Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C12C(C3C=CC(O)=CC=3)C(CCC1)CCC2.C1O[C@H]1CCl.C([O:47][C:48](=O)[C:49]#[C:50][CH2:51][F:52])C>C(O)(C)(C)C>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:48](=[O:47])[CH:49]=[C:50]([CH2:51][F:52])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: CCOC(=O)C#CCF
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2C3CCCC2CCC3)cc1
Solvent: CC(C)(C)O
Product: O=c1cc(CF)n2c(n1)O[C@H](COc1ccc(C3C4CCCC3CCC4)cc1)C2
Yield: 123.5 %

Procedure:
To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine (1.1 g, 3.5 mmol) (prepared from 4-bicyclo[3.3.1]non-9-yl-phenol and R-epichlorohydrin employing the procedures in Steps 1 through 2 of Example 1) in t-butanol (13 mL) was added 0.82 g (0.63 mmol) of 4-fluoro-but-2-ynoic acid ethyl ester (prepared in accordance with the procedures as described in Poulter, J Org Chem 1981, 46, 1532). The reaction mixture was refluxed for 6 hours after which it was concentrated and loaded on silica gel column and eluted with 1-6% EtOH/CH2Cl2 to afford 0.31g of the title compound. [α]D25 −26.00 (c 0.5, CHCl3).
Reaction SMILES: O1CCC1.Br[CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.CN(C)C=O>[N:13]([CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1)=[N+:14]=[N-:15]
Reactant: OCC1(CBr)COC1
Reactant: [N-]=[N+]=[N-]
Agent: C1COC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC1(CO)COC1

Procedure:
The oxetane of the present invention has the formula: ##STR1## The oxetane of Formula I, 3-azidomethyl-3-nitratomethyloxetane (ANMO), is synthesized using 3-bromomethyl-3-hydroxymethyl oxetane (BMHMO) as the starting material. Reaction of 3-bromomethyl-3-hydroxymethyloxetane with sodium azide (NAN3) in acetone or dimethylformamide (DMF) gives the corresponding 3-azidomethyl-3-hydroxymethyloxetane in essentially quantitative yield. Subsequent reaction of 3-azidomethyl-3-hydroxymethyloxetane with acetyl nitrate gives the oxetane AMNO.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[C:8]=1[CH3:11])=[O:19]
Reactant: O=C(Cl)CCCCCl
Reactant: COc1ccc2occ(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COc1ccc2oc(C(=O)CCCCCl)c(C)c2c1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized in Example A104(2) above, 5-chlorovaleryl chloride (1.74 mL) and nitromethane (40 mL) was added aluminum chloride (2.47 g) at 0° C., and the mixture was stirred for 2 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title object compound (2.63 g, 76%) as a pale-yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](OC)=[O:20])[CH:17]=2)[N:12]=[CH:11][N:10]1[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C(O)(=O)C>CO.CN(C=O)C>[OH:3][NH:2][C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:9]2=[O:8])=[O:20]
Reactant: COC(=O)c1ccc2ncn(C(C)(C)c3ccccc3)c(=O)c2c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(c1ccccc1)n1cnc2ccc(C(=O)NO)cc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
A mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10.0 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogeneous. To this heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6.0 mL). A precipitate formed on mixing. After heating at 90° C. for 30 minutes, the mixture was cooled to rt and the solids were allowed to settle. The resulting solution was assumed to contain 1.7 M hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (2.0 mL, 3.5 mmol) was added to a solution of methyl 4-oxo-3-(2-phenylpropan-2-yl)-3,4-dihydroquinazoline-6-carboxylate (0.11 g, 0.35 mmol) in methanol (0.75 mL) and DMF (0.50 mL). After stirring for 4 h at rt, excess reagent was quenched by the addition of acetic acid (0.2 mL, 3.5 mmol). The mixture was concentrated to dryness and the residue was twice co-evaporated with toluene. The crude product was purified by preparative HPLC to afford N-hydroxy-4-oxo-3-(2-phenylpropan-2-yl)-3,4-dihydroquinazoline-6-carboxamide (84 mg, 75%). LC-MS: (FA) ES+ 324; 1H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.14 (dd, J=8.5, 2.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.34-7.14 (m, 5H), 1.96 (s, 6H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:36])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:32]1[N:31]=[CH:30][C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:36])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:33]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M6) (390 mg, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (168 mg).
Reaction SMILES: SC1SCCN=1.O[C:8]1[CH:28]=[CH:27][C:11]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17](O)=[CH:18][C:19]=3O)[O:14][C:13]=2CBr)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[C:12]([C:11]2[CH:27]=[CH:28][CH:8]=[CH:9][CH:10]=2)=[CH:13]1
Reactant: O=c1c(-c2ccc(O)cc2)c(CBr)oc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: SC1=NCCS1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)coc2ccccc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
2-Mercaptothiazoline (35 mg) was added to a mixture of 4',5,7-trihydroxy-2-bromomethylisoflavone (50 mg), anhydrous potassium carbonate (21 mg) and N,N-dimethylformamide (1 ml), and the resulting mixture was stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:chloroform), giving 32 mg of 4',5,7-trihydroxy-2-[2-thiazolin-2-ylthio)methyl]isoflavone as amorphous powder.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]([CH2:12]Cl)=O)[CH3:6]>C(O)C>[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]1[N:4]=[C:1]([CH3:2])[S:3][CH:12]=1)[CH3:6]
Reactant: CC(N)=S
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(C)n1
Yield: 75.2 %

Procedure:
Prepare a solution of thioacetamide (10 g, 133 mmol) in ethanol (75 mL). Add ethyl-4-chloroacetoacetate (16.5 mL, 122 mmol). Stir the reaction overnight at 50° C. and then concentrate in vacuo. Dissolve the resulting oil in water (75 mL) and extract with diethyl ether (3×50 mL). Extract the aqueous layer with CHCl3 (3×50 mL). Wash the combined organic layers with brine (50 mL), dry (Na2SO4), filter, and concentrate in vacuo to afford (2-methylthiazol-4-yl)acetic acid ethyl ester (17 g) as a solid. 1H NMR (CDCl3) δ 7.02 (s, 1H), 4.15-4.25 (m, 2H), 3.79 (s, 2H), 2.71 (s, 3H), 1.25 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:21]COC)=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=[O:16])[CH3:2].O>CC(C)=O.Cl>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCc1cccc2c(/C(C)=C/C(=O)O)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCc1cccc2c(/C(C)=C/C(=O)O)cc(OC)c(O)c12
Reaction time: 1 h
Yield: 72.9 %

Procedure:
280 mg of (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoic acid was dissolved in 8 ml of acetone, to which 1 ml of concentrated hydrochloric acid was added at room temperature. After stirring for 1 hour, 30 ml of water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated to obtain 177 mg of the titled compound as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:15][O:14][CH2:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:16]([O:18][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[O:22])=[O:17])[CH2:10]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (10 g, 38.61 mmol) in DCM (100 mL) was added (2-bromo-1-(4-bromophenyl)-ethanone (11.8 g, 42.47 mmol) and triethylamine (7.8 g, 77.22 mmol). The reaction mixture was stirred at RT for 3 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate, concentrated, and purified by column chromatography to provide the title intermediate (12 g, 56% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ(ppm) 1.438-1.466 (d, 9H, J=11.2 Hz), 2.024-2.056 (t, 1H, J=12.8 Hz), 2.553 (s, 2H), 3.214-3.776 (m, 6H), 4.410-4.850 (t, 1H, J=15 Hz), 5.155-5.549 (m, 1H), 7.270-7.278 (t, 1H, J=1.6 Hz), 7.636-7.654 (d, 1H, J=7.2 Hz), 7.765-7.774 (d, 1H, J=3.6 Hz).
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[CH:4][C:5]2[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][C:6]=2[CH:21]=1.[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34](OB(O)O)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([C:2]2[C:3]([CH3:22])=[CH:4][C:5]3[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][C:6]=3[CH:21]=2)=[CH:35][CH:36]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)C1=Cc2cc(Br)c(C)cc2N(CC(C)C)CCC1
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2cc3c(cc2C)N(CC(C)C)CCCC(C(=O)OC)=C3)cc1
Reaction time: 1 h
Yield: 67 %

Procedure:
A suspension of methyl 8-bromo-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (900 mg) and 4-(2-butoxyethoxy)phenyl boric acid (759 mg) and potassium carbonate (883 mg) in toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under argon atmosphere for 1 hour. Then, tetrakis(triphenylphosphine)palladium (142 mg) was added and the mixture was refluxed for 6 hours. After returning 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. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate=30:1→6:1) to give methyl 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (790 mg) as a yellow oily material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:11].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl.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>[CH:19]1([N:12]([CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])[C:10](=[O:11])[CH2:9][CH2:8][O:7][CH2:6][CH2:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(CN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1)OC
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: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Temperature: 100 °C
Yield: 108.3 %

Procedure:
To 3-(3-bromophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide (1.4 g), prepared as in Preparation 3 Step iii), within a 35 mL microwave tube with stirrer were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.92 g), potassium carbonate (0.88 g) and Pd(Ph3P)4 (0.18 g) followed by methanol (8 mL). The vial was sealed and heated within a CEM Discover microwave at 100° C. for 15 min. The mixture was diluted with DCM and washed once with water, once with brine, dried over sodium sulphate and the solvent evaporated to afford crude material as an orange oil. This was purified on silica using ethyl acetate as the eluent to afford the product (1.52 g). MS [M+H-MeOH]+=412 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.78 and 7.77 (2×s, 1H), 7.40-7.32 (m, 2H), 7.23 and 7.22 (2×t, J=7.6 Hz, 1H), 7.07-7.03 (m, 1H), 4.52 and 4.36 (2×t, J=5.3 Hz, 1H), 4.05-3.95 and 3.69-3.60 (2×m, 1H), 3.901 and 3.898 (2×s, 3H), 3.75-3.64 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.34 and 3.25 (2×d, J=5.1 Hz, 2H), 2.84 and 2.83 (2×t, J=6.6 Hz, 2H), 2.65 and 2.63 (2×t, J=6.1 Hz, 2H), 1.79-1.04 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:32])=[CH:14][CH:15]=2)[N:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH3:32])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[OH:8])[N:18]=2)[CH2:20]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (500 mg, 1.14 mmol) in CH2Cl2 (15 mL) was added TFA (5 mL). The mixture was stirred for 1 h and then neutralized with a 1 M NaOH solution, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 3-20% EtOAc/CH2Cl2 gave 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol. LC/MS: m/z 339.5 (M+H)+ at 0.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21](SC)=[CH:20][CH:19]=3)[OH:17])=[CH:12][C:11]=2[C:26]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[CH:5][CH:4]=1.[CH:42]1C=C(Cl)C=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[S:58]([O-:62])([O-])(=[O:60])=S.[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([S:58]([CH3:42])(=[O:62])=[O:60])=[CH:20][CH:19]=3)[OH:17])=[CH:12][C:11]=2[C:26]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(O)c3ccc(SC)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(C(O)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)(4-(methylthio)phenyl)methanol (241 mg, 0.423 mmol) was dissolved in DCM (4.0 mL) and the reaction flask was cooled in an ice water bath under nitrogen. Then, mCPBA (180.5 mg, 1.046 mmol) was added as a solution in DCM (5 mL) via syringe, and the reaction was warmed to room temperature and stirred. After 45 min, more mCPBA (58 mg, 0.34 mmol) was added, and stirring was continued. After 25 min, more mCPBA (27.3 mg, 0.158 mmol) was added, and stirring was continued. After 15 minutes, the reaction was treated with a solution made of 10 mL saturated sodium bicarbonate and 2 mL saturated sodium thiosulfate. The mixture was stirred at room temperature for 30 min. Then, the layers were separated and the aqueous phase was extracted with DCM and then with 10:1 DCM/MeOH. The organic extracts were combined, washed with brine, concentrated, and dried under high vacuum in a water bath (about 40° C.) to give (6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)(4-(methylsulfonyl)phenyl)methanol, which was taken on directly to the next step. 1H NMR (CDCl3, 400 MHz) δ 12.54 (s, 1H), 9.75 (s, 1H), 8.40 (s, 1H), 8.27-8.21 (m, 2H), 8.17 (d, J=8.22 Hz, 1H), 7.95-7.89 (m, 2H), 7.74-7.68 (m, 2H), 6.78 (d, J=10.17 Hz, 1H), 6.01 (s, 1H), 5.85 (d, J=11.93 Hz, 1H), 4.21 (d, J=13.11 Hz, 1H), 3.95 (s, 3H), 3.87-3.77 (m, 1H), 3.03 (s, 3H), 2.97-2.89 (m, 1H), 2.89 (s, 3H), 2.19-1.95 (m, 3H), 1.93-1.65 (m, 3H). m/z (ESI, +ve ion) 602 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([OH:30])[CH3:29])[CH:9]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[CH3:48][S:49]([O:30][CH:28]([C:10]1[CH:9]=[C:8]([N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:39])([CH3:1])[CH3:40])[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=1)[CH3:29])(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethanol (6.1 g, 10.4 mmol) in methylene chloride (100 mL) and triethylamine (7.1 mL, 50.9 mmol) under nitrogen was added methanesulfonyl chloride (2.4 mL, 31.0 mmol) dropwise. After 15 minutes the reaction was complete by HPLC. The contents of the flask were transferred to a separatory funnel, washed twice with water and twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethyl methanesulfonate (6.8 g; 98% yield) as a dark yellow oil that was used as is for the following step. HPLC: 6.18 min (Method D). LCMS: ESI+ m/z of 662 (M+H)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=O.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35]([N:30]([CH2:29][C:19]1[CH:20]=[C:21]([C:24]2[O:25][CH:26]=[CH:27][N:28]=2)[CH:22]=[CH:23][C:18]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:10])=[O:11])[CH3:31])=[O:37]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(Cl)cc2Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (30 mg, 0.068 mmol, prepared as described in Step (A) of Example 28) and 2,4-dichlorobenzoic acid (13.1 mg, 0.068 mmol) in 0.68 ml of CH2Cl2, 1,3-diisopropylcarbodiimide (9.5 mg, 0.075 mmol) was added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 20% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 80% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (20 mg, 48%) as a white solid, m.p. 134°-142° C. (amorphous).
Reaction SMILES: [H-].[Na+].C(OC(=O)C[SH:8])C.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][CH2:17]Br.[C:19]([O:22][CH2:23][CH3:24])(=O)[CH3:20]>O1CCCC1>[CH2:23]([O:22][C:19](=[S:8])[CH2:20][CH2:17][CH2:16][CH2:15][C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)[CH3:24]
Reactant: CCOC(=O)CS
Reactant: CCOC(C)=O
Reactant: BrCCCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=S)CCCCc1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
995 mg (22.8 mmol) of sodium hydride in the form of a 55% suspension in mineral oil are placed at from 0° to 5° in 30 ml of tetrahydrofuran, and 2.1 25 ml (19 mmol) of thioglycolic acid ethyl ester are added dropwise thereto. The mixture is stirred for 30 minutes at from 0° to 5°; 3.9 g (19 mmol) of 3-(2-thienyl)propyl bromide are added dropwise under nitrogen at from 0° to 5° and the mixture is allowed to rise to room temperature and is then stirred for 3 hours. The mixture is then again cooled to from 0° to 5°, 200 ml of ethyl acetate and 100 ml of ice-water are added and the organic phase is separated off and then shaken twice with 100 ml of ethyl acetate each time. The combined organic phases are washed three times with 100 ml of water each time and then with saturated sodium chloride solution, dried over sodium sulfate, filtered, concentrated by evaporation under reduced pressure at 35° and distilled. 3.755 g (80.2% of theory) of 3-(2-thienyl)propylthioacetic acid ethyl ester are obtained in the form of a bright-yellow liquid.