Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)([OH:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Brc1ccccn1
Reactant: O=C(O)c1ccc(B(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: [Na+]
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ccccn2)cc1

Procedure:
2-Bromopyridine (1.26 g, 7.97 mmol), 4-carboxyphenylboronic acid (1.32 g, 7.95 mmol), and Pd(PPh3)4 (0.48 g, 0.42 mmol) were stirred at 90° overnight in CH3CN (40 mL) and 0.4 M Na2CO3 solution (40 mL, 16 mmol). After this time, the mixture was filtered hot, and the filtrate was concentrated to half-volume under reduced pressure. The remaining liquid was washed with CH2Cl2 (2×20 mL) and then acidified to pH 1 with concentrated HCl. The resulting precipitate was collected by filtration, washed with H2O, and allowed to air-dry to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.74 (m, 1H), 8.19–8.23 (m, 2H), 7.99–8.12(m, 4H), 7.47–7.52 (m, 1H); MS (ESI+) m/z 200 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH:13]=O)[C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:16]O.[OH-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O>C1COCC1.C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:16])[C:4]=2[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C[C@@H]1C[C@H]1c1cccc2c1CCO2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Reaction time: 18 h
Yield: 70.5 %

Procedure:
A mixture of (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxaldehyde (1.98 g, 10.5 mmol), hydroxylamine hydrochloride (2.29 g, 33 mmol), and 30% NaOH (3.5 mL, 35 mmol), in 5:1 ethanol/water (50 mL) was heated on a steam bath for 2 h. The solution was concentrated in vacuo, and the residue mixed with water. The mixture was extracted with CH2Cl2. The organic extracts were dried and concentrated in vacuo to give a solid which NMR analysis showed to be a mixture of the cis and trans oximes. This material was dissolved in THF (20 mL) and added to solution of alane in THF [prepared from LAH (1.14 g, 30 mmol) and H2SO4 (1.47 g, 15 mmol) at 0° C⟧ The reaction was stirred for 18 h, and quenched successively with water (1.15 mL), 15% NaOH (1.15 mL), and then water (3.45 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was mixed with ether and washed with water and then 1N HCl. The acid washes were made basic and extracted with CH2Cl2. The extracts were dried and concentrated in vacuo to give the amine product (1.4 g, 70.5%). The amine was converted to the fumarate salt in ethanol (mp: 197-198° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:15]2[CH2:28][CH2:27][N:18]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=4[C:25]([F:26])=[C:17]3[C:16]2=[O:29])=[N:8][CH:9]=[CH:10][C:11]=1B(O)O)(=[O:3])[CH3:2].Cl[C:31]1[CH:32]=[C:33]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([CH:52]4[CH2:55][O:54][CH2:53]4)[CH2:48][C@@H:47]3[CH3:56])=[CH:42][N:41]=2)[C:34](=[O:38])[N:35]([CH3:37])[N:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:15]2[CH2:28][CH2:27][N:18]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=4[C:25]([F:26])=[C:17]3[C:16]2=[O:29])=[N:8][CH:9]=[CH:10][C:11]=1[C:31]1[CH:32]=[C:33]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([CH:52]4[CH2:53][O:54][CH2:55]4)[CH2:48][C@@H:47]3[CH3:56])=[CH:42][N:41]=2)[C:34](=[O:38])[N:35]([CH3:37])[N:36]=1)(=[O:3])[CH3:2]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)n2)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 231c (200 mg, 0.50 mmol), (S)-6-chloro-2-methyl-4-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridazin-3(2H)-one 224c (195 mg, 0.50 mmol), PdCl2(dppf) (24 mg, 0.030 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (98 mg, 1.0 mmol), acetonitrile (30 mL), and water (3 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 231d as a yellow solid (213 mg, 60%). MS-ESI: [M+H]+ 712.3
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2]C(C)=O.[N:14]([O-])=[O:15].[Na+].S(=O)(=O)(O)O>[OH-].[Na+]>[OH:15][N:14]=[CH:2][C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=NO)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Acetoacetanilide (25.0 g, 0.14 mol) and sodium nitrite (12.65 g, 0.18 mol) were dissolved in aqueous sodium hydroxide solution (140 ml, 1 N) and the resulting solution was added dropwise over 20 min to an aqueous solution of sulfuric acid (120 ml conc. H2SO4 in 950 ml water) cooled in an ice bath. The reaction mixture was stirred at 0° C. for 30 min, then the precipitate was filtered and washed with water to yield 2-hydroxyiminoacetanilide (22.64 g., 78% yield) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Cl)nc1N1CCCCC1

Procedure:
Method 1 was followed using 2,4-dichloro-5-nitropyrimidine (1.0 eq), and piperidine (2.0 eq) in EtOH at 0° C. to rt, yielding after washing with 1M citric acid and 1M HCl (to remove the bis addition product), 2-chloro-5-nitro-4-(piperidin-1-yl)pyrimidine (67%) LCMS (m/z): 242.9 (MH+); LC Rt=4.09 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11](=[O:31])[C@:10]([CH2:33][C:34]#[N:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH:36]1[C:34]([CH2:33][C@@:10]2([CH3:32])[CH2:9][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]2=[O:31])=[N:35][N:38]=[N:37]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(Cc2nnn[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 120 h

Procedure:
To a solution of (S)-tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(cyanomethyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (101 mg, 0.196 mmol; Example 128, Step B) in DMF (0.50 mL) was added sodium azide (127 mg, 1.96 mmol) and NH4Cl (105 mg, 1.96 mmol). The resulting mixture was stirred at 90° C. for 5 days. Then, the reaction was quenched (aq. 10% citric acid), extracted (2×EtOAc), and washed (3×sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by RP-HPLC (60 to 85% AcCN/H2O, gradient elution) provided the title compound as a white solid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:33])[CH:8]([O:30][CH2:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH:11]=1)C>O.O1CCCC1>[CH2:31]([O:30][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)[CH:11]=1)[C:7]([OH:33])=[O:6])[CH3:32]
Reactant: CCOC(=O)C(Cc1cccc(OCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1cccc(OCCc2ccc(OS(C)(=O)=O)cc2)c1)C(=O)O
Yield: 96.6 %

Procedure:
Lithium hydroxide hydrate (0.175 g; 4.18 mmole) in water (5 ml) was slowly added to a solution of 2-ethoxy-3-{3-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 22) (1.66 g; 3.80 mmole) in tetrahydrofuran (17 ml) at 0° C. After stirring at room temperature for 2 hours tetrahydrofuran was removed by evaporation in vacuo. The residue was extracted with diethyl ether. The water phase was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 1.5 g (96.5% yield) of 2-ethoxy-3-{3-[2-(4-methanesulfonyloxyphenyl)ethoxy]-phenyl}propanoic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].II.[PH2](O)=O>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: II
Agent: O=[PH2]O
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 160 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose, 127 mg of iodine and 110 mg of aqueous hypophosphorous acid solution (about 30%) and the mixture was refluxed with stirring in a water bath at 60° C. for 6 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was then subjected to an after-treatment similar to that described in Example 11 to give 11.56 g (80.0%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥98%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH:12]=1)[C:9](O)=[O:10].C[N:26](C=O)C>S(Cl)(Cl)=O>[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH:12]=1)[C:9]([NH2:26])=[O:10]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A solution of 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (9.63 g, 24 mmol) in thionyl chloride (20 ml) and DMF (50 μl) was heated at 45° C. for 1.5 hours. The excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The resulting solid was suspended in THF (250 ml) and methylene chloride (100 ml) and ammonia was bubbled though the mixture for 30 minutes and the mixture stirred for a further 1.5 hours at ambient temperature. The volatiles were removed by evaporation, the residue was dissolved in water and applied to a Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted with water/methanol (100/0 to 95/5). The solvent was removed by evaporation from the fractions containing product and the residue was dissolved in a minimum of methanol and the solution was diluted with ether. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzamide (7.23 g, 73%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[CH3:19])[CH:10]=[C:9]([CH3:20])[C:5]=1[C:6]([NH2:8])=[O:7])[CH3:2].[OH-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1C=CC=CC=1.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:8][C:6](=[O:7])[C:5]2[C:9]([CH3:20])=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C@H:14]3[CH3:19])=[CH:12][C:4]=2[S:3][CH2:1][CH3:2])=[CH:26][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCSc1cc(N2CCOC[C@H]2C)cc(C)c1C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCSc1cc(N2CCOC[C@H]2C)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 32.4 %

Procedure:
To a solution of 2-ethylsulfanyl-6-methyl-4-[(3R)-3-methyl-morpholin-4-yl]-benzamide (0.05 g, 0.17 mmol) in benzene-tetrahydrofuran (1:1) (2 ml) are added tetrabutylammonium hydrogensulfate (0.006 g, 0.017 mmol) and 50% sodium hydroxide solution (1.5 ml) at RT. 4-Chlorobenzyl bromide (0.038 g, 0.19 mmol) is added and the reaction mixture is slowly heated to 70° C. The reaction mixture is stirred at 70° C. for additional 45 min. After completion of the reaction (monitored by TLC), the organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 ml). The organic layer is washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 8% acetone/hexane) to yield N-[(4-chlorophenyl)-methyl]-2-ethylsulfanyl-6-methyl-4-[(3R)-3-methyl-morpholin-4-yl]-benzamide (example 4) (0.023 g, 0.055 mmol, 32%). [M+H]+ 419.2.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][NH:24][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)(C)(C)C.C(N(C(C)C)CC)(C)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>CN(C)C=O>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([C:39]([NH:38][CH2:36][CH3:37])=[O:40])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3)c1
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)N1CCc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc21
Temperature: 60 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
4-(3-t-Butoxyphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (20 mg, 0.056 mmol) was dissolved in dimethylformamide (1 mL), and diisopropylethylamine (29 μL, 3 equivalents) and ethyl isocyanate (13 μL, 3 equivalents) were added, followed by stirring at 60° C. for 2 days. The reaction mixture was poured onto water, followed by extraction with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtering off the drying agent, concentration was carried out under reduced pressure, and the resulting residue was stirred at room temperature for 30 minutes in trifluoroacetic acid. Concentration was carried out under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane), to obtain the desired compound (colorless powder, 1.7 mg, 9%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@:6]([C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[F:20])([CH3:12])[C:7]([F:11])([F:10])[CH2:8][OH:9])=[O:4].CCCCCCC>C(OCC)(=O)C>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([F:20])=[C:13]([C@:6]2([CH3:12])[C:7]([F:11])([F:10])[CH2:8][O:9][CH2:2][C:3](=[O:4])[NH:5]2)[CH:18]=1
Reactant: C[C@@](NC(=O)CBr)(c1cc(Br)ccc1F)C(F)(F)CO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@]1(c2cc(Br)ccc2F)NC(=O)COCC1(F)F
Yield: 64.9 %

Procedure:
Prepared in an analogous manner as described for intermediate A27A from 2-Bromo-N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-3-hydroxy-1-methyl-propyl]-acetamide (intermediate A15B) (700 mg; 2.82 mmol). After silica gel column chromatography with heptane and ethyl acetate the (R)-5-(5-bromo-2-fluoro-phenyl)-6,6-difluoro-5-methyl-[1,4]oxazepan-3-one (366 mg, 1.83 mmol, 65% yield) was obtained as a white solid. MS (ISP): m/z=337.0 [(M+H)+] and 339.0 [(M+2+H)+].
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[C:20]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([NH:12][C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[O:5][CH2:4][C:3]([OH:38])=[O:2])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(OC)cc4)c(-c4ccc(OC)cc4)c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2oc3ncnc(Nc4cccc(OCC(=O)O)c4)c3c2-c2ccc(OC)cc2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dissolve 107 mg (0.209 mmol) of 3-{[5,6-bis(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}-phenoxyacetic acid methyl ester in 2 ml of THF, add 0.628 ml of 1N sodium hydroxide solution at RT and stir at 50° C. for 1 h. Cool to RT and remove the THF under reduced pressure. Add water to the residue and then, with ice cooling, 1N hydrochloric acid. Filter off the precipitated solid, wash repeatedly with water and dry at 40° C. under reduced pressure. 92.5 mg (88.9% of theory) of the target compound are obtained as white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[C:13](Cl)([Cl:15])=[O:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:10])([F:11])[F:12])[C:13]([Cl:15])=[O:14]
Reactant: O=C(Cl)Cl
Reactant: CNc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C(=O)Cl)c1ccccc1C(F)(F)F
Yield: 82.6 %

Procedure:
A mixture of 1.00 g (5.71 mmole) of 2-(methylamino)benzotrifluoride, 9 mL (17.3 mmole) of 1.93M phosgene in toluene, and 10 mL of toluene was stirred under N2 for a hour and then treated with 20 mL of 2.5N sodium hydroxide (aqueous). The layers were separated, and the organic phase was concentrated in vacuo to yield 1.12 g (83%) of the title compound as a clear oil, which eventually solidified after prolonged standing: mp 44°-46° C.; homogeneous by TLC in 3:1 hexane-EtOAc; IR spectrum νCO 1750 cm-1 ; FAB-MS m/e 237 (M+1)+.
Reaction SMILES: [Si:1]([O:8][C:9]1([C:13]2[S:14][C:15]([C:18]3[CH:19]=[C:20]([N:27]([C:35]4[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([N+:24]([O-])=O)[CH:23]=3)=[CH:16][N:17]=2)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:24][C:22]1[CH:21]=[C:20]([N:27]([C:35]2[N:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=[CH:37][N:36]=2)[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[CH:19]=[C:18]([C:15]2[S:14][C:13]([C:9]3([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12]3)=[N:17][CH:16]=2)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2cnc(C3(O[Si](C)(C)C(C)(C)C)CCC3)s2)cc([N+](=O)[O-])c1)c1nccc(C(F)(F)F)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cc(N)cc(-c2cnc(C3(O[Si](C)(C)C(C)(C)C)CCC3)s2)c1)c1nccc(C(F)(F)F)n1
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a solution of the product of Step 1 (200 mg, 0.307 mmol) in ethyl acetate (1.5 mL) was added 10% Pd/C (65 mg, 0.061 mmol), and the vessel headspace was evacuated and purged with H2. The mixture was stirred under an atmosphere of H2 (balloon) for 3 hours, at which point LCMS analysis indicated incomplete reaction. The headspace was evacuated and purged with N2, then 100 mg additional catalyst was added and the headspace evacuated again and purged with H2. The catalyst was deactivated by adding dichloromethane, then the mixture was filtered through a pre-packed Celite cartridge (ethyl acetate rinse) and concentrated in vacuo. Purification by chromatography on silica gel (80:20 to 0:100, hexanes:ethyl acetate) provided 112 mg (0.180 mmol, 59%) of tert-butyl {3-amino-5-[2-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclobutyl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[Si:20]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 37.2 %

Procedure:
To a suspension of 4-hydroxyindole (5.65 g, 42.4 mmol) in chloroform (200 mL) are added imidazole (4.33 g, 63.6 mmol) and tert-butylchlorodimethylsilane (7.03 g, 46.6 mmol), and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is washed with a mixture of a saturated brine and water (1:1, 100 mL), and the organic layer is dried over anhydrous potassium carbonate, filtered, and the filtrate is concentrated to about 50 mL under reduced pressure. The resultant is purified by silica gel column (300 g, ethyl acetate:hexane=1:5→1:1) to give the title compound as a white solid (3.90 g, yield: 37%), and the starting compound (2.62g, recovery rate: 46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Br:10])[C:3]=1[CH2:11][C:12]#[N:13].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)[CH:5]=[C:4]([Br:10])[C:3]=1[CH2:11][C:12]#[N:13]
Reactant: C1=COCCC1
Reactant: N#CCc1c(Br)cc(CO)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: N#CCc1c(Br)cc(COC2CCCCO2)cc1Br
Reaction time: 0.75 h
Yield: 85.1 %

Procedure:
A solution of 2,6-dibromo-4-hydroxymethyl-phenyl)-acetonitrile (59) (1.4 g, 4.59 mmol) in methylene chloride (30 mL) at room temperature was treated with 3,4-dihydro-2H-pyran (0.46 mL, 5.04 mmol) and p-toluenesulfonic acid monohydrate (16.10 mg, 0.085 mmol). The reaction mixture was stirred for 45 min and was then treated with a saturated aqueous sodium bicarbonate solution (3 mL), a saturated aqueous sodium chloride solution (10 mL) and water (10 mL). This mixture was extracted with methylene chloride (3×50 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution (30 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting oil was purified by flash chromatography (Isco 120 g column) using silica gel eluted with 15% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum to afford an oil which was dried under high vacuum to afford of [2,6-dibromo-4-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-acetonitrile (60) as a pale yellow oil (1.52 g, 85.4%). Used without further purification. Molecular Weight=389.0892; Exact Mass=386.9470