Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:30]4[CH2:31][CH2:32][CH:26]3[CH2:27][N:28]([CH:33]3[CH2:36][O:35][CH2:34]3)[CH2:29]4)=[CH:21][N:20]=2)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[C@@H:30]4[CH2:31][CH2:32][C@H:26]3[CH2:27][N:28]([CH:33]3[CH2:36][O:35][CH2:34]3)[CH2:29]4)=[CH:21][N:20]=2)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C5CCC4CN(C4COC4)C5)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3[C@@H]4CC[C@H]3CN(C3COC3)C4)cn2)c1=O
Temperature: 35 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
A mixture of 152f (180 mg, 0.26 mmol) and lithium hydroxide (215 mg, 5.1 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 35° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water and ethyl acetate. The water phase was separated and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 152 (12 mg, 71%) as a yellow solid. MS-ESI: [M+H]+ 663.3. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=2.5 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.32 (s, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.25-7.23 (m, 1H), 7.20 (d, J=9.0 Hz, 1H), 6.57 (s, 1H), 4.96-4.94 (m, 1H), 4.48-4.43 (m, 3H), 4.39-4.37 (m, 3H), 4.25-4.19 (m, 5H), 3.85 (d, J=11.5 Hz, 1H), 3.59 (s, 3H), 2.66-2.54 (m, 4H), 2.40-2.36 (m, 3H), 2.17 (d, J=10.5 Hz, 2H), 1.94-1.65 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH:5]1[N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[CH:12]=2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.Cl>O1CCOCC1.C(OCC)C>[CH3:21][C:13]1[CH:12]=[C:11]([N:10]2[CH2:9][CH2:8][NH:7][CH2:6][CH:5]2[CH2:4][C:3]([O:2][CH3:1])=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1c1cc(C)nc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)CC1CNCCN1c1cc(C)nc2ccccc12
Reaction time: 8 h
Yield: 90.4 %

Procedure:
tert-Butyl 3-(2-methoxy-2-oxo-ethyl)-4-(2-methyl-4-quinolyl)piperazine-1-carboxylate (239 mg, 0.28 mmol) was dissolved in dioxane (1 ml), combined with a solution of HCl in dioxane (4N, 4 ml, 16 mmol) and stirred overnight. The mixture was diluted with diethylether, the precipitate was collected by filtration and dissolved in DCM. The solution was washed with a saturated solution of sodium bicarbonate and dried over sodium sulfate. The solvent was removed under reduced pressure, the residue was triturated with diethylether to yield 85 mg of a yellow solid (0.253 mmol, 72%).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[S:16][C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 205.1) and pyrimidin-5-ylboronic acid to afford a white powder. HPLC (Condition 4) tR=5.22 min, UPLC-MS (Condition 3) tR=1.03 min, m/z=480.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.77 (m, 1H) 1.79-1.94 (m, 1H) 2.82-2.94 (m, 1H) 3.22 (m, J=11.10, 4.10 Hz, 2H) 3.32-3.45 (m, 1H) 4.14-4.29 (m, 1H) 4.87 (d, J=3.91 Hz, 1H) 7.58-7.80 (m, 2H) 7.96 (dd, J=11.73, 1.96 Hz, 1H) 8.08 (d, J=2.35 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.43 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[Si:19]([O:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a solution of {3-[3-(benzyloxy)phenyl]propoxy}(tert-butyl)dimethylsilane (2.90 g) in MeOH (30 mL) was added 10% palladium on carbon (300 mg) and the mixture was stirred at ambient temperature for 3 hours under hydrogen atmosphere (3 atm). The mixture was filtered through a bed of Celite. The filtrate was evaporated in vacuo to afford 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)phenol (1.78 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cn[nH]c4)n3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1cc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)cn1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 4) from 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl]piperidine, sodium hydride and ethyl bromoacetate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21](O)=[O:22])=[CH:8][C:7]2=[O:24].[CH3:25][CH:26]1[O:31][CH:30]([CH3:32])[CH2:29][N:28]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:27]1>>[CH3:32][CH:30]1[O:31][CH:26]([CH3:25])[CH2:27][N:28]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:21]([C:9]3[O:10][C:11]4[C:6]([C:7](=[O:24])[CH:8]=3)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=4[N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[O:22])=[CH:35][CH:34]=2)[CH2:29]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Reactant: CC1CN(c2ccc(N)cc2)CC(C)O1
Agent: Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CC(C)OC(C)C4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 4-(2,6-dimethyl-morpholin-4-yl)-phenylamine (Maybridge) as prepared in Example 12, yielding a yellow solid. (70 mg=49%), LCMS-m/z=507.5.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[C:11]1([O:17][C:18]([N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH2:21]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])=O.[K+]>ClCCl.O>[C:11]1([O:17][C:18]([N:20]2[CH:25]=[C:24]([CH:9]=[O:10])[CH:23]=[C:22]([Cl:26])[CH2:21]2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: O=C(Oc1ccccc1)N1C=CC=C(Cl)C1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=CC1=CN(C(=O)Oc2ccccc2)CC(Cl)=C1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.6 %

Procedure:
Phosphorus oxychloride (5.4 g, 57.9 mmol) was added slowly to a stirred solution of DMF (8.9 mL, 116 mmol) in dichloromethane (10 mL) at 0° C. After addition, the solution was stirred at same temperature for 25 min., then transferred a solution of 3-chloro-2H-pyridine-1-carboxylic acid phenyl ester (5.67 g, 26.3 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The ice bath was removed and stirring was continued at r.t. for 2 h, then the mixture was refluxed for 40 min. After the mixture was cooled to 0° C., an aqueous solution of KOAc (15 g, 153 mmol) in water (50 mL) was added slowly. The mixture was refluxed for 20 min., organic layer was separated, and aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, washed with saturated NaHCO3, water and brine then dried over MgSO4, concentrated to give the crude product (Yield: 6.7 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=2[C:20]2([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[C:20]2([CH2:25][O:26][CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COCC1(c2cc(C(=O)OC)ccc2-c2cc(OC)ncc2F)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-(methoxymethyl)cyclopentyl)benzoate (77.0 mg, 206 μmol) in THF (4.0 mL) was added LAH (0.42 mL, 1.0 M solution in diethyl ether, 412.0 μmol) at 0° C. The reaction mixture was stirred at 45° C. for 3 hours. After work up, the solvent was removed to provide the product which was used in the next step. MS ESI (pos.) m/e: 346.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH:15]([O:17][N:18]=[C:19]([C:50]1[N:54]=[C:53]([NH2:55])[S:52][N:51]=1)[C:20]([NH:22][CH:23]1[C:48](=[O:49])[N:25]2[C:26]([C:32]([O:34]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:33])=[C:27]([CH:30]=[CH2:31])[CH2:28][S:29][C@H:24]12)=[O:21])[CH3:16])=[O:14])(C)(C)C.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH:15]([O:17][N:18]=[C:19]([C:50]1[N:54]=[C:53]([NH2:55])[S:52][N:51]=1)[C:20]([NH:22][CH:23]1[C:48](=[O:49])[N:25]2[C:26]([C:32]([OH:34])=[O:33])=[C:27]([CH:30]=[CH2:31])[CH2:28][S:29][C@H:24]12)=[O:21])[CH3:16])([OH:14])=[O:12]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)C(=O)OC(C)(C)C)c3nsc(N)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
Trifluoroacetic acid (9.6 ml) was added to a solution of benzhydryl 7-[2-(1-tert-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.4 g) in methylene chloride (5 ml) and anisole (2.4 ml) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The resultant solution was added dropwise to diisopropyl ether (100 ml) and the precipitates were collected by filtration. The precipitates were added to a mixture of water and ethyl acetate and then adjusted to pH 7.5 with 10% aqueous sodium hydroxide. The separated aqueous layer was saturated with sodium chloride and adjusted to pH 1.5 with 10% hydrochloric acid, followed by extraction with a mixed solvent of ethyl acetate and tetrahydrofuran (1:1 by volume). The extract was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. Removal of the solvent gave 7-[2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.55 g).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=3[C:42]3[CH:43]=[C:44]([CH:47]([CH3:49])[CH3:48])[CH:45]=[CH:46][C:41]=3[Cl:40])[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)c1ccc(Cl)c(B(O)O)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc([N+](=O)[O-])ccc1Br
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(Cl)c(-c2ccc([N+](=O)[O-])cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 80 °C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one (950 mg, 1.80 mmol) in a toluene (5.2 mL): ethanol (2.6 mL): water (1.3 mL) mixture was added (2-chloro-5-isopropylphenyl)boronic acid (325 mg, 1.64 mmol), tetrakis(triphenylphosphine)palladium(0) (188 mg, 10 mol %) and sodium carbonate (346 mg, 3.26 mmol). The resulting mixture was heated in an 80° C. oil bath for 12 h. The reaction crude was evaporated into dryness. The resulting residue was taken up by a mixture of water and EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by SiO2 (Biotage 40+S cartridge, EtOAc/hexane, gradient) to afford the titled compound. LC-MS: 601.19 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 8.31-8.30 (m, 1 H), 8.24-8.28 (m, 1 H), 7.85-7.89 (m, 1 H), 7.68-7.76 (m, 2 H), 7.42-7.48 (m, 2 H), 7.26-7.30 (m, 1 H), 7.04-7.11 (m, 1 H), 5.74 (d, J=7.8 Hz, 0.5 H), 5.58 (d, J=8.0 Hz, 0.5 H), 4.92 (d, J=15.8 Hz, 0.5H), 4.76 (d, J=16.2 Hz, 0.5H), 3.97-4.04 (m, 1.5 H), 3.82 (dt, J=8.0, 6.6 Hz, 0.5H), 2.89-2.99 (m, 1H) 1.22-1.29 (m, 6 H), 0.60 (d, J=6.4 Hz, 1.5 H), 0.52 (d, J=6.6 Hz, 1.5 H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]([NH:31][C:32]([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=2)=[O:33])[CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)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.C(OCC)(=O)C.C1(C)C=CC=CC=1.O.C(O)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[C:20]([NH:31][C:32]([C:34]2[CH:35]=[N:36][CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:39]=2)=[O:33])[CH:19]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2F)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
Ethanol (0.62 mL), water (0.31 mL), sodium carbonate (70 mg), 2-fluorophenylboronic acid (37 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added to a toluene (2.1 mL) suspension of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 91-85% hexane/ethyl acetate] to obtain tert-butyl 4-(2-fluorophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 78.3 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.15 g, 0.56 mmol) was reacted with 4-methoxybenzaldehyde (0.078 g, 0.56 mmol) in the presence of glacial acetic acid (0.033 g, 0.56 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.042 g, 0.67 mmol) in methanol (5 ml) (Procedure D) to give compound 16e (0.17 g, 78%) as an oil.
Reaction SMILES: N[CH2:2][C:3]1[C:4]([CH3:24])=[N:5][C:6]2[N:7]([N:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.CCN(CC)CC>C1COCC1>[C:29]([O:28][C:26]([CH2:2][C:3]1[C:4]([CH3:24])=[N:5][C:6]2[N:7]([N:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:25])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1nc2nc(C)c(CN)c(-c3ccc(Cl)cc3Cl)n2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1nc2nc(C)c(CC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3Cl)n2n1
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a stirred solution of methyl 6-(aminomethyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (Example 27, 50 mg, 0.14 mmol) in THF (3 mL) was added (BOC)2O (75 μL, 0.34 mmol) and Et3N (100 μl, 0.70 mmol). After 2 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography (50% EtOAc in hexanes) afforded methyl 6-((tert-butoxycarbonyl)methyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (13 mg, 20%) as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[C:21]1([C:20]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(C(=C2c3ccccc3-c3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.9 %

Procedure:
Dry tetrahydrofuran (500 ml) was added to a mixture of fluorene (10.00 g, 60.16 mmoles) and potassium tert-butoxide (7.43 g, 66.18 mmoles) under nitrogen and stirred at room temperature for 5 minutes. Benzophenone (10.96 g, 60.16 mmoles) was then added as a solid and the reaction mixture was stirred for a further 20 hours under nitrogen at room temperature. Aqueous ammonium chloride (sat., 200 ml) was then added and stirred until the colour had faded. Diethyl ether (100 ml) was added and the aqueous layer separated and extracted with diethyl ether (2×100 ml). The combined organic layers were washed with water (3×200 ml), dried over anhydrous magnesium sulfate and evaporated. The crude product (16.0 g) was recrystallised twice from dichloromethane:hexane (100:200 ml) and then from dichloromethane:acetonitrile (100:200 ml) and then dried under vacuum to give white crystals of 9-(diphenylmethylene)-9H-fluorene (7.34 g).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].[H-].[Na+].[F:9][C:10]([F:29])([F:28])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20]([CH3:26])([CH3:25])[C@@H:19]1[O:27][C@H:18]21.O>CS(C)=O>[OH:27][C@@H:19]1[C@@H:18]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][C:10]([F:29])([F:9])[F:28])[CH:16]=2)[O:21][C:20]1([CH3:26])[CH3:25]
Reactant: CNS(C)(=O)=O
Reactant: CC1(C)Oc2ccc(OCCCC(F)(F)F)cc2[C@H]2O[C@H]21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CNS(=O)(=O)C[C@H]1c2cc(OCCCC(F)(F)F)ccc2OC(C)(C)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Under argon, 0.77 g (7.1 mmol) of N-methyl-methanesulfonamide was added to a suspension of 0.065 g (2.7 mmol) of 80 percent sodium hydride in 3 ml of DMSO, and the mixture was stirred at RT for 20 min. 1.65 g (5.5 mmol) of (3R,4R)-(+)-6-(4,4,4-trifluorobutoxy)-2,2-dimethyl-3,4-epoxychroman, dissolved in 5 ml of DMSO, were then added dropwise and the batch was left to stand at RT for 4 days and then heated at 45° C. for a further 9 h. The mixture was subsequently poured into water and the precipitate was filtered off with suction and dried thoroughly under reduced pressure, giving 1.9 g of (3R,4S)-(+)-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-methanesulfonamide, which was recrystallized from a little isopropanol (->1.4 g; m.p. 178-179° C.; optical purity (chiral HPLC) 100%).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:27]2[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:5]1[C:6]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(O)cc1
Yield: 80.2 %

Procedure:
Methyl ether (163) (0.12 g, 0.27 mmol) was treated with BBr3 in CH2Cl2 to give the crude product as a yellow viscous oil, which was purified by reverse phase preparation HPLC on Agilent 1100 to afford 95 mg (82%) of the title compound (164) as a white solid. mp 107-109° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.78 (t, J=7.4 Hz, 3H), 1.15-1.29 (m, 2H), 1.40-1.50 (m, 2H), 2.62 (t, J=7.9 Hz, 2H), 6.26 (d, J=15.9 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 7.30-7.40 (m, 3H), 7.47 (t, J=7.9 Hz, 1H), 7.53 (d, J=15.9 Hz, 1H), 7.71 (s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H). LCMS (ESI): m/z 439 (M+H)+, m/z 437 (M−H)−. Anal. Calc for C29H26O4.⅙H2O: C, 78.89; H, 6.01. Found: C, 78.71; H, 5.91.