Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]1=[NH:18].[CH3:19][C:20]1([CH3:28])[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]1=[N:18][C:25]([CH:21]1[C:22]([CH3:24])([CH3:23])[C:20]1([CH3:28])[CH3:19])=[O:26]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: COCCn1c(-c2ccccc2)c(C)sc1=N
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccccc2)c(C)sc1=NC(=O)C1C(C)(C)C1(C)C

Procedure:
A mixture of the product of Example 119A (290 mg, 1.16 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (182 mg, 1.28 mmol), HATU (661 mg, 1.74 mmol) and triethylamine (0.97 mL, 6.96 mmol) in 15 mL of DMF was processed according to the method of Example 2B to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.17 (s, 6H) 1.26 (s, 6H) 1.49 (s, 1H) 2.01 (s, 3H) 3.02 (s, 3H) 3.43 (t, J=6.0 Hz, 2H) 4.06 (t, J=5.8 Hz, 2H) 7.39-7.43 (m, 2H) 7.50-7.57 (m, 3H); MS (DCI/NH3) m/z 373 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:13]#[C:14][NH2:15].[Na]>C(O)C>[C:14]([N:15]=[C:11]([C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)[NH2:12])#[N:13]
Reactant: N#Cc1cccc2ncccc12
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CN=C(N)c1cccc2ncccc12
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A mixture of Example 24A (750 mg, 4.81 mmol) and sodium cyanamide (312 mg, 4.81 mmol) in ethanol (10 mL) was heated at reflux for 10 hours and cooled to ambient temperature. The solvent was removed under reduced pressure and the crude mixture was purified by silica gel chromatography, eluting with a gradient of 0-6% of methanol/methylene chloride to provide 0.3 g of the title compound. MS (ESI+) m/z 197 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>>[F:10][C:11]1[CH:16]=[C:15]([N+:1]([O-:4])=[O:2])[CH:14]=[CH:13][C:12]=1[F:17]
Reactant: Fc1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(F)c1
Temperature: -12 °C
Reaction time: 0.75 h

Procedure:
This material is prepared as described by R. W. Taft, G. B. Klingensmith, and S. Ehrenson (J. Am. Chem. Soc., 87, 3620 (1965). To a stirred mixture of 5.0 ml of concentrated nitric acid and 13.9 ml of concentrated sulfuric acid cooled to -12° C. is added 9.7 g (0.085 mole) of 1,2-difluorobenzene. A slight exotherm is observed and the mixture is cooled to -20° C. whereupon it solidifies. The mixture is stirred for 45 minutes at -5° to 0° and is then allowed to warm slowly to room temperature. After 1 hour the mixture is poured onto ice, and the mixture extracted with diethyl ether (3×75 ml). The combined ether extracts are washed with water, 10% aqueous Na2CO3, and water again. The ether solution is dried (MgSO4) and concentrated in vacuo without external heating to give the crude product (11.9g), which is distilled (kugelrohr apparatus) to give 10.2 g of colorless liquid. The nmr spectrum of this material is consistent with the structure.
Reaction SMILES: ClC(OCC)=[O:3].[NH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[C:9]1=[O:20].[N:21]1[CH:26]=CC=[CH:23][CH:22]=1>>[CH2:22]([NH:21][C:26]([NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[C:9]1=[O:20])=[O:3])[CH3:23]
Reactant: COc1ccc2c(c1)CCC(N)C2=O
Reactant: c1ccncc1
Reactant: CCOC(=O)Cl
Product: CCNC(=O)NC1CCc2cc(OC)ccc2C1=O
Reaction time: 2 h

Procedure:
Pour 4.77 g (0.044 mol) of ethyl chloroformate at 0° C. into 5 g (0.022 mol) of 2-amino-6-methoxy-3,4-dihydro-2H-naphthalen-1-one dissolved in pyridine. After two hours at ambient temperature, concentrate the pyridine, take up in dichloromethane and then wash the organic phase with 0.1N hydrochloric acid solution and then with saturated sodium hydrogen carbonate solution and water; dry over magnesium sulphate, filter, and evaporate off the solvent. 5.48 g of an orange solid are obtained.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)[CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][NH:20]C(OCC1C=CC=CC=1)=O)=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:15]
Reactant: [H][H]
Reactant: O=C(C[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NCCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NCCCNC(=O)C[C@H](N)CCCN
Yield: 100.1 %

Procedure:
In 18 ml of methanol were suspended 144 mg (0.238 mmol) of (R)-3,6-bis(benzyloxycarbonylamino)-N-(3-benzyloxycarbonylaminopropyl)hexanamide. To the resulting suspension was added a suspension of 81.0 mg of 10% palladium-carbon in 2 ml of water, followed by stirring. Hydrogen gas was passed through the resulting mixture at room temperature for 3 hours to effect the hydrogenolysis reaction. The palladium-carbon was filtered off from the reaction mixture obtained, and the filtrate was then concentrated to dryness. The residue obtained was dissolved in 1 ml of water and the resulting solution was subjected to chromatography on a column of "Amberlite CG-50" (trade name, NH4+ -form, 5 ml). After the column was washed with 25 ml of water, the column was eluted with aqueous ammonia at concentrations gradiently varying from 0.5% to 7.0% (0.5%-increased steps; 25 ml at each concentration). Fractions of the eluate as eluted with 4.0% to 6.0% aqueous ammonia were combined together and concentrated to dryness, to afford 48.2 mg of (R)-3,6-diamino-N-(3-aminopropyl)hexanamide as a colorless paste.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:43][NH2:44]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[C:29]3[C:28]([C:31]([NH2:32])=[N:43][NH:44]3)=[CH:27][CH:26]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(F)c(F)c4)C3)nc(N)n2)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccc(F)c(F)c3)C2)n1
Temperature: 150 °C
Yield: 70.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3,4-difluorophenyl)-3-piperidinecarboxamide (90 mg, 0.199 mmol), 3 mL of EtOH, hunig's base (0.104 ml, 0.597 mmol), and hydrazine anhydrous (0.025 ml, 0.796 mmol) weres added, and the yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford the title compound (65 mg) as a light yellow solid. LC-MS (ES) m/z=465 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 1H), 1.69-1.96 (m, 2H), 2.06 (m, 1H), 3.19 (m, 1H), 3.40-3.55 (m, 1H), 4.36-4.56 (m, 2H), 4.73-4.97 (m, 1H), 6.91-7.09 (m, 1H), 7.25-7.52 (m, 4H), 7.66-8.03 (m, 4H), 10.25-10.42 (m, 1H), 10.33 (d, J=8.8 Hz, 1H), 12.09 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[C:7]([CH2:9][C:10](O)=[O:11])#[N:8]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[C:7]([CH2:9][C:10]([O:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])=[O:11])#[N:8]
Reactant: C[Si](C)(C)CO
Reactant: N#CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)COC(=O)CC#N
Yield: 69.7 %

Procedure:
In a reactor fitted with a Dean-Stark apparatus hydroxymethyltrimethylsilane (3.8 g, 0.036 mol) and cyanoacetic acid (3.1 g, 0.036 mol) in 50 ml of toluene are refluxed for 4 hours in the presence of one drop of concentrated sulfuric acid. The organic phase is washed twice with water and is dried over sodium sulfate. It is concentrated under reduced pressure. Distillation under vacuum (b.p. 80° C. under 0.4 hPa) gives 4.3 g (69% yield) of trimethylsilanylmethyl cyanoacetate in the form of a colorless liquid which is used as it is in the following step.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]1([C:13]([F:16])([F:15])[F:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>C(Cl)Cl>[N+:19]([C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:3][C:2]([F:1])([F:17])[F:18])([C:13]([F:15])([F:14])[F:16])[O:5][C:6]=2[CH:12]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 54.4 g of 2-(2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole in 75 ml of methylene chloride was added dropwise to a mixture of 40 ml of 65% strength by weight nitric acid and 40 ml of concentrated sulphuric acid at i0° C. The mixture was subsequently stirred at room temperature for 1 hour and then poured onto ice-water, the organic phase was separated off and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with water, dried and freed from readily volatile constituents. 95 g of the product (=86% of theory) with a melting point of 87° to 88° C. remained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:11][S:12](O)(=[O:14])=[O:13].S(=O)(=O)(O)N.S(Cl)(Cl)=O>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: NS(=O)(=O)O
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
135.2 g (1.0 mol) of acetanilide are added in portions to 349.5 g (3.0 mol) of chlorosulfonic acid and 2 g of sulfamic acid such that the temperature remains at 40° C. The mixture is then heated to 60° C. and stirred at this temperature for 60 minutes, then 142.8 g (1.2 mol) of thionyl chloride are added dropwise over the course of 2 hours and the mixture is stirred until evolution of gas has ended. For working up, the mixture is dripped into ice water, and the precipitated crystals are filtered off with suction and washed with water. 394.9 g of 4-acetamidobenzenesulfonyl chloride (water content: 41.7%; chloride content: 58.1%), corresponding to 230.2 g (98.5%) calculated as dry material, having a melting point of 139° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.Cl.Cl.NC[C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[CH2:28]([NH2:30])C>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1.[NH2:30][CH2:28][N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[CH:19]1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCc1nc2ccccc2[nH]1
Reactant: CCN
Agent: Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1
Product: NCn1cnc2ccccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a flask under nitrogen atmosphere was charged 500 ml of NMP and 3-fluoro-4 nitro benzoic acid methylester (15.64 g, 78.5 mmol, 1 eq) followed by aminomethyl-benzimidazole dihydrochloride (20.16 g, 91.6 mmol, 1.2 eq). To this, Diispropyl ethylamine (55 ml, 316 mmol, 4 eq) was charged and stirred for 16 hours. The reaction was then poured into 1200 ml of ice water resulting in a yellow/orange solid. The solid was filtered and resuspended in 300 ml of cold water, stirred for 1 hour, filtered and dried to constant weight. Yield 85%, 18.8 g. TLC elution solvent system 5% methanol/95% dichloromethane, Rf=0.6.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=O)=[C:4]2[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:36][O:37][C:38](=[O:43])[C@H:39]([CH2:41][OH:42])[NH2:40].C(N(CC)CC)C>CN(C)C=O.O>[OH:42][CH2:41][C@H:39]([NH:40][C:17]([C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12)=[O:19])[C:38]([O:37][CH3:36])=[O:43]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 70 h
Yield: 68.3 %

Procedure:
A suspension of 11.3 g (0.0437 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 220 ml of dimethylformamide was treated portionwise with 7.80 g (0.048 mol) of carbonyldiimidazole while gassing with argon. After completion of the CO2 evolution the mixture was stirred at 55° for 2 hrs. After cooling to 0°-5° the pale yellow solution obtained was treated with 7.48 g (0.0532 mol) of L-serine methyl ester hydrochloride and with 6.7 ml (0.048 mol) of triethylamine and stirred at room temperature for 70 hrs. The light suspension was completely freed from the solvents. The residue was dissolved in hot water and extracted continuously with ethyl acetate. The yellow oily residue was chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 10.7 g (68%) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-ylcarbonylamino)-propionate as a white solid. An analytical sample was recrystallized from ethyl acetate/diethyl ether and gave white crystals; m.p. 180°-181°. [α]D20 =+12.9° (CHCl3, c=1%).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:19]3[N:20]=[C:21]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[O:22][C:18]=3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:29](=O)[CH3:30].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[Cl:50]CCCl>CO.C(Cl)Cl>[ClH:50].[ClH:50].[CH2:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([S:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)(=[O:13])=[O:12])[C:19]=3[N:20]=2)[CH2:24][CH2:25]1)[CH3:30]
Reactant: ClCCCl
Reactant: O=S(=O)(c1cccc2ccccc12)c1cccc2oc(N3CCNCC3)nc12
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCN(c2nc3c(S(=O)(=O)c4cccc5ccccc45)cccc3o2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(1-naphthylsulfonyl)-2-piperazin-1-ylbenzoxazole (0.070 g, 0.18 mmol), acetaldehyde (0.016 g, 0.36 mmol), NaBH(OAc)3 (0.075 g, 0.36 mmol), and acetic acid (0.021 g, 0.36 mmol) in 1,2-dichloroethane was stirred at room temperature overnight, diluted with 20% MeOH in CH2Cl2 (with 0.5% NH4OH) and filtered through a pad of silica gel. The filtrate was concentrated and purified by Gilson reverse phase HPLC. The purified material was treated with a solution of HCl in ether, stirred at room temperature for 5 minutes and concentrated to dryness to five the title compound (17 mg, 19%), characterized by NMR and mass spectral analyses. MS (ES+) m/e 422 (MH+).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([CH2:58][N:59]5[CH2:62][CH:61]([F:63])[CH2:60]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([CH2:58][N:59]5[CH2:62][CH:61]([F:63])[CH2:60]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CN5CC(F)C5)cccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CN5CC(F)C5)cccc4c3=O)cc2)CCC1
Yield: 57 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[8-(3-fluoro-azetidin-1-ylmethyl)-4-oxo-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was subjected to flash chromatography (SiO2, gradient 0 to 15% MeOH in DCM) to afford the title compound as a white solid (13 mg, 57%). 1H NMR (400 MHz, DMSO-d6): δ 7.97 (dd, J=8.0 and 1.7 Hz, 1H), 7.74 (dd, J=7.1 and 1.4 Hz, 1H), 7.47-7.28 (m, 8H), 7.08 (d, J=8.2 Hz, 2H), 5.27-5.06 (m, 1H), 3.94 (s, 2H), 3.65-3.56 (m, 2H), 3.29-3.16 (m, 2H), 2.36-2.27 (m, 2H), 2.11-1.87 (m, 5H), 1.65-1.54 (m, 1H). LCMS (Method E): RT=2.31 min, [M+H]+=455.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5]1.B(Br)(Br)[Br:25].CO>C(Cl)Cl>[BrH:25].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:5]1
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1OC)C[C@@H](c1ccccc1)C[C@H]2CN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Br
Product: NC[C@@H]1C[C@H](c2ccccc2)Cc2c1ccc(O)c2O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
[1R,3S]1-Aminomethyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydro-naphthalene hydrochloride (0.2 g, 0.67 mmol), from Step 1, was suspended in 13 mL of methylene chloride and the suspension was cooled to -78° C. in a dry ice/acetone bath. Boron tribromide (3 mL of a 1M solution in methylene chloride, 3 mmol) was added and the reaction mixture was allowed to warm to ambient temperature, kept at ambient temperature for 1.5 h then cooled to -78° C. Methanol (3 mL) was added to the reaction mixture and it was again allowed to warm to ambient temperature then concentrated in vacuo. The residue was redissolved in methanol and reconcentrated. The residue was again redissolved in methanol and the methanol solution was added to a large excess of diethyl ether. The resultant precipitate was filtered and recrystallized from ethanol/diethyl ether to give 0.14 g (64% yield) of the title compound as a white powder, m.p. 256°-259° C. 1H NMR (d6 -DMSO) delta 1.63 (q, 1H), 2.1-2.25 (m, 1H), 2.4-2.5 (m, 1H), 2.75-2.95 (m, 2H), 3.02 (dd, 1H), 3.15-3.3 (m, 1H), 3.4-3.5 (m, 1H), 6.68 (s, 2H), 7.2-7.3 (m, 1H), 7.3-7.4 (m, 4H), 7.8 (br s, 3H), 8.2 (br s, 1H), 9.1 (br s, 1H).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH:6]1([Mg]Cl)[CH2:10][CH2:9][CH2:8][CH2:7]1.O>CCCCCC.CCOCC>[CH:6]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cl[Mg]C1CCCC1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)(Cl)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopentanesulfonyl chloride was prepared according to the procedure of S. N. Bhattacharya, et. al., J. Chem. Soc. (C), 1265-1267 as follows. To a solution of 2.7 g (1.6 mL, 20 mmol) of sulfuryl chloride in 5 mL of hexane at 0° C. was added a solution of 5 mL (10 mmol) of 2 M cyclopentylmagnesium chloride in ether over a 15-min period. The reaction mixture was allowed to warm to room temperature and stir overnight. The mixture was recooled to 0° C. and a 5-mL portion of ether was added followed by a 10-mL portion of water. The layers were separated and the organic phase was washed with water, dried over sodium sulfate and concentrated to give 1.12 (70%) of cyclopentanesulfonyl chloride. This compound was used without further purification to prepare the title compound from the Cbz amine from Example 3 in a manner analogous to that of Example 5: 1H NMR (400 MHz, CDCl3) δ7.34-7.30 (m, 5H), 7.13 (s, 4H), 6.44 (br s, 1H), 5.07 (s, 2H), 4.74 (br, s, 1H), 3.50-3.39 (m, 3H), 2.76 (br t, 2H), 2.09-1.91 (m, 4H), 1.86-1.76 (m, 2H), 1.64-1.54 (m, 2H); FAB MS m/z 403 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24]
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.44 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (1.0 g), anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH:14]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[F:15].[CH3:22][C:23]([CH3:37])=[CH:24][CH2:25][CH2:26]/[C:27](/[CH3:36])=[CH:28]/[CH2:29][CH2:30]/[C:31](/[CH3:35])=[CH:32]/[CH:33]=[O:34].Cl>O1CCCC1>[F:13][C:14]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])([F:15])[CH:33]([OH:34])[CH:32]=[C:31]([CH3:35])[CH2:30][CH2:29][CH:28]=[C:27]([CH3:36])[CH2:26][CH2:25][CH:24]=[C:23]([CH3:22])[CH3:37]
Reactant: COP(=O)(OC)C(F)F
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COP(=O)(OC)C(F)(F)C(O)C=C(C)CCC=C(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Combine diisopropylamine (22.24 mL, 0.159 mol) with tetrahydrofuran (250 mL) and cool to -20° C. Add n-butyllithium (63.3 mL, 2.5N in hexane, 0.159 mol) dropwise to the solution. Stir for 30 minutes and cool to -78° C. Add dropwise a solution of dimethyl difluoromethylphosphonate (25.8 g, 0.159 mol) in tetrahydrofuran (20 mL) while maintaining the temperature below -75° C. After addition is complete, stir for 2 minutes and then slowly add a solution of trans, trans-farnesal [prepared according to Biller, S. A.; Forster, C. Tetrahedron 1990, 46(19), 6645] (14 g, 0.0636 mol) prepared in step a above, in tetrahydrofuran (10 mL) maintaining the temperature below -72° C. After addition is complete, stir for an additional 2 hours at -78° C. and then pour the reaction into 0.1N hydrochloric acid (500 mL). Extract the reaction with diethyl ether (2×1 L). Combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography [40% ethyl acetate/hexane, Rf (50% ethyl acetate/hexane)=0.44] to provide the title compound (9.3 g, 39%) as an oil.