Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.[C:13]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([NH:30][C:25]1[C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:31]=[CH:32][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:8]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1cc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)ccc1C
Yield: 28 %

Procedure:
Using the procedure described in Example 102, Part A, 3-methoxy-4-methylbenzoic acid (3.6 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 210 mg (28%) of the title compound. MS-FD m/e 416.3 (M+). Anal. for C26H28N2O3: Calc: C, 74.98; H, 6.78; N, 6.73; Found: C, 69.00; H, 6.30; N, 5.91.
Reaction SMILES: [CH3:1][S:2][CH:3]([F:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=[O:5].[F:15][N+]1C=CC(C)=CC=1S([O-])(=O)=O.CCCCCC.C(Cl)(Cl)Cl>ClC(Cl)CCl>[CH3:1][S:2][C:3]([F:15])([F:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=[O:5]
Reactant: Cc1cc[n+](F)c(S(=O)(=O)[O-])c1
Reactant: CSC(F)C(=O)c1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: ClCC(Cl)Cl
Product: CSC(F)(F)C(=O)c1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
In a 20 ml solution of 0.5 g (2.3 mmol) of 2-methylthio-2,2',4'-trifluoroacetophenone [Compound (2b-1)] in 1,1,2-trichloroethane, 0.7 g (3.7 mmol) of N-fluoro-4-methylpyridinium-2-sulfonate ("MEC-02", trade name; Daikin Industries, Ltd.) was added at an internal temperature of 80° C., followed by stirring at an internal temperature of 100° C. for 20 minutes. After cooling, the reaction mixture was added to n-hexane. The insoluble matter so precipitated was filtered off. The insoluble matter was then washed with ethyl ether, followed by combination with the hexane layer. The layers so combined were washed successively with water and saturated saline, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column using chloroform, whereby 0.26 g of the title Compound (2c-1) was obtained in the form of a light yellow oil (yield: 48.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([NH2:22])[CH3:21]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:22][CH2:20][CH3:21])=[O:13]
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Reactant: CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 5-bromo-1H-indazole-3-carboxylic acid (1.2 g, 5.0 mmol) in dichloromethane (20 mL) was added oxalyl chloride (1.26 g, 10 mmol) and 1 drop of N,N-dimethylformamide. The mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was concentrated and the residue was dissolved in dichloromethane (20 mL). Ethylamine (1.1 g, 25 mmol) was added dropwise. The reaction was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated to provide the title compound (1.27 g). +ESI (M+H+1) 270.9.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8]>C(O)C>[S:1]([CH:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8])[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: N#CSC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1

Procedure:
To a solution of 300 ml. of anhydrous ethanol and 0.15 moles of sodium thiocyanate is added 35 g. (0.12 moles) of α, 2'-dichloro-4-biphenylylacetic acid and stirred for 15 hours. The reaction mixture is filtered and washed with absolute ethanol. The filtrate is evaporated to dryness, the residue is dissolved in 250 ml. of ether and washed several times with water. The ether is then dried and evaporated to dryness to obtain α-thiocyanato-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:23]=1.C([O-])(=O)C.[K+].[CH3:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.C(#N)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>[CH:20]([N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:9]1[S:8][C:7]2[C:6]3[N:23]=[C:2]([C:35]4[C:30]([CH3:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)([CH3:22])[CH3:21]
Reactant: Cc1ncccc1B(O)O
Reactant: CC(C)n1ccnc1-c1cc2c(s1)-c1nc(Cl)ccc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ncccc1-c1ccc2c(n1)-c1sc(-c3nccn3C(C)C)cc1CCO2
Temperature: 140 °C

Procedure:
To a solution of 9-Chloro-2-(1-isopropyl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (63 mg, 0.18 mmol;), Potassium acetate (60.2 mg, 0.613 mmol;), 2-methylpyridine-3-boronic acid, (32.2 mg, 0.235 mmol;) and Tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol;) in Acetonitrile (2 mL, 30 mmol;) and Water (2 mL, 100 mmol;) was degassed. The reaction was heated in the microwave at 140° C. for 20 minutes. The reaction was cooled to r.t., then extract with ethyl acetate. The combined organics were concentrated and purified by reverse phase HPLC to give 304. MS: (ESI+)=403.1. 1H NMR (400 MHz, DMSO) δ 8.55-8.47 (m, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.50-7.43 (m, 2H), 7.36 (dd, J=7.7, 4.9 Hz, 1H), 7.29 (s, 1H), 7.00 (s, 1H), 4.82 (dt, J=13.3, 6.5 Hz, 1H), 4.43 (t, J=4.6 Hz, 2H), 2.65 (s, 3H), 1.44 (d, J=6.6 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH3:5].CS(O[CH2:11][CH2:12][S:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]2[CH2:22][C@@H:17]1[C:18]2([CH3:24])[CH3:23])(=O)=O.O>ClCCl>[CH3:23][C:18]1([CH3:24])[C@H:17]2[CH2:22][C@@H:19]1[CH2:20][CH2:21][C@H:16]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11][N:4]([CH2:3][CH2:2][OH:1])[CH3:5]
Reactant: CC1(C)[C@H]2CC[C@@H](CCSCCOS(C)(=O)=O)[C@@H]1C2
Reactant: CNCCO
Solvent: ClCCl
Solvent: O
Product: CN(CCO)CCSCC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
10 ml of N-(2-hydroxyethyl)-N-methylamine were added to the solution of 2-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethylthio]ethyl methanesulfonate in dichloromethane obtained above. The dichloromethane was then distilled off under reduced pressure, and the remaining reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was worked up by adding 30 ml of water and extracting the mixture with ethyl acetate. The organic phase was separated and concentrated. The remaining residue was purified by chromatography on silica gel using n-hexane/dichloromethane/methanol as the eluent. 2.6 g of N-(2-[2((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethy lthio]ethyl]-N-(2-hydroxyethyl)-N-methylamine were obtained.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:21])[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O.O>C(Cl)Cl>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([Br:28])=[C:13]3[C:18](=[O:21])[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCC2c3c1cccc3N(C(=O)c1ccccc1)C2c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C1CCC2c3c(ccc(Br)c31)N(C(=O)c1ccccc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.6 %

Procedure:
A portion (2.0 g) of the compound obtained in Example 1 was dissolved in anhydrous methylene chloride (20 ml) and to the solution was added N-bromosuccinimide (NBS; 1.01 g). The mixture was stirred for 3 days at room temperature. After adding water, the reaction mixture was extracted three times with methylene chloride. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride/hexane/ethyl acetate=5:5:1) and further crystallized from an ether/hexane mixed solvent to yield 2.02 g (83%) of the titled compound as pale yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15](O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([SiH](CC)CC)C>>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC(Cc1ccccc1)c1ccccc1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccccc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.6 %

Procedure:
Trifluoroacetic acid (46 ml) was added in one portion to a stirred mixture of 1-(2-bromophenyl)-2-phenylethan-1-ol (16.51 g, prepared as described in Example 3) and triethylsilane (13.80 g). The resulting mixture was stirred at room temperature for about 22 hours, then the excess trifluoroacetic acid was removed under reduced pressure. The residue was dissolved in ether and washed successively with water, aqueous sodium bicarbonate (×3) and water (×2), then dried, concentrated under reduced pressure, and chromatographed using 10% dichloromethane in petrol as eluant to give 1-(2-bromophenyl)-2-phenylethane (8.02 g, 52%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:41][C:42]1([F:55])[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][C@@H:49]([NH:53][CH3:54])[CH:50]([CH3:52])[CH3:51])[CH2:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:53]([C@@H:49]([CH:50]([CH3:52])[CH3:51])[CH2:48][N:44]1[CH2:45][CH2:46][CH2:47][C:42]([F:55])([F:41])[CH2:43]1)[CH3:54])=[O:7]
Reactant: CN[C@H](CN1CCCC(F)(F)C1)C(C)C
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CN1CCCC(F)(F)C1)N(C)C(=O)c1ccc(F)c(Cl)c1
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
3-Chloro-4-fluorobenzoic acid (0.087 g, 0.50 mmol), TBTU (0.175 g, 0.54 mmol) and NMM (0.125 mL, 1.13 mmol) was mixed in DMF (2 mL). After 10 min at rt was (S)-1-(3,3-difluoropiperidin-1-yl)-N,3-dimethylbutan-2-amine (Compound S2) (0.1 g, 0.45 mmol) and additional DMF (1 mL) added. The resultant mixture was stirred at rt overnight. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (80 mg, 47%). HRMS (M+H)+: calculated 377.1607. found 377.1613.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[F:25][C:26]([F:30])([F:29])[CH2:27][OH:28]>O>[C:8]1([C:7]2[O:6][C:5]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)=[N:4][C:3]=2[CH2:2][O:28][CH2:27][C:26]([F:30])([F:29])[F:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCC(F)(F)F
Reactant: CC(=O)N1CCC(c2nc(CCl)c(-c3ccccc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CCC(c2nc(COCC(F)(F)F)c(-c3ccccc3)o2)CC1
Temperature: 72 °C

Procedure:
A solution of 1-[4-(4-chloromethyl-5-phenyl-oxazol-2-yl)-piperidin-1-yl]ethanone (30 g, 94.1 mmol), prepared as in Intermediate 3B, in 2,2,2-trifluoroethanol (450 ml) is treated with a solution of NaOH (56 g, 1412 mmol) in water (150 ml). After heating at 72° C. for 15 hours, the reaction mixture is concentrated. The residue is partitioned between EtOAc and water. The aqueous phase is reextracted once with EtOAc, and the combined organic phases are washed with saturated brine, dried (Na2SO4) and concentrated to afford 1-{4-[5-phenyl-4-(2,2,2-trifluoroethoxymethyl)-oxazol-2-yl]-piperidin-1-yl}-ethanone.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:13])[CH3:12])=[N:9][CH:10]=1)[CH3:3].CC1(C)N([O])C(C)(C)CCC1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:13])[CH3:12])=[N:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1ccc(C(C)O)nc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OC(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
1-[5-(1-Methylethoxy)pyridin-2-yl]ethanol (22 mg, 0.119 mmol) was dissolved in acetone (1.2 mL). The resultant mixture was added with 2,2,6,6-tetramethylpiperidine 1-oxyl (2.0 mg, 0.012 mmol) and trichloroisocyanuric acid (30 mg, 0.131 mmol) under ice-cold conditions, and stirred at 0° C. for 10 minutes. The reaction solution was concentrated in vacuo, added with an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and 1-[5-(1-methylethoxy)pyridin-2-yl]ethanone (20 mg, yield 94%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[O:15]C)=[C:4](N)[CH:3]=1.N([O-])=O.[Na+].NC(N)=O>OS(O)(=O)=O.O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=3[O:15][C:9]=2[CH:10]=1
Reactant: COc1cc(Br)ccc1-c1ccc(Br)cc1N
Agent: NC(N)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Brc1ccc2c(c1)oc1cc(Br)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a suspension of 4,4′-Dibromo-2′-methoxy-biphenyl-2-ylamine (3.5 g, 9.8 mmol) in H2SO4 (2.4 g) and water (8.5 ml) at 0° C. was added slowly a solution of NaNO2 (682 mg, 9.8 mmol) in water (9 ml). The mixture was stirred at 0° C. for 2 hours. Urea (1.2 g, 20 mmol) was added and the mixture was stirred for 12 hours. The mixture was diluted with water and was heated at 70° C. for 24 hours. The mixture was cooled to 25° C. and was filtered. The collected solid was re-crystallized from benzene/methanol to give 3,7-dibromo-dibenzofuran (2.27 g).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C=O)C>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[I:3])[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccccc1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (216 mg; 5.0 mmol) in anhydrous DMF (4 mL) is added a solution of 2-iodobenzyl alcohol (1.17 gm; 5.0 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 45 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (702 mg; 5.0 mmol) in anhydrous DMF (3 mL), and allowed to room temperature over 4 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. for 3 hours to give 1.40 grams of 2-fluoro-6-(2-iodobenzyloxy)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:27]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([CH3:43])[CH3:42])(=O)=O>CN(C=O)C>[F:20][C:14]1[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:18]=2[CH:17]=[C:16]([O:19][CH2:40][C:41]([F:44])([CH3:43])[CH3:42])[CH:15]=1
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1c(F)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(F)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reaction time: 0.17 h

Procedure:
A vial was charged with (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (61.0 mg, 0.167 mmol), cesium carbonate (82 mg, 0.251 mmol), and DMF (670 μL). The resulting mixture was stirred vigorously for 10 min, then the vial was placed in large ice-bath for 10 min. 2-fluoro-2-methylpropyl trifluoromethanesulfonate (33.3 μL, 0.201 mmol) was added dropwise and the ice-bath was removed after 5 minutes. The mixture was stirred at for 6 hours, then the mixture was diluted with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12 g Redi-Sep column, eluting with 5-60% gradient of DCM/MeOH/NH4OH (90:10:1) in DCM to give (S)-4′-fluoro-2′-(2-fluoro-2-methylpropoxy)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid. Found MS: MH+=439.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])(C)[O:9]2)[CH2:5][O:4]1.BrCC1OCC(O)C(O)CO1.C(=O)[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH:3]1[O:4][CH2:5][CH:6]2[CH:10]([O:9][CH:8]([C:14]3[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=3)[O:7]2)[CH2:11][O:12]1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)OC2COC(CBr)OCC2O1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: OC1COC(CBr)OCC1O
Solvent: ClC(Cl)Cl
Product: BrCC1OCC2OC(c3ccccc3)OC2CO1
Reaction time: 192 h

Procedure:
4-Bromomethyl-9-phenyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane was prepared in a similar way to 4-bromomethyl-9,9-dimethyl-3,5,8, 10-tetraoxabicyclo[5.3.0]decane from 64.7 g of 2-bromomethyl-5,6-dihydroxy- 1,3-dioxepane (285 mmol) and 187.0 g of benzaldehyde (1760 mmol) in chloroform. The reaction time was 8 days, a fresh spatula tip of toluenesulphonic acid being added every day.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:25][CH2:26][CH2:27][N:28]3[C:32](=[O:33])[C:31]4=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]4[C:29]3=[O:38])[C:15]2=[O:23])[CH2:12][CH2:13]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
A mixture of Compound 9 (42.2 g, 0.13M), prepared in Example 9, and N-(3-bromopropyl)phthalimide (35 g, 0.13M) were dissolved in DMF (300 ml). Cesium carbonate (100 g, 0.3M) was added in one portion and the resulting heterogenous mixture heated in an 80° C. oil bath for 16 hours. The mixture was cooled to room temperature and the DMF removed under reduced pressure. The residue was poured into ice water (800 ml) and stirred at room temperature overnight. The white solid precipitates were collected and dried to give the desired product (60 g, 92%). The BOC group was removed by treatment of a solution of the compound in methylene chloride (500 ml) with excess trifluoroacetic acid (46 ml, 0.6M). The mixture was stirred at room temperature overnight and evaporated to dryness under reduced pressure. The resulting white solids were washed with diethyl ether and dried to give the desired TFA salt. m.p. 173-175° C. 1H NMR (300 MHz, DMSO-d6) δ8.79 (m, 1H; 8.54 (m, 1H); 7.82 (s, 4H); 7.35 (m, 1H); 7.25 (m, 1H); 7.07-6.90 (m, 2H); 4.55 (m, 1H); 3.90 (t, J=7 Hz, 2H); 3.63 (t, J=7 Hz, 2H); 3.42 (m, 2H); 3.15 (m, 2H); 2.60(m, 2H); 2.07 (m, 2H); 1.90 (m, 2H). MS: m/z (MH+) 405
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH:17]1([CH2:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.[BH4-].[Na+].Cl>C(O)C>[CH:17]1([CH2:22][NH:23][CH2:15][C:13]2[C:14]3[C:5]([CH:6]=[C:7]4[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]4)=[CH:4][CH:3]=[CH:2][CH:1]=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCC1CCCC1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc2c(CNCC3CCCC3)c3ccccc3cc2c1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A mixture of 43.5 g of 9-anthraldehyde, 20.97 g of cyclopentylmethylamine and 150 ml of ethanol is heated under reflux for 1.5 hours. The hot solution of N-cyclopentylmethyl-9-anthracenemethyleneimine so obtained is allowed to cool to 60°, and 8.2 g of sodium borohydride is added in small portions, with stirring, while the temperature is maintained at 55-60°. The mixture is then stirred for another 1.5 hours, concentrated hydrochloric acid (35 ml) is added with cooling, and stirring is continued for 0.5 hour. The mixture is then made basic and extracted with methylene chloride. Removal of the solvent from the dried extracts gives 59.1 g of N-cyclopentylmethyl-9-anthracenemethylamine as an oil; nmr spectrum: τ 1.8-3.1 (m, 9); 5.6 (s, 2), 7.5 (d, 7Hz, 2) and 7.8-9.3 (m, 10).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[S:20][C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:22]([CH3:25])[C:23]=2Br)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].[CH3:40]B1OB(C)OB(C)O1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[S:20][C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:22]([CH3:25])[C:23]=2[CH3:40])[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2sc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(Br)c2C)cc1
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2sc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(C)c2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(3-bromo-5-(4-ethylbenzyl)-4-methylthiophen-2-yl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (56) (200 mg, 0.320 mmole) in toluene/water (4 mL/2 mL) were added trimethylboroxine (134 μL, 0.960 mmole), Pd(OAc)2 (7.2 mg, 0.0320 mmole), tricylcohexylphosphine tetrafluoroborate (23.6 mg, 0.0640 mmole), and K3PO4 (272 mg, 1.28 mmole). The mixture was stirred at 100° C. overnight. The reaction mixture was filtered through celite bed and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound 57 (125 mg, 0.223 mmole, 70%) as a yellow solid. [M+Na]+ 583.