Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][C:41]=1O)[C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C.O>[F:31][C:32]1[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:39]=[CH:40][C:41]=1[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)c1
Temperature: 60 °C
Yield: 83.3 %

Procedure:
(Step A: To a solution of (R)-tert-butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 2 g, 5.5 mmol) in DMF (20 mL) was added potassium carbonate (0.99 g, 7.2 mmol) and methyl 3-fluoro-4-hydroxybenzoate (1.1 g, 6.6 mmol) and the reaction was heated to 60° C. overnight. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with 1 N NaOH (20 mL), and brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum to give (S)-tert-butyl 4-(3-(2-fluoro-4-(methoxycarbonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2 g, 83%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:24]2([CH2:28][CH:27]([C:29]([NH2:31])=[O:30])[NH:26][CH2:25]2)[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[C@H:27]([C:29]([NH2:31])=[O:30])[CH2:28][C:24]4([CH2:22][CH2:23]4)[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)C1CC2(CC2)CN1
Agent: Cl
Product: NC(=O)[C@@H]1CC2(CC2)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Yield: 16.8 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 50 mg, 176 μmol) was reacted with 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 135 b, 37.3 mg, 211 μmol) and purified by chiral HPLC to obtain the title compound (12 mg, 17%) as colorless oil, MS (EI): m/e=407.3 [MH+].
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Cl>CO>[CH3:1][NH:2][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([C:4]([F:14])([F:13])[F:3])[CH:6]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CN
Solvent: CO
Product: CNCc1cccc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
To a solution of methylamine 2M in MeOH (61.5 mL, 123.3 mmol), MeOH (30 mL) was added. The mixture was heated at 50° C. under stirring and 3-(trifluoromethyl)benzyl chloride (1.6 mL, 10.3 mmol) dissolved in MeOH (10 mL) were added. The reaction mixture was stirred at this temperature for 5 h. The solvent was removed under vacuo, then NaOH 1M was added and the aqueous layer was extracted with DCM. The organic layer was filtered through a phase separator and concentrated in vacuo to give 2.19 g of a colourless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.69 (s, 1H), 7.57 (d, 1H), 7.49 (t, 2H), 3.88 (s, 2H), 2.56, (s, 3H). UPLC-MS: Rt=0.39; m/z (ES+): 190 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.O[C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C@H:29]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Yield: 13 %

Procedure:
A solution of 4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenol (1.3 g, 3.6 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.05 g, 5.4 mmol), 1,1′-(azodicarbonyl)dipiperidine (1.36 g, 5.4 mmol) and triphenylphosphine (1.42 g, 5.4 mmol) in toluene (40 ml) was stirred at 80° C. for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the extract was washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give the object compound as an oily substance. 250 mg, (yield 13%)
Reaction SMILES: Cl[C:2]1[N:3]([CH2:30][CH2:31][CH3:32])[C:4](=[O:29])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][C:14]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[CH:15][CH:16]=3)=[N:8][C:9]=2[N:10]=1.C([O-])=O.[NH4+]>[Pd].CN(C=O)C>[CH2:30]([N:3]1[C:4](=[O:29])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][C:14]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=4)=[CH:15][CH:16]=3)=[N:8][C:9]=2[N:10]=[CH:2]1)[CH2:31][CH3:32]
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(NCc4cccc(C(F)(F)F)c4)nc3)[nH]c2c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3ccc(NCc4cccc(C(F)(F)F)c4)nc3)[nH]c2c1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-Chloro-1-propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one (0.094 g, 0.2 mmol), Ammonium formate (0.256 g, 0.4 mmol), Pd/C (0.094 g) and DMF (4 ml) were stirred for 30 minutes at 60° C. The reaction mixture was cooled to room temperature and filtered through celite bed. The organic volatiles were evaporated and the residue was acidified with citric acid. The solid precipitated out was filtered to get pure 1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one as off white solid (16 mg, 40%). 1HNMR (400 MHz, DMSO d6): δ 0.84-0.90 (m, 3H); 1.66-1.73 (m, 2H); 3.94-3.99 (m, 2H); 4.65 (d, J=5.6 Hz, 2H); 6.66 (d, J=9.2 Hz, 1H); 7.55-7.79 (m, 4H); 8.13 (dd, J=8.8 Hz, 2.4 Hz, 1H); 8.30 (s, 1H); 8.78 (d, J=2.4 Hz, 1H); 13.56 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]1([C@@H:14]([NH2:16])[CH3:15])[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:16][C@H:14]([CH:11]2[CH2:13][CH2:12]2)[CH3:15])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: C[C@H](N)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cnc(Cl)cn1)C1CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 79.8 %

Procedure:
A mixture of 5-chloropyrazine-2-carboxylic acid (0.5 g, 3 mmol), (1S)-1-cyclopropylethanamine (0.30 g, 3.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.8 g, 4.7 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.5 mmol) in methylene chloride (5 mL) was stirred at room temperature overnight (22 h.). The mixture was concentrated under reduced pressure. The residue was was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (0.54 g). LCMS (M+H)+: m/z=226.1.
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Br[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)[CH2:23][CH2:24]1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Reactant: BrCCCN1CCOCC1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCCN3CCOCC3)cc2c1
Yield: 68.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 4-(3-bromopropyl)morpholine (310 mg, 1.49 mmol) were converted to the title compound (180 mg, 69%). 1H NMR (DMSO-d6) δ 9.53 (br s, 1H), 8.06 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.73-7.68 (m, 1H), 7.55 (dd, J=8.4, 1.5 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 4.20 (t, J=5.8 Hz, 2H), 4.00 (d, J=11.0 Hz, 2H), 3.65 (t, J=11.6 Hz, 2H), 3.51 (d, J=12.3 Hz, 2H), 3.37-3.32 (m, 2H), 3.17-3.07 (m, 2H), 2.23-2.16 (m, 2H); MS (ESI+) m/z 350.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:13][C:7]2[N:8]=[CH:9][NH:10][C:11](=[O:12])[C:6]=2[CH:5]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:8]1[C:7]2[S:13][C:4]([CH3:3])=[CH:5][C:6]=2[C:11](=[O:12])[NH:10][CH2:9]1
Reactant: Cc1cc2c(=O)[nH]cnc2s1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(s1)N(CCCCBr)CNC2=O
Reaction time: 96 h

Procedure:
To a stirring mixture of NaH (1.7 g, 0.072 mol) in 150 ml anhydrous DMF at room temperature was added 4.0 g (0.024 mol) of 6-methyl thieno[2,3-d]pyrimidin-4(3H)-one (IV-3) and, after the cessation of gas evolution, 20.7 g (0.96 mol) of 1,4-dibromobutane was added. Reaction was complete after 4 days. The solution was concentration in vacuo, the residue partitioned between CH2Cl2 and water, and the organic phase isolated, dried (MgSO4), and filtered. The filtrate was concentrated and excess dibromobutane removed by Kugelrohr distillation. The solid product residue weighed 4.12 g (57%). The NMR was consistent with the assigned structure.
Reaction SMILES: [OH-].[Na+].Cl.C([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:19][C:18]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)=[CH:11][C:10]=1[F:32])(=O)C>C(O)C.O>[Cl:31][C:26]1[CH:25]=[C:24]([C:18]2([C:20]([F:21])([F:23])[F:22])[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[C:10]([F:32])[CH:11]=3)[CH2:19]2)[CH:29]=[C:28]([Cl:30])[CH:27]=1
Reactant: CC(=O)OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Yield: 69.9 %

Procedure:
In a solution of 1.50 g of crude 3-(4-acetoxymethyl-3-fluorophenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 10 ml of ethanol, 2.00 g of sodium hydroxide dissolved in 20 ml of water was added, and stirred under reflux with heat for 4.5 hours. After the completion of the reaction, the reaction mixture was cooled with ice, and adjusted to pH 2-3 by carefully adding concentrated hydrochloric acid, and extracted with ethyl acetate (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.95 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:30]([OH:31])[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1>O1CCOCC1.Cl>[OH:31][C:30]1[N:17]2[C:18]([C:19]3[CH:20]=[C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:12]([C:9]4[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=4)=[N:13][C:14]=3[CH:15]=[CH:16]2)=[N:28][N:29]=1
Reactant: Oc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ccn4c(O)nnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 8-(4-[1,3]dioxolan-2-yl-phenyl)-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-ol (3-5, 2.7 g, 6.6 mmol) in dioxane (20 mL) and 2N HCl (20 mL) was stirred at room temperature for 20 min. It was concentrated to remove most dioxane at 25° C. The residue was poured into ice cold water to give a brown solid which was collected via filtration and dried with toluene azeotropically to give the title compound. LRMS m/z (M+1) Calcd: 367.1. Found 367.1.
Reaction SMILES: C1(CCC(/[N:11]=[C:12](/[NH:41]C(=O)CCC2C=CC=CC=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[N:19]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:18]2[C:31]([O:33]CC2C=CC=CC=2)=[O:32])=O)C=CC=CC=1>C1COCC1.Cl.[Pd]>[NH:13]([CH2:14][CH2:15][CH2:16][C@H:17]1[C:20](=[O:21])[N:19]([C:22](=[O:30])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:18]1[C:31]([OH:33])=[O:32])[C:12]([NH2:41])=[NH:11]
Reactant: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N(C(=O)Nc2ccccc2)[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@H]1C(=O)N(C(=O)Nc2ccccc2)[C@@H]1C(=O)O
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of 150 (10 mg, 1.0 eq.) in THF (3 mL) and 1N HCl (0.5 mL) was added 10% Pd/C (20 mg). The reaction flask was then evacuated and flushed with hydrogen and stirred under an atmosphere of hydrogen for 18 hours. The reaction was then filtered through Celite and concentrated in vacuo. The crude material was purified via HPLC (C18, acetonitrile/water, 0.1% TFA) to yield 151 (0.5 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Br)(=[O:30])=[O:29].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1)(=[O:30])=[O:29]
Reactant: COc1ccccc1S(=O)(=O)Br
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1OC)C2

Procedure:
Prepared analogously to Example 5 from methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride and o-methoxybenzenesulphonyl bromide in chloroform in the presence of triethylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([O:26]C)=[O:25].[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1nc(-c2cc(OC)c(OC)c(OC)c2)nc2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylate (1.0 g, 2.69 mmol, 1.00 equiv), tetrahydrofuran (10 mL) and sodium hydroxide (10 mL, 20%). The resulting solution was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of dichloromethane. The pH value of the solution was adjusted to 2 with hydrogen chloride (20%). The solids were collected by filtration. This resulted in 0.6 g (62%) of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.75-3.80 (m, 3H), 3.91-3.96 (m, 6H), 7.89 (s, 2H), 8.02-8.07 (m, 1H), 8.22-8.27 (m, 2H); MS (ESI) m/z 359 ([M+H]+).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=3[CH3:39])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: COc1cccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(3-methoxyphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.21-7.38 (m, 3H), 6.96-7.04 (m, 2H), 6.72 (d, J=7.8 Hz, 1H), 5.08 (s, 2H), 3.60 (s, 3H), 2.91 (t, J=7.2 Hz, 2H), 2.51 (t, J=7.5 Hz, 2H), 2.23 (s, 3H), 2.067 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H22F3NO4S, 464.1 (M−H). found 464.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 74.7 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-tert-butylphenol (28 μL, 0.182 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-tert-butyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 75%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.57-7.67 (m, 2H), 7.12-7.28 (m, 2H), 7.00-7.09 (m, 1H), 6.82-6.94 (m, 1H), 5.20 (s, 2H), 1.34 (s, 9H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[N:32]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: COc1ccccc1-c1cc(F)cc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C=C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(F)cc2c1O[C@@H](CN=[N+]=[N-])CC2
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
A solution ((R)-8-(2-methoxyphenyl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (300 mg, 0.67 mmol) and sodium azide (0.22 g, 3.4 mmol) in anhydrous DMF (20 mL) was heated to 90° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 10 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Chromatography with 0–30% ethyl acetate in hexanes afforded 190 mg (90%) of (2R)-2-azidomethyl-8-(2-methoxy-phenyl)-6-fluoro-chroman as a colorless oil.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:25][C:24]3[C:15]([CH3:38])([CH:16]4[CH:21]([CH2:22][CH:23]=3)[CH:20]3[CH2:26][CH2:27][CH:28]([CH:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:30])[C:19]3([CH3:37])[CH2:18][CH2:17]4)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:39]([OH:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45].O1CCOCC1>CCCCCC>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:46][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH3:38])[C:24](=[CH:23][CH2:22][C@@H:21]3[C@@H:16]2[CH2:17][CH2:18][C@@:19]2([CH3:37])[C@H:20]3[CH2:26][CH2:27][C@@H:28]2[C@H:29]([CH3:30])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(C)C(=CCC4C3CCC3(C)C(C(C)CCCC(C)C)CCC43)C2)cc1
Reactant: OCCCCCCO
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 52 %

Procedure:
By use of the procedure described in the literature [Kosower, E. M. and Weinstein, S., J. Am. Chem. Soc., 78 (1956) 4347-4354; Davis, M., J. Chem. Soc., (1962) 178-181] cholesteryl p-toluenesulfonate and 1,6-hexanediol were condensed in boiling dioxane to give cholest-5-en-3β-yl 6-hydroxyhexyl ether in 52% yield as colorless plates (from hexane), m.p. 75.9°-81° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>O1CCCC1.CCOCC.C(OC(=O)C)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1nccc(OCc2ccccc2)c1OCc1ccccc1
Reaction time: 8 h

Procedure:
To 154.8 g of the product of Example 2, 86.4 g benzylalcohol and 210 g triphenylphosphine suspended in 1.5 liters (dry) tetrahydrofurane was added a solution of 139.2g diethylazodicarboxylate in 500 ml tetrahydrofuran within 20 minutes. The temperature rose to 53° C. for several hours. After 4.5 hours a clear solution was obtained. After standing overnight, a solution of HCl in ether (28 g) was added. Hydrochlorides of Example 3 and 3 A crystallized from the solution. After cooling they were isolated by filtration and washed with ether and petroleum ether. 230 g of the mixture of HCL salts of 3 and 3A was suspended in 2 liters of ethyl acetate and 1 liter of water. The pH was adjusted to 7.0 with concentrated NaOH solution. The organic phase and two organic was phases were combined and dried over Na2SO4. Filtration and distilling off the solvent yielded an oily residue which was passed through a column with 600 g SiO2. Ethylacetate as eluent. Only the title compound of Example 3B, 151.8 g, was eluted from the column. Eluation of 3A is possible with CH3OH. M.P.=92° C. (title comp. 3)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:15][C:14](=[O:16])[C:13]([CH3:17])=[C:12]([O:18]COC)[C:11]=3[CH3:22])=[CH:7][C:6]=2[CH:23]=1>Cl.C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:15][C:14](=[O:16])[C:13]([CH3:17])=[C:12]([OH:18])[C:11]=3[CH3:22])=[CH:7][C:6]=2[CH:23]=1
Reactant: COCOc1c(C)c(-c2cc3cc(N)ccc3o2)oc(=O)c1C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(-c2cc3cc(N)ccc3o2)oc(=O)c(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
THF (20 ml) was added to and stirred with 6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (58 mg), one drop of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure and the residue was purified by thin-layer chromatography (n-hexane/AcOEt =1/1) to obtain 6-(5-aminobenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.