Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[N:14][CH:13]=1.[C:21](O)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:19])[C:21](=[O:23])[CH3:22])=[N:14][CH:13]=3)[O:20][C:2]=2[CH:7]=1.[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[N:14][CH:13]=3)[O:20][C:2]=2[CH:7]=1
Reactant: CC(=O)O
Reactant: CNc1ccc(C(=O)Nc2ccc(OC)cc2O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CNc1ccc(-c2nc3ccc(OC)cc3o2)cn1
Product: COc1ccc2nc(-c3ccc(N(C)C(C)=O)nc3)oc2c1
Reaction time: 0.42 h

Procedure:
N-(2-Hydroxy-4-methoxyphenyl)-6-(methylamino)nicotinamide (0.23 g, 0.84 mmol) was mixed with acetic acid (4 mL) and the reaction was run in a microwave reactor at 200° C. for 25 minutes. The reaction mixture was added to water and made basic with sodium bicarbonate (sat. aq.). The aqueous solution was extracted three times with diethyl ether and the combined organic layers were washed with brine, dried (MgSO4) and evaporated. The crude product was purified first by flash column chromatography (hexane/ethyl acetate-gradient; 30-50% ethyl acetate), followed by preparative HPLC, resulting in the isolation of N-[5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-yl]-N-methylacetamide (6 mg) as a minor product, together with the title compound (0.13 g) as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.90 (d, 1H) 8.23 (dd, 1H) 7.59 (d, 1H) 7.10 (d, 1H) 6.94 (dd, 1H) 6.52 (d, 1H) 5.26 (br. s, 1H) 3.89 (s, 3H) 2.82-3.16 (m, 3 H); MS m/z (M+H) 256.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]2[CH:14]=1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=1>>[Cl:13][C:12]1[C:7]2[N:8]([CH:14]=[C:5]([CH2:1][CH2:2][C:3]#[C:4][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=3)[N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cn2cccc(Cl)c2n1
Product: FCc1cccc(C#CCCc2cn3cccc(Cl)c3n2)n1
Yield: 54.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg, 2.44 mmol, Example 255(B)) and 2-bromo-6-(fluoromethyl)pyridine (487 mg, 2.57 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 420 mg (1.34 mmol, 55%) of 8-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine as a slightly yellow solid (M.P.=73-74.5° C.).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: Cn1cnc2c(Cl)nc(C#CCCO)nc21
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2c(N)nc(C#CCCO)nc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl)but-3-yn-1-ol (650 mg, 2.74 mmol) in dioxane (4 ml) was added 30% w/w water solution of ammonia (8 ml). The reaction mixture was stirred overnight in an autoclave at 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].CCOCC.[OH-].[Na+]>C(O)(C(F)(F)F)=O.O>[NH3:8].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCN(CC)CCCCOc1ccc2c(c1)CCN2c1ccc(Br)cc1
Product: N
Yield: 76.7 %

Procedure:
104 mg (0.25 mmol) {4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine in 1 ml TFA were treated with 32 mg (0.5 mmol) NaCNBH3 at 0° C. for 5 min and 30 min at RT. Ether and water were added, followed by 2M NaOH. The inorganic phase was extracted with ether, the combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 19:1-1%sat.NH3 in MeOH yielded 40 mg (38%) {4-[1-(4-Bromo-phenyl)-2,3-dihydro-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow waxy solid, MS: 417 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)(Cl)=O.CCOCC.C(O)C.[NH3:22]>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH2:22])[CH:5]=[N:4][CH:3]=1
Reactant: N
Reactant: OCc1cncc(Br)c1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CCOCC
Product: NCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
3-Bromo-5-hydroxymethylpyridine (1.1 g, 5.8 mmol) was added to thionyl chloride (5 mL) at 0° C. under nitrogen over 5 min. The solution was stirred at room temperature for 1 h, re-cooled to 0° C., and dry ether (40 mL) was added. The resulting solid was filtered off, washed with ether and added to a stirred solution of ammonia (28%, 30 mL) and ethyl alcohol (40 mL) at 0° C. The solution was then stirred at room temperature for 20 h. The solvent was removed by rotary evaporation and the crude material partitioned between sodium hydroxide (2N, 30 mL) and dichloromethane (60 mL). The organic layer was dried (Na2SO4), the solvent removed by rotary evaporation and the residue purified by flash chromatography, using CHCl3: ethanol: concentrated aqueous ammonia solution (100:6:1) as eluent, to afford (5-bromo-3-pyridyl)methylamine (785 mg, 72% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)[C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:50]1[CH2:55][CH2:54][O:53][CH2:52][CH:51]1[C:56]1[C:64]2[S:63][C:62]([NH2:65])=[N:61][C:60]=2[C:59]([O:66][CH3:67])=[CH:58][CH:57]=1>C1COCC1.C(Cl)(Cl)Cl>[O:50]1[CH2:55][CH2:54][O:53][CH2:52][CH:51]1[C:56]1[C:64]2[S:63][C:62]([NH:65][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][N:14]=[C:6]([CH2:5][O:4][CH2:3][C:2]([F:1])([F:16])[F:15])[CH:7]=3)=[N:61][C:60]=2[C:59]([O:66][CH3:67])=[CH:58][CH:57]=1
Reactant: O=C(O)c1ccnc(COCC(F)(F)F)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(COCC(F)(F)F)c3)nc12

Procedure:
From 2-(2,2,2-trifluoro-ethoxymethyl)-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+121.3° (c=1.05, CHCl3), ES-MS m/e (%): 484 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:40][C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])(=O)=O.O>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH2:40][C@@H:41]5[CH2:45][CH2:44][CH2:43][N:42]5[C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1cc(Nc2ncnc3cc(O)ccc23)cn1)Nc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4)c3)ncnc2c1
Yield: 60.9 %

Procedure:
A solution of N-(3-fluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.590 g, 0.97 mmol), cesium carbonate (1.95 g, 5.98 mmol) and tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 1.16 mmol) in dimethylacetamide (10 ml) was heated at 80° C. for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and evaporated in vacuo to leave a brown oil which was purified by silica gel chromatography. Elution with 5 to 7% methanol in dichloromethane gave tert-butyl (2S)-2-[({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.332 g, 61% yield) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:7]=1.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]2=[C:19]([C:26](O)=[O:27])[CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[C:12]([NH:13][C:26]([C:19]3[CH:18]=[N:17][N:21]4[CH:22]=[CH:23][CH:24]=[N:25][C:20]=34)=[O:27])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:7]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: COc1ccc(Cl)cc1-c1nn(C)cc1N
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (258 mg, 0.869 mmol, 1.00 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (157 mg, 0.961 mmol, 1.11 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (541 mg, 1.04 mmol, 1.20 eq), N,N-diisopropylethylamine (0.40 mL, 2.3 mmol, 2.6 eq), and 4-dimethylaminopyridine (30.7 mg, 0.251 mmol, 0.29 eq) in 8.0 mL N,N-dimethylformamide was stirred at 50° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated to yield 232.3 mg (70%) of the crude product. The crude product was purified by reverse phase HPLC and lyophilized to give N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; 1H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 9.32 (d, 1H), 8.76 (d, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 7.48 (d, 1H), 7.40 (s, 1H), 7.28 (m, 2H), 3.91 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15].C(OC([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[C:40]3[O:39][CH:38]=[CH:37][C:36]=3[CH:35]=[C:34]([NH2:41])[CH:33]=2)[CH2:27][CH2:26]1)=O)(C)(C)C>C(Cl)Cl.C1COCC1>[ClH:7].[ClH:7].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:41][C:34]1[CH:33]=[C:32]([CH2:31][N:28]2[CH2:27][CH2:26][NH:25][CH2:30][CH2:29]2)[C:40]2[O:39][CH:38]=[CH:37][C:36]=2[CH:35]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(N)cc3ccoc23)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cl
Product: O=S(=O)(Nc1cc(CN2CCNCC2)c2occc2c1)c1ccccc1Cl
Reaction time: 3 h
Yield: 34.8 %

Procedure:
Dry pyridine (20 μL, 0.24 mmol) and 2-chlorobenzenesulfonyl chloride (25 μL, 0.18 mmol) were added to a solution of 4-(5-amino-benzofuran-7-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.12 mmol; obtained in Step 2) in a mixture of dry DCM:THF (2:1; 3 mL). The resulting mixture was stirred for 3 h and volatiles were then evaporated. The product was purified using flashtube (15% MeOH in DCM). The residue was dissolved in TFA:water (9:1; 2 mL) and the mixture was stirred at room temperature for 30 min to accomplish removal of the N-t-BOC group. The reaction mixture was made basic by addition of saturated aqueous Na2CO3 (pH 8-9) and extracted with DCM (×2). The organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified with preparative HPLC (System A; 10-40% MeCN). Pure fractions were combined and concentrated. The obtained TFA salt was dissolved in MeOH and 1 M HCl in ether was added, followed by concentration to give the title compound (10 mg, 18%) as a light yellow solid. HPLC 100%, RT=1.38 min (System A; 10-97% MeCN over 3 min), 100%, RT=1.23 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 2.86-2.92 (m, 4H) 3.25-3.28 (m, 4H) 4.04-4.08 (m, 2H) 6.73 (d, J=2.26 Hz, 1H) 7.15 (d, J=2.01 Hz, 1H) 7.26-7.31 (m, 1H) 7.32 (d, J=2.26 Hz, 1H) 7.42-7.47 (m, 1H) 7.47-7.52 (m, 1H) 7.70 (d, J=2.26 Hz, 1H) 7.90 (dd, J=8.03, 1.51 Hz, 1H). MS (ESI+) for C19H20ClN3O3S m/z 406 (M+H).
Reaction SMILES: [H][H].[OH:3][C:4]1[C:21]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[C:20]([O:27][CH3:28])[CH:19]=[CH:18][C:5]=1[C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1>C(OCC)(=O)C.[Pd]>[OH:3][C:4]1[C:21]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:20]([O:27][CH3:28])[CH:19]=[CH:18][C:5]=1[C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COc1ccc(C=CC(=O)c2ccc(OC)c(CC=C(C)C)c2O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)c2ccc(OC)c(CCC(C)C)c2O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To 20 ml of a suspension of 0.31 g of 5% palladium/carbon in ethyl acetate, in which hydrogen had been adsorbed in advance, was added 1.03 g of the 2'-hydroxy-4,4'-dimethoxy-3'-(3-methyl-2-butenyl)chalcone obtained in Specific Example 16, and the mixture was stirred at room temperature for 5 hours and hydrogen was absorbed. After the reaction, the suspension was filtered to remove the palladium/carbon, and the solvent was removed from the filtrate by distillation to obtain 1.03 g (yield 98.7%) of 1-(2-hydroxy-4-methoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]#[N:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C[Si]([N:65]=[N+:66]=[N-:67])(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]1[N:12]([CH2:13][CH2:14][C:15]#[N:16])[N:67]=[N:66][N:65]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-2-t-butoxycarbonylamino-3-biphenyl-4-yl-N-(2-cyanoethyl)-propionamide (18 g, 45.7 mmol) in THF (375 mL) under nitrogen is added triphenylphosphine (12 g, 45.7 mmol). The solution is cooled to 0° and treated with diethyl azodicarboxylate (DEAD, 7.2 mL, 24.3 mmol) followed by trimethylsilyl azide (3.2 mL, 24.3 mmol). The solution is warmed up to room temperature and stirred for 18 hours. One additional equivalent of triphenyl phosphine (12 g, 45.7 mmol), DEAD (7.2 mL, 24.3 mmol) and trimethylsilyl azide (3.2 mL, 24.3 mmol) are added and stirring is continued for 3 days. The solution is cooled to 0°. Ceric ammonium nitrate (2.2 L; 10% aqueous solution) is added dropwise. After 20 minutes of stirring, extraction is carried out with methylene chloride (3×200 mL). The combined organic layers are dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo. The residue is taken up in ethyl acetate (500 mL) and hexane (50 mL). A small amount of (S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile crystallizes out. The filtrate is concentrated and the residue purified by flash-chromatography eluting with a gradient of ethyl acetate in hexane (30% to 50%). The pure fractions of product (Rf=0.6 in 1/1 ethyl acetate/hexane) are combined and concentrated under reduced pressure to give (S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile as a colorless crystalline solid, m.p. 184°-185°, [α]D =-2.90° (c 0.89, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCOCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-morpholin-4-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine and 4-(2-chloroethyl)-morpholine hydrochloride following General Procedure H.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])=[O:5].[CH3:14][S:15][CH3:16]>ClCCl.C(OCC)C>[Br-:1].[CH3:14][S+:15]([CH3:16])[CH2:3][C:4]([C:6]1[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=1[F:12])=[O:5]
Reactant: CSC
Reactant: CC(=O)c1c(F)cccc1F
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Product: C[S+](C)CC(=O)c1c(F)cccc1F
Product: [Br-]
Reaction time: 144 h
Yield: 37.4 %

Procedure:
A solution of bromine (4.1 ml, 80 mmoles) in dichloromethane (6 ml) was added dropwise to a solution of 2,6-difluoroacetophenone (12.4 g, 80 mmoles) in anhydrous diethyl ether (100 ml). the reaction solution was evaporated and the resulting liquid was dissolved in tetrahydrofuran (150 ml) and methyl sulfide (9 ml, 120 mmoles) was added. The mixture was allowed to stand at room temperature for 6 days (approximately 144 hours). The crystals were filtered to yield 8.9 g (38%) of dimethyl-2,6-difluorophenacylsulfonium bromide. A mixture of the sulfonium salt (8.9 g) and isopropyl nitrate (6.4 ml, 60 mmoles) was stirred in dichloromethane (80 ml) for 7 days (approximately 168 hours) at room temperature. The volatiles were evaporated and the residue was dissolved in diethyl ether (250 ml). The organic solution was washed 4 times with 100 ml portions of water, saturated sodium chloride, dried (sodium sulfate), and evaporated to give 6.8 g of a solid. Recrystallization from carbon tetrachloride (250 ml) gave 4.9 g (23%) of crystals, melting point 138°-140° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]=[CH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C1(OC)C=CC=CC=1>[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1/[CH:20]=[CH:21]/[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=Cc1cccnc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C(=C/[C@@H]1CCCN1)\c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (1 mL) was added dropwise to a stirred ice-cold solution of (2S)-N-(tert-butoxycarbonyl)-2-(2-(3-pyridyl)vinyl)pyrrolidine (280 mg, 1.02 mmol) in anisole (2 mL). The reaction mixture was allowed to warm to room temperature, stirred for 16 h, then neutralized with saturated aqueous NaHCO3 solution, saturated with solid NaCl and extracted with chloroform (5×10 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated on a rotary evaporator to give a viscous dark oil, which was chromatographed with chloroform:methanol (9:1, v/v) and 1% triethylamine as eluant. Selected fractions containing the product were combined and concentrated on a rotary evaporator to give 130 mg (73.1% yield) of a colorless oil.
Reaction SMILES: [C:1]([P:3](=[O:6])([O-:5])[O-:4])#[N:2].[Li+].[Na+].C([O:11][C:12](=[O:15])[CH2:13]N)C.[H][H]>O.[Pd]>[P:3]([O-:5])([O-:11])([O-:4])=[O:6].[P:3]([CH2:1][NH:2][CH2:13][C:12]([OH:15])=[O:11])([OH:5])([OH:4])=[O:6]
Reactant: CCOC(=O)CN
Reactant: N#CP(=O)([O-])[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Product: O=P([O-])([O-])[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 0.93 %

Procedure:
Sodium lithium cyanophosphonate was dissolved in water in a Fisher Porter bottle containing a magnetic stir bar, and glycine ethyl ester was added. A catalyst of 5% palladium on carbon (Lot #323810, water 52.38%, Engelhard) was added. After three pressure-release cycles with hydrogen, the bottle was pressurized to 25 psi with hydrogen and stirred overnight at 50° C. The pressure was then released and the reaction mixture was filtered through Celite and washed with D2O. HPLC analysis (system for phosphate analysis) gave a 0.93% yield of N-phosphonomethylglycine.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]([C@@H:14]([CH2:18][CH3:19])[C:15](O)=[O:16])[C:10]2=[O:13])=[CH:5][CH:4]=1.C([O:26][C:27](=[O:45])[CH2:28][C@H:29]([NH2:44])[CH:30]([OH:43])[CH2:31][O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=1[F:42])(C)(C)C>>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]([C@@H:14]([CH2:18][CH3:19])[C:15]([NH:44][C@H:29]([C:30](=[O:43])[CH2:31][O:32][C:33]3[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=3[F:42])[CH2:28][C:27]([OH:45])=[O:26])=[O:16])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: CC[C@@H](C(=O)O)n1ccc2ccc(C(F)(F)F)cc2c1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2ccc(C(F)(F)F)cc2c1=O

Procedure:
This compound was prepared using (S)-2-(7-trifluoromethyl-1-oxo-1H-isoquinolin-2-yl)-butyric acid (prepared as described in methods A-E, see example 2) and (3S)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods N-P) using procedures similar to those described in methods F, G and E. The product was isolated as a white solid (90% last step). IR (solid) 1791.6, 1649.5, 1516.8, 1493.1, 1322.5 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.85 (3H, t), 1.90-2.20 (2H, 2×m), 2.50-2.90 (2H, 2×m), 4.70 (1H, m), 5.25 (2H, dd), 5.45 (1H, m), 6.80 (1H, d), 7.65 (1H, m), 7.70 (1H, d), 7.95 (1H, d), 8.05 (1H, d), 8.45 (1H, s), 9.00 (1H, d) ppm; 19F NMR (376 MHz, d6-DMSO) (proton decoupled) δ −56.60, −70.15, −136.38, −152.08.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:21]([CH3:20])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CNc1ccccn1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(c1ccccn1)S(=O)(=O)c1cc(Br)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
To 5-bromo-4-chloro-2-fluorobenzenesulfonyl chloride (1.5 g, 4.89 mmol) in dry DCM (15 mL), at −20° C. was added pyridine (1.98 mL, 24.5 mmol) followed by methyl-pyridin-2-yl-amine (1.06 g, 9.78 mmol). The mixture was allowed to warm slowly to ambient temperature over 16 hrs. 1N NaOH solution (5 mL) was added and stirred for 15 mins. The mixture was extracted with DCM and the organics were washed with brine, dried over MgSO4 and the filtrate evaporated. The residue was purified by silica gel chromatography [eluent: 10% ethyl acetate in hexane] to give 5-bromo-4-chloro-2-fluoro-N-methyl-N-pyridin-2-yl-benzenesulfonamide as an oil (0.57 g, 31%). MS: 380.9 (M+H)+; tR=2.80 min (method 1).