Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-])=O.C(O)=O>CO.[Pd]>[N:11]1([CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(OCCCN2CCCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: Nc1ccc(OCCCN2CCCCC2)cc1N
Reaction time: 3 h
Yield: 95 %

Procedure:
1-[3-(3,4-Dinitro-phenoxy)-propyl]-piperidine [3.2 g] was dissolved in methanol (20 ml) and palladium on carbon (1.12 g, 10%) and formic acid (2 ml) was added. The mixture was hydrogenated at 50 psi for 3 hours and the mixture was filtered through celite. The filtrate was concentrated to afford 4-(3-piperidin-1-yl-propoxy)-benzene-1,2-diamine [2.45 g, Intermediate (39)] product as a dark oil. LC/MS: 250 (M+H).
Reaction SMILES: FC1C=CC(C[O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][F:25])[N:18]=[N:17]3)=[C:12]([F:26])[CH:11]=2)=CC=1.Br>C(O)(=O)C>[F:26][C:12]1[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][C:13]=1[N:16]1[C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][F:25])[N:18]=[N:17]1
Reactant: O=c1n(CCCF)nnn1-c1ccc(OCc2ccc(F)cc2)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=c1n(CCCF)nnn1-c1ccc(O)cc1F
Temperature: 25 °C
Yield: 111 %

Procedure:
To a solution of 5.60 g (0.0153 mole) of 1-[4-(4-fluorophenylmethoxy)-2-fluorophenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one in 60 mL of glacial acetic acid was added 5 mL of 49% hydrobromic acid. This mixture was heated at reflux for 90 minutes, after which it was cooled to room temperature. The reaction mixture was then poured over ice, and the resulting aqueous solution was extracted with diethyl ether. The combined extract was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving 4.35 g of 1-(2-fluoro-4-hydroxyphenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one as a residue.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[I:11][CH3:12]>>[I-:11].[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:12]
Reactant: CI
Reactant: Cc1nc2ccccc2s1
Product: Cc1sc2ccccc2[n+]1C
Product: [I-]
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A solution of 2-methylbenzothiazole (5.00 g) and iodomethane (50 g) were stirred in an oil bath at 45° C. for 44 hours. After cooling to room temperature the solid was collected through filtration and the solid was washed with ethyl acetate (2×100 mL) and dried in an oven under high vacuum at 50° C. overnight. There was obtained 8.02 g (82.3% yield) of product.
Reaction SMILES: [O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)[CH:10]=[C:11]([O:17]CC2C=CC=CC=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]>C(O)(=O)C.C(OCC)(=O)C>[O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[O:26]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reaction time: 0.75 h

Procedure:
A mixture of 1.2 g of 2-[3-(2-oxopropylsulfonyl)-4-n-propoxy-5-benzyloxyphenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (STEP J), 400 mg 10% PD/C, 1-2 drops of acetic acid in 100 mL of ethyl acetate was stirred under H2 at 40 psi for 45 minutes. The reaction mixture was filtered over a bed of celite and evaporated in vacuo to yield the title compound: NMR (200 MHz, CDCl3) δ 1.10 (t, CH2CH2CH3), 1.92 (m, CH2CH2CH3), 1.9-2.6 (m, 3-CH2 δ 4-CH2), 2.40 (s, CH3C(O)CH2), 3.86 (s, OCH3), 3.90 (s, 2 OCH3), 4.12 (t, CH2CH2CH3), 4.42 (s, CH3C(O)CH2), 5.10-5.28 (m, 2-CH δ 5-CH), 6.64 (s, 5-ArH), 7.35 δ 7.47 (2 d, 2-ArH).
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][S:10][C:11]1[C:21]2[O:20][CH2:19][CH2:18][C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:9][S:10]([C:11]1[C:21]2[O:20][CH2:19][CH2:18][C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:2]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCOC(=O)C1=Cc2cccc(SC)c2OCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cccc(S(C)=O)c2OCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 23.6 %

Procedure:
A solution of potassium peroxymonosulfate (6.7 g) in water (33 ml) was added dropwise to a mixture of ethyl 2,3-dihydro-9-methylthio-1-benzoxepin-4-carboxylate (2.6 g) and tetrabutylammonium hydrogen sulfate (0.7 g) in ethyl acetate (26 ml) and water (13 ml) and the mixture was stirred at ambient temperature for 2.5 hours. The separated organic layer was washed with 10% aqueous sodium thiosulfate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and toluene (1:1) as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 2,3-dihydro-9-methanesulfinyl-1-benzoxepin-4-carboxylate (0.65 g).
Reaction SMILES: [Na].C(O[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22].Cl>CCO>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[O:11])[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve sodium metal (0.345 g) in absolute EtOH (25 mL), add diethyloxalate (10 mL) and then add 4-methyl-3-nitrobenzonitrile (1b, m=0, 1.6 g, Aldrich) as an EtOH solution (25 mL). Stir the reaction mixture at rt for 16 hours, neutralize the reaction by addition of 5N HCl (3 mL) and remove the EtOH under reduced pressure. Partition the residue between CH2Cl2 (100 mL) and H2O (50 mL). Wash the organic layer successively with H2O (50 mL) and brine (50 mL), dry (MgSO4) and concentrate to give a crude oil. Purify the oil by chromatography on SiO2 eluting with cyclohexane-EtOAc, 70-30 v/v, to afford gave after drying (40° C., house vacuum), the title compound (1.5 g) as yellow crystals, mp 118° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:41][CH2:42][C:43]=5[C:44]5[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=5)[CH2:35][CH2:34][N:33]([CH:36]([CH2:39][F:40])[CH2:37][F:38])[CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15]C)=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.O[Li].O.Cl>O1CCCC1.CO>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:41][CH2:42][C:43]=5[C:44]5[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=5)[CH2:35][CH2:34][N:33]([CH:36]([CH2:37][F:38])[CH2:39][F:40])[CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([OH:15])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(CF)CF)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(CF)CF)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265I (320 mg) in tetrahydrofuran (4 mL) and methanol (2 mL) was added LiOH H2O (120 mg) and the solution was stirred overnight. The reaction was cooled, carefully neutralized with 1N aqueous HCl and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]([CH:11]([OH:13])[CH3:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[CH2:14]=O.O.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CC(O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][C:9]([CH:11]([OH:13])[CH3:12])=[C:10]([CH2:14][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C=O
Reactant: C1COCCN1
Reactant: CC(O)c1cc2c(N)ncnn2c1
Solvent: CC(=O)O
Solvent: O
Product: CC(O)c1cc2c(N)ncnn2c1CN1CCOCC1
Temperature: 60 °C
Yield: 67 %

Procedure:
To a solution of AcOH (70 mL) was added 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)ethanol (611 mg, 3.43 mmol) followed by the addition of a 0.5 M solution of 37% formaldehyde in water (0.26 mL, 3.43 mmol) and morpholine (0.30 mL, 3.43 mmol) in AcOH (6.86 mL) was added. The reaction was heated to 60° C. for 1.5 h. The solution was allowed to cool to rt and was then evaporated via rotary evaporation chasing the remaining AcOH with toluene. The crude material was purified by column chromatography (85:15 v/v CH2Cl2-EtOAc) to afford 633 mg of the above compound (2.28 mmol, yield 67%). 1H-NMR (DMSO-d6) δ 7.79 (s, 1H), 7.57 (br s, 2H), 6.85 (s, 1H), 4.94 (m, 1H), 3.84 (m, 2H), 3.49 (m, 4H), 2.37 (m, 4H), 1.41 (d, J=6.6 Hz, 3H); MS [M+H]+=278.0; LCMS RT=1.01 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:34]1([CH3:64])[C:35]([C:40]([CH2:42][N:43]2[C:49]3[CH:50]=[C:51]([CH3:54])[CH:52]=[CH:53][C:48]=3[N:47]([C:55](=[O:61])[C:56]3[S:60][CH:59]=[CH:58][CH:57]=3)[CH2:46][CH:45]([NH2:62])[C:44]2=[O:63])=[O:41])=[CH:36][CH:37]=[CH:38][CH:39]=1>O1CCCC1>[C:34]1([CH3:64])[C:35]([C:40]([CH2:42][N:43]2[C:49]3[CH:50]=[C:51]([CH3:54])[CH:52]=[CH:53][C:48]=3[N:47]([C:55](=[O:61])[C:56]3[S:60][CH:59]=[CH:58][CH:57]=3)[CH2:46][CH:45]([NH:62][C:16]([NH:1][C:2]3[CH:14]=[CH:13][CH:12]=[C:4]([C:5]([O:7][C:8]([CH3:10])([CH3:11])[CH3:9])=[O:6])[CH:3]=3)=[O:18])[C:44]2=[O:63])=[O:41])=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)OC(C)(C)C)c1)CN2C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 249.7 %

Procedure:
Tert-butyl 3-aminobenzoate (1.09 g) was dissolved in tetrahydrofuran (20 ml), triphosgene (0.61 g) was added to a solution under ice-cooling. Subsequently, under ice-cooling triethylamine (2.12 g) was added dropwise, and the mixture was stirred at room temperature for one hour. A solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.23 g) in tetrahydrofuran (20 ml) was added to the mixture, stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue and extracted with chloroform. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1), to thereby obtain 3.35 g of the title compound as colorless amorphous (Yield: 100%).
Reaction SMILES: [CH3:1][C:2]1[O:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:1][C:2]1[O:8][C:5]([CH2:6][NH:7][C:15]2[CH:16]=[N:17][CH:18]=[CH:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=C(O)c1ccncc1F
Product: Cc1ccc(CNc2cnccc2C(=O)O)o1
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from 5-methylfurfurylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.35 (s, 1H), 7.86 (d, 1H, J=5.0 Hz), 7.77 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz), 6.24 (d, 1H, J=2.9 Hz), 6.00 (d, 1H, J=2.0 Hz), 4.50 (s, 2H), 2.23 (s, 3H). [M+H] calc'd for C12H12N2O3, 233. Found 233.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([F:10])[CH:3]=1.[NH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(O)C.[O:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:28]([O:27][CH2:26][CH3:25])[C:29]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([C:12]#[N:11])=[CH:14][CH:15]=2)=[O:24])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: N#Cc1ccc(CN)cc1
Reactant: C1COCCO1
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluorobenzaldehyde was reacted according to general procedure A using ethanol/dioxane as a solvent. The product of this reaction was subsequently coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide. Light yellow oil. MS 391.1 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CCN(CC)CC.[CH:17]1([CH:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH2:19][CH2:18]1>CC#N>[Cl:8][C:6]1[CH:7]=[C:2]([N:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[CH:17]2[CH2:19][CH2:18]2)[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C1CNC(C2CC2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(Cl)cc(N2CCCC2C2CC2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (95 mg, 0.576 mmol) in CH3CN (5 mL) was added Et3N (0.25 mL, 1.75 mmol) followed by 2-cyclopropylpyrrolidine (74 mg, 0.50 mmol), and the reaction mixture was stirred for 4 hours at 80° C. The reaction was poured onto water (a precipitate was formed), and filtered. Flash chromatography SiO2 (gradient: EtOAc/hexanes) afforded the title compound (70 mg) as a white solid. LC-MS (ES) m/z=239, 241 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:11][CH:12]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Oc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
To a mixture of 4-fluorophenol (2.1 g, 19 mmol), 2,5-dibromopyridine (3.0 g, 13 mmol) and N,N-dimethylformamide (30 mL) was added sodium hydride (730 mg, 15 mmol, 50% in oil) at 0° C., which was stirred for 10 minutes at room temperature. The reaction mixture was then stirred for 5 hours at 110° C. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water twice, and then washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=15:1) to obtain the title compound (2.6 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH:10]1[N:15]2[C:16](I)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:18]=[C:14]2[C:13](=[O:31])[NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH:10]1[N:15]2[C:16]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:18]=[C:14]2[C:13](=[O:31])[NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(I)n21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(-c3ccccc3)n21
Yield: 54.8 %

Procedure:
To a solution of tert-butyl(2-{6-iodo-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate (100 mg, 0.177 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere, 64.7 mg (0.531 mmol) of phenyboronic acid, 7.2 mg (0.009 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepaladium complex with dichloromethane and 172 mg (0.531 mmol) of cesium carbonate, were subsequently added. The mixture was heated at 80° for 1 hour in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash chromatography on silica gel column (DCM/EtOAc/EtOH 6/4/0.5), and further purification by HPLC/MS preparative method 1, 50 mg (54%) of tert-butyl(2-{1-oxo-6-phenyl-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate were obtained.
Reaction SMILES: [CH:1]1(CNC(C2N(C)C=C(C(C3C(C4C=CC(F)=CC=4)=NOC=3C)=O)C=2)=O)CC1.[CH:29]1([NH:34][C:35]([C:37]2[NH:38][CH:39]=[C:40]([C:42]([C:44]3[C:45]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[CH:51]=4)=[N:46][O:47][C:48]=3[CH3:49])=[O:43])[CH:41]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([NH:34][C:35]([C:37]2[N:38]([CH3:1])[CH:39]=[C:40]([C:42]([C:44]3[C:45]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[CH:51]=4)=[N:46][O:47][C:48]=3[CH3:49])=[O:43])[CH:41]=2)=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1cc(C(=O)NCC2CC2)n(C)c1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCCC2)c1
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)c1cc(C(=O)NC2CCCC2)n(C)c1
Yield: 27.6 %

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4fluorophenyl)-isoxazole-4-carbonyl)-1-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid cyclopentylamide (example 178) in 27.6% yield as white solid. (m/e): 396.2 (M+1; 100%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[C:13]3[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26]>>[C:1]1([C:7]#[C:8][C:9]2[C:13]3[CH:14]=[C:15]([CH:18]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2occ(C#Cc3ccccc3)c2c1
Product: O=C1NC(=O)C(=Cc2ccc3occ(C#Cc4ccccc4)c3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 3-Phenylethynyl-benzofuran-5-carbaldehyde (intermediate 59) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:12]=[C:11]([C:22]([OH:24])=O)[CH:10]=1.[NH2:25][C@@H:26]([CH3:29])[CH2:27][OH:28].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[OH:28][CH2:27][C@@H:26]([NH:25][C:22]([C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:12]=1)=[O:24])[CH3:29]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cccc(F)c3F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-c3cccc(F)c3F)c2)nc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2′,3′-difluoro-5-(5-methylpyridin-2-yl)biphenyl-3-carboxylic acid (30.00 mg, 0.09222 mmol), (2S)-2-Aminopropan-1-ol (8.3119 mg, 0.11066 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.087662 g, 0.23055 mmol), N,N-diisopropylethylamine (0.064252 mL, 0.36888 mmol), N,N-dimethylformamide (0.157 mL, 2.03 mmol) and the reaction stirred over night at room temperature. The solvent was removed under reduced pressure and the residue purified by prep HPLC to get the compound as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:12]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](O)=[O:34]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH:16][C:33]([C:24]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]=2[OH:22])=[O:34])[CH2:13][C@H:12]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Product: O=C(N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-4-[(1 -hydroxy-naphthalene-2-carbonyl)-amino]-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C26H24N3O5 [(M+H)+] 458, obsd. 458.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.[H-].[Na+]>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:21]=[CH:22][C:23]=1[O:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](CO)CC1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OC[C@H]2CC[C@H](O)CC2)c(Cl)c1
Reaction time: 1 h

Procedure:
(Trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol (275 mg, prepared according to a procedures in WO 2008/124878) and 3-chloro-4-fluorobenzenesulfonamide (259 mg) in tetrahydrofuran (15 mL) were treated with sodium hydride (180 mg, 60%) overnight. The reaction was quenched with water (1 mL) and trifluoroacetic acid (4 mL) was added. The resulting mixture was stirred for 1 hour and concentrated. The residue was triturated with water and methanol to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][OH:11]>CO>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NO
Solvent: CO
Product: ON=Cc1ccc(O)cc1
Reaction time: 2 h

Procedure:
Into a 500 ml round bottom flask equipped with a magnetic stirring bar, 40.49 g (331.6 mmol) of 4-hydroxybenzaldehyde were added. The aldehyde was dissolved in 240 ml methanol. To the stirred solution, 22.99 g (348.1 mmol) of 50% aqueous solution of hydroxylamine was added over a 15 min. period. The mixture was stirred for an additional 2 hr, at which time it was judged to be complete by the disappearance of the starting aldehyde as observed by thin layer chromatography (SiO2/CH3OH: CH2CL2 5:95). The solvent was removed in vacuo to give the product 4-hydroxybenzaldehyde oxime as a dark tan oil, which was recrystallized from water.