was filtered over celite, evaporated and purified by flash chromatography to give 1.56 g (66%) of the title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].B.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(CCCCO)cc1OC
Yield: 98.4 %

Procedure:
4-(3,4-Dimethoxyphenyl)butyric acid (13 g, 58 mmol) was dissolved in dry THF (150 mL) then BH3.THF (110 mL, 1M solution, 110 mmol) was added drop wise with vigorous stirring under an argon atmosphere. The reaction mixture was then stirred overnight at room temperature. After this time, the reaction was quenched with water and 10% HCl solution at 0° C. and extracted with ethyl acetate. The organic fraction was dried with sodium sulfate and passed through a pad of silica gel. The solvent was removed at reduced pressure to give 23 (12.0 g, 99%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.62 (m, 4H), 2.0 (s, 1H), 2.62 (m, 2H), 3.65 (m, 2H), 3.82 (s, 3H), 3.84 (s, 3H) 6.67–6.82 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:24][C@@H:25]2[C@@H:32]3[C@@H:28]([O:29][C:30]([CH3:34])([CH3:33])[O:31]3)[C@H:27]([N:35]3[C:39]4[N:40]=[CH:41][N:42]=[C:43]([NH:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=5[O:54][CH3:55])[C:38]=4[CH:37]=[CH:36]3)[O:26]2)[CH:21]([CH3:23])[CH3:22])[CH2:17]1>CC(O)=O>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:14][CH2:15][CH:16]3[CH2:17][CH:18]([N:20]([CH2:24][C@@H:25]4[C@H:32]5[O:31][C:30]([CH3:33])([CH3:34])[O:29][C@H:28]5[C@H:27]([N:35]5[C:39]6[N:40]=[CH:41][N:42]=[C:43]([NH:44][CH2:45][C:46]7[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:47]=7[O:54][CH3:55])[C:38]=6[CH:37]=[CH:36]5)[O:26]4)[CH:21]([CH3:22])[CH3:23])[CH2:19]3)=[N:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
N-(2-Amino-4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanamide (670 mg, 0.87 mmol) was dissolved in HOAc (8 mL) and then heated to 65° C. with stirring overnight. Solvent was removed in vacuo. The residue was dissolved in DCM (60 mL), then washed with NaHCO3 (sat. 20 mL) and water (20 mL), the organic phase was dried and concentrated. The crude was purified by Prep-TLC (DCM:MeOH=10:1) to afford the desired compound (470 mg, yield: 73%) as a white solid, which was then separated by Chiral HPLC to afford cis (243 mg) and trans isomers (180 mg) as a white solids.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)nc1
Product: CCCc1c(OCc2cccc(Sc3ccc(C#N)cn3)c2)ccc(C(C)=O)c1O
Yield: 139.2 %

Procedure:
Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) nicotinonitrile (1.25 g, 5.15 mmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (1.00 g, 5.15 mmol) affords the title compound (3.00 g). MS (APCI-neg) m/z (rel intensity): 417 (M−H, 100%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:18])([F:17])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>>[F:6][C:7]([F:17])([F:18])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=1)=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(Nc1ccccc1)C(F)(F)F
Product: O=C(Nc1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F

Procedure:
Chlorosulfonic acid (100 g.) was cooled to 0° C. and trifluoroacetanilide (30 g.) was added portionwise with vigorous stirring keeping the temperature below +5° C. The reaction was stirred at room temperature overnight, and cautiously poured onto ice. The white solid produced was filtered, washed copiously with water, and dried to give 4-trifluoroacetamido benzenesulfonyl chloride (39.14 gl)(m.r. 143°-146° C.).