Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:52])[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([S:22]([N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]3[S:34]([CH2:36][C:37]3[C:42]([CH3:43])=[C:41]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])[CH:40]=[CH:39][N:38]=3)=[O:35])(=[O:24])=[O:23])[CH:19]=[CH:18][C:17]=2[O:50][CH3:51])(=O)=O)=CC=1.C([O-])(O)=O.[Na+:58]>CC#N.O>[Na+:58].[CH3:51][O:50][C:17]1[CH:18]=[CH:19][C:20]([S:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[S:34]([CH2:36][C:37]2[C:42]([CH3:43])=[C:41]([O:44][CH2:45][C:46]([F:47])([F:48])[F:49])[CH:40]=[CH:39][N:38]=2)=[O:35])(=[O:23])=[O:24])=[CH:21][C:16]=1[CH2:15][CH2:14][C:13]([O-:52])=[O:12]
Reactant: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1CCC(=O)OCCS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1CCC(=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 3-[2-methoxy-5-{2-(3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl)-benzimidazole-1-sulfonyl}phenyl]propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 63, 1.0 g, 1.26 mmol) in 10 mL of CH3CN was added the solution of NaHCO3 (127 mg, 1.51 mmol, 1.2 eq) in 5 mL of H2O. The mixture was heated to 65° C. for 4 h. Thereafter all the volatile materials were removed under vacuum, the mixture was washed with Et2O-EtOAc (10:1)), and then the aqueous layer was lyophilized overnight. The solid was dissolved in 100 mL of CH2Cl2, and then the mixture was filtered to remove insoluble material. The filtrate was concentrated and the residual oil was dissolved in 5 mL of CH2Cl2. Et2O was added to the mixture to precipitate a white solid. The precipitate was filtered, washed with Et2O, and dried under vacuum to yield 730 mg (91%) of 3-[2-methoxy-5-{2-(3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl)-benzimidazole-1-sulfonyl}phenyl]propionic acid sodium salt (Compound 36) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]([CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[CH:14](O)[CH3:15])=[O:7].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]([CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[CH:14]([Cl:20])[CH3:15])=[O:7]
Reactant: Cc1cccc(C(C)O)c1C(=O)c1cccs1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc(C(C)Cl)c1C(=O)c1cccs1

Procedure:
A mixture of 14.7 parts of 3-(1-hydroxyethyl)-o-tolyl 2-thienyl ketone and 126 parts of benzene is stirred while cooling on an ice-bath. Then 9.5 parts of thionyl chloride are added and the whole is stirred further over week-end at room temperature. The reaction mixture is evaporated in vacuo, yielding 3-(1-chloroethyl)-o-tolyl 2-thienyl ketone as a residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)/[CH:9]=[CH:10]/[CH:11]([CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>F.C(#N)C>[C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)/[CH:9]=[CH:10]/[CH:11]([CH2:19][OH:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](/C=C/C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1)Cc1ccc2ccccc2c1
Agent: F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](/C=C/C(CO)Cc1ccccc1)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
((1R,2E)-4-(tert-Butyldimethylsilanyloxymethyl)-1-(2-naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert-butyl ester (0.75 g, 1.38 mmol) was dissolved in 2% hydrogen fluoride in acetonitrile (50 ml) and stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was chromatographed on silica (80 g) using dichloromethane/heptane/methanol (4/10/1) as eluent. Three fractions were isolated containing compounds with Rf 0.1-0.2. The major fraction (eluting second) was concentrated in vacuo to give 0.35 g of ((1R,2E)-4-hydroxymethyl-1-(2-naphthyl)methyl-5-phenylpent-2-enyl) carbamic acid tert butyl ester as a mixture of diastereomers.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21]>C(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
A solution of amorphous ibandronic acid (5 g) in ethanol (50 ml) was stirred at room temperature. Aqueous sodium hydroxide (0.63 g, 12.5 ml) was added, and the reaction mixture was stirred at room temperature for an additional 2 hours. The precipitate was isolated by vacuum filtration, washed with ethanol (50 ml), and dried in a vacuum oven at 50° C. for 24 hours to obtain 5.5 g of ibandronate sodium crystal form Q5.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([CH2:21][CH3:22])[CH2:19][OH:20])=[C:15]([CH:25]=[CH2:26])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([CH2:21][CH3:22])[CH:19]=[O:20])=[C:15]([CH:25]=[CH2:26])[CH:14]=1
Reactant: C=Cc1cc(OC)ccc1C[C@@H](CC)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=Cc1cc(OC)ccc1C[C@H](C=O)CC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
DMSO (4.9 mL, 68.8 mml) is added to a solution of oxalyl chloride (4.5 mL, 51.6 mmol) in dry DCM (100 mL) at −78° C. and the mixture is stirred at −78° C. for 10 min. A solution of (R)-2-(4-methoxy-2-vinylbenzyl)-butan-1-ol (5.70, 25.9 mmol) in DCM (30 mL) is added. The mixture is stirred at −78° C. for 15 min and then at −40˜−30° C. for 1 h. Triethylamine (18 mL, 129 mmol) is added slowly. The mixture is stirred at −10˜0° C. for 15 min. The mixture is partitioned between DCM and aq. NH4Cl. The organic extract is dried with MgSO4 and concentrated to give the title compound as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C@@H:19]([C:23]([O:25]C(C)(C)C)=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[ClH:38]>O>[ClH:38].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C@@H:19]([C:23]([OH:25])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)O)C(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-[[4-[(4-methylphenyl)thio]-phenyl]sulfonyl]-N-[2-(4-morpholinyl)ethyl]-D-valine, 1,1-dimethylethyl ester, from Example 2b (3.5 g, 6.4 mmole) in water (50 ml) was added concentrated HCl (50 ml). After stirring for 1 hour at room temperature for 30 minutes under reflux, the reaction was concentrated to give N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-N-[2-(4-morpholinyl)-ethyl]-D-valine, monohydrochloride, as a white foam (3.5 g, 100%): MS MH+ calc'd for C24H32N2S2O5 ; 493, found: 493.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8](F)[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[C:9]([F:10])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1cc(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1c(F)cc(C#N)c(F)c1F

Procedure:
Using 2,3,4,5-tetrafluorobenzonitrile (876 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg), the title compound was obtained as a colorless solid (yield: 922 mg) by an operation similar to that in Example 3.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[C:12]([O:20][CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[C:12]([O:20][CH:21]1[CH2:22][C:23]2[C:8]3[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=3)[NH:10][C:24]=2[CH2:25][CH2:26]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C1CCC(OC(=O)c2ccccc2)CC1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(OC(=O)c1ccccc1)CC3
Yield: 47.9 %

Procedure:
4-Cyanophenyl hydrazine hydrochloride (20.2 g) and 4-benzoyloxycyclohexanone (25.9 g) were dissolved in glacial acetic (400 ml) and the mixture was heated under reflux for 1.5 hr. After allowing to cool, the mixture was filtered, and the flitrate was evaporated to dryness, and neutralized with aqueous sodium bicarbonate solution to give a solid precipitate, which was purified by chromatography (SiO2 ; hexane/ethyl acetate) to give 3-benzoyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole (18 g). This product (11.6 g) was suspended in ethanol (230 ml) and treated with 2.5% aqueous potassium hydroxide solution (120 ml), and heated under reflux for 1 hr. The cooled mixture was neutralized with glacial acetic acid and evaporated to a solid residue, which was washed with water, and dried to give 3-hydroxy-6-cyano-1,2,3,4-tetrahydrocarbazole (6.6 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]3[CH:19]=2)=[CH:2]1.[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(#N)C.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.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:26]4[CH:27]=[C:22]([CH2:21][OH:20])[CH:23]=[CH:24][CH:25]=4)=[CH:14][N:13]3[CH:19]=2)=[CH:2]1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Brc1ccc2nc(-c3coc4ccccc34)cn2c1
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: Cc1ccccc1
Solvent: CC#N
Product: OCc1cccc(-c2ccc3nc(-c4coc5ccccc45)cn3c2)c1
Yield: 40.5 %

Procedure:
100 mg of 2-(benzofuran-3-yl)-6-bromoimidazo[1,2-a]pyridine, 73 mg of 3-(hydroxymethyl)phenylboronic acid and 11 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube. 2 ml of acetonitrile, 2 ml of toluene and 1.5 ml of a 2M solution of sodium carbonate are added thereto. The tube is placed in a microwave device and irradiated at 150° C. for 15 min. The organic phase is separated, dried, and then concentrated under reduced pressure. The oily residue is taken up with 3 ml of dichloromethane and triturated for 1 hour. The precipitate is recovered by filtration, washed with diisopropyl ether and dried in a desiccator under reduced pressure. 44 mg of compound are obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Br[CH2:11][CH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CCN(CCO)c1ccccc1

Procedure:
A mixture of 101 ml (800 mmol) of freshly distilled N-ethylaniline 14, 71.0 ml (1.00 mol) of 2-bromoethanol, 138 g (1.00 mol) of anhydrous K2CO3 and 8.30 g (50.0 mmol) of anhydrous KI is dissolved in 300 ml of dry n-butanol is refluxed for four days under argon atmosphere and vigorously stirring. After cooling down, the inorganic salts are filtered off and washed with diethylether. The solvents are evaporated under reduced pressure and the crude reaction product is purified by means of a vacuum destillation.
Reaction SMILES: C([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)=[C:11]([F:28])[CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>O1CCCC1.[Pd]>[Cl:23][C:20]1[CH:21]=[C:22]2[C:14]([CH2:13][C:12]3[C:11]([F:28])=[CH:10][C:9]([OH:8])=[C:25]([O:26][CH3:27])[CH:24]=3)=[CH:15][NH:16][C:17]2=[N:18][CH:19]=1
Reactant: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(F)cc1O

Procedure:
3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (224, 48 mmol) was dissolved in tetrahydrofuran (300 mL) and 20% palladium on carbon (50% water wet, 2.3 g) was added. The mixture was stirred under an atmosphere of hydrogen at 50 psi in the presence of acetic acid (100 mL). The reaction mixture was filtered through Celite and evaporated to dryness to give the desired compound 225. MS (ESI) [M+H+]+=307.1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(O[K])(C)(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:23][C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: O=C(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexanol (611 mg), 4-(chloroacetyl)morpholine (1.05 g) and tert-butoxy potassium (718 mg) in THF (10 mL) was stirred at room temperature overnight and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (882 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>Cl[Ti](Cl)(Cl)Cl.ClCCl>[C:17]([C:16]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=2[CH:10]=1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. The TiCl4 in the reaction path stands for titanium chloride. To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (409 mg, 2.00 mmol) were added titanium chloride (417 mg, 2.20 mmol) and pivaloyl chloride (361 mg, 2.99 mmol) followed by stirring at 120° C. for 1 hour. The reaction solution was diluted by dichloromethane, and the organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (40/3) as an elution solvent. The yield was 53.6 mg (9.0%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([O:12][C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([O:28][CH3:29])[N:19]3C3CCCCO3)=[C:15]([NH2:30])[N:14]=2)[CH2:11][CH2:10][CH2:9]1>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([O:12][C:13]2[NH:14][C:15]([NH2:30])=[C:16]3[C:20]([N:21]=2)=[N:19][C:18]([O:28][CH3:29])=[N:17]3)[CH2:9][CH2:10][CH2:11]1
Reactant: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2nc(OC3CCC3)[nH]c(N)c-2n1
Temperature: 20 °C
Reaction time: 21 h
Yield: 78.6 %

Procedure:
Trifluoroacetic acid (3 ml, 38.9 mmol) was added to a solution of 2-(cyclobutyloxy)-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.27 g, 3.98 mmol) in methanol (50 ml) and the mixture stirred at 20° C. under an atmosphere of nitrogen for 21 hours. The solvent was removed in vacuo, and the residual solid was triturated with 1,1-dimethylethyl methyl ether and then collected by filtration and dried in vacuo to give the title compound as a cream solid (1.0922 g).
Reaction SMILES: N(C[C@H]1OC(=O)N(C2C=CC(SC)=C(F)C=2)C1)=[N+]=[N-].ICC.[N:23]([CH2:26][C@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:36]([S:39][C:40](C3C=CC=CC=3)(C3C=CC=CC=3)[C:41]3C=CC=CC=3)=[C:35]([F:59])[CH:34]=2)[CH2:28]1)=[N+:24]=[N-:25]>>[N:23]([CH2:26][C@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:36]([S:39][CH2:40][CH3:41])=[C:35]([F:59])[CH:34]=2)[CH2:28]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Agent: CSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Solvent: CCI
Product: CCSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-one from iodoethane (0.117 ml, 1.47 mmol) and 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one (0.500 g, 0.979 mmol). Yield 0.267 g (92%). MS (m/z): [M+H]+=297.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O1CCCC1.[OH-].[Na+]>Cl[Pd](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.O>[C:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-c3ccccc3)nc2c1
Yield: 26.5 %

Procedure:
To a mixture of 0.78 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of phenylboronic acid, 5 ml of tetrahydrofuran and 0.14 g of dichlorobis(triphenylphosphine)palladium (II), 3 ml of 10% aqueous solution of sodium hydroxide was added and heated to reflux for three hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.18 g of 2-(3-phenyl pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 32”).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].CCOC(C)=O.O=[Si]=O>C(NC(C)C)(C)C.C1COCC1.Cl[Pd](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.[Cu]I>[CH3:11][C:8]1([CH3:12])[CH2:7][O:6][C:5]2[CH:13]=[CH:14][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: CC1(C)COc2ccc(I)cc2OC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=[Si]=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC1(C)COc2ccc(C#C[Si](C)(C)C)cc2OC1
Temperature: 57 °C

Procedure:
To a mixture of [PdCl2(PPh3)2] (1.73 g) and copper(I) iodide (845 mg) under Ar is added a degassed solution of 7-iodo-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (7) (15.0 g) in diisopropylamine (225 ml) and THF (225 ml). Trimetylsilylacetylene (7.27 g) is added and the mixture is stirred over night at 57° C. After addition of AcOEt (1 L) and filtration over dicalite, the solution is washed with 1 N aq. HCl sol. (3×1 L) and brine (2×1 L). The organic layer is dried over Na2SO4 and the solvent is evaporated to yield (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-trimethyl-silane (6b) as a brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[C:9]1([S:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCCCCCSc1ccccc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(6-chlorohexyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]3[C:35](O[C:38](=[O:39])[C:31]=3[CH:30]=2)=[O:36])=[CH:24][CH:23]=1)([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]3[C:17](O[C:20](=[O:21])[C:13]=3[CH:12]=2)=[O:18])=[CH:6][CH:5]=1)[CH3:3].[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>CN(C=O)C>[CH3:3][C:2]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[C:31]3[C:32](=[CH:33][CH:34]=2)[C:35](=[O:36])[N:40]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)[C:38]3=[O:39])=[CH:24][CH:23]=1)([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:14](=[CH:15][CH:16]=2)[C:17](=[O:18])[N:40]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)[C:20]3=[O:21])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)(c1ccc(Oc2ccc3c(c2)C(=O)OC3=O)cc1)c1ccc(Oc2ccc3c(c2)C(=O)OC3=O)cc1
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Oc2ccc3c(c2)C(=O)N(c2ccc(O)cc2)C3=O)cc1)c1ccc(Oc2ccc3c(c2)C(=O)N(c2ccc(O)cc2)C3=O)cc1

Procedure:
247.2 g of 4,4′-(4,4′-isopropylidenediphenoxy)bis(phthalic anhydride) (0.47 mol) are dissolved in 200 ml of DMF in a 3 l three-necked flask with reflux divider, reflux condenser and distillation bridge. 105.8 g of 4-aminophenol (0.095 mol) are slowly added dropwise. The mixture is heated at reflux for 2 hours. Water is continuously removed by distillation during this process. The mixture is then cooled, diluted with 500 ml of dichloromethane, and washed twice with water. Finally, the product is washed with saturated NaCl solution. The organic phase is concentrated, and the residue is brought to the boil in 300 ml of methanol. After cooling, the residue is isolated by suction filtration and then washed with 200 ml of methanol.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C@H:3]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH:29](I)([CH3:31])[CH3:30].C1CCN2C(=NCCC2)CC1>C(#N)C>[OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:29]([CH3:31])[CH3:30])=[O:17])[C@H:3]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC[C@@H]1[C@@H](C/C=C\CCCCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: CC(C)I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCCCCC[C@@H]1[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O

Procedure:
The compound (27-5) was reacted with isopropyl iodide and DBU in dry acetonitrile and the resultant was purified on silica gel column to give the titled compound (27-6).