Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH2:2][CH:3]([CH2:9][SH:10])[C:4]([O:6]CC)=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:15]=[CH:16][C:17]=1[CH:18](Cl)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.N12CCCN=C1CCC[CH2:37][CH2:36]2>C1COCC1.C(O)C>[CH2:36]([NH:2][CH:3]([CH2:9][S:10][CH:18]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:17]1[CH:16]=[CH:15][C:14]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)=[CH:13][C:12]=1[Cl:11])[C:4]([OH:6])=[O:5])[CH3:37]
Reactant: CCOC(=O)C(N)CS
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(CSC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl)C(=O)O

Procedure:
Sodium (0.075 mol) was added portionwise to ethanol (50 ml) under N2 atmosphere and this mixture was stirred until complete dissolution. Ethyl 2-amino-3-mercaptopropanoate (0.075 mol) was added and the mixture was stirred for 2 hours at RT. The solvent was evaporated, THF (50 ml) was added to the residue, and a solution of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol) in THF (50 ml) was added. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mol) was added and the resulting reaction mixture was stirred overnight at RT. The solvent was evaporated. The residue was stirred in water and extracted with CH2Cl2. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. This fraction was purified by HPLC over silica gel (eluent: CH2Cl2/CH2OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off, washed and dried, yielding (±)-ethyl α-[[[(4-chlorophenyl)[2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]methyl]thio]methyl]glycine (compound 95).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=O)/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C(O)(=O)C>CN(C)C=O.[Pd]>[CH2:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[NH2:19]
Reactant: O=C(/C=C/c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1cccc(CCCc2cccc(N)c2)c1
Reaction time: 72 h
Yield: 4.7 %

Procedure:
To a solution of (2E)-1,3-bis(3-nitrophenyl)prop-2-en-1-one (2.8 g, 0.0094 mol) in N,N-dimethylformamide (20 mL) was added 10% (by wt.) palladium on carbon and acetic acid (2.0 mL). The mixture was degassed with vacuum and purged with hydrogen three times before shaking on a Parr shaker for 72 hours under a hydrogen atmosphere. The mixture was filtered through celite, evaporated and purified by preparative LCMS (pH 10) to give the desired product (101 mg, 5%). LCMS for C15H19N2 (M+H)+: m/z=227.2.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:11]=[CH:10][NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]>C1COCC1>[CH3:18][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:9]3[CH:10]=[CH:11][C:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:8]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:14])[CH2:16][CH3:17]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CC(C)NC(=O)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC(C)C)c3)ccc2n1CC1CCOCC1
Yield: 63.1 %

Procedure:
Following the same procedure in Example 29, using N-isopropyl-1H-pyrrole-3-carboxamide (76 mg, 0.50 mmol) (see following step B for preparation), sodium hydride (159 mg, 60%, 3.97 mmol) and 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (535 mg, 1.39 mmol) in THF (15 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to give 158 mg (64%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.77 (t, J=7.42 Hz, 3 H), 1.15 (d, J=6.64 Hz, 6 H), 1.39-1.56 (m, 4 H), 1.59 (s, 6 H), 1.94 (q, J=7.42 Hz, 2 H), 2.19-2.38 (m, 1 H), 3.23-3.35 (m, 2 H), 3.83-3.96 (m, 2 H), 4.01-4.15 (m, 1 H), 4.41 (d, J=7.62 Hz, 2 H), 6.67 (dd, J=3.32, 1.56 Hz, 1 H), 7.28 (dd, J=3.12, 2.34 Hz, 1 H), 7.79-7.86 (m, 1 H), 7.88-7.99 (m, 2 H) 8.26 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=501.3; Anal. Calcd for C26H36N4O4S+1.2 TFA+0.1H2O (615.50): C, 55.33; H, 6.11; N, 9.09. Found: C, 55.38; H, 6.16; N, 9.04.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:16][C@@H:15]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:29].[Na+]>CC(C)=O.OP(O)=O.O[Mo](O)(=O)=O>[CH2:1]([O:8][C@@H:9]1[CH2:16][C@@H:15]([CH2:17][I:29])[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)C[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Reactant: [I-]
Agent: O=[Mo](=O)(O)O
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CO[C@@H]1C[C@H](OCc2ccccc2)C[C@@H](CI)O1
Reaction time: 24 h
Yield: 75.2 %

Procedure:
Methyl 3-O-benzyl-6-O-tosyl-2,4-dideoxy-α-D-erythro-hexopyranoside (3.0 g; 7.34 mmoles) and sodium iodide (13 g; 86.7 mmoles) are dissolved in acetone (130 ml). The resulting solution is refluxed under nitrogen and protected from the light for 24 hours. When tlc shows the reaction is complete (fluorosilica-methylene chloride, visualization with phosphomolybdic acid and heat), the acetone is evaporated in vacuo. The residue is partitioned between ether and water. The ether layer is washed with dilute aqueous sodium thiosulfate, then twice with water, dried (MgSO4), filtered, and the solvent is evaporated in vacuo to give crude product which is purified by flash chromatography on silica gel on a 60 mm×150 mm column. Elution with methylene chloride gives 2.0 g of methyl 3-O-benzyl-6-iodo-2,4,6-trideoxy-α-D-erythro-hexopyranoside. [α]D24 +53.45 (c, 0.66 CHCl3). Pmr (300 MHz) (DCCl3) δ1.52 (1H, m); 1.75 (1H, m); 1.95 (1H, m) 2.02 (1H, m); 3.21 (2H, m); 3.47 (3H, s); 3.78 (1H, m) 4.10 (1H, m); 4.56 (2H, q); 4.81 (1H, d); 7.24-7.42 (5H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([N:18]([CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].CC1C=CC=C(C)N=1.[Si:50](OS(C(F)(F)F)(=O)=O)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>C(Cl)Cl>[CH2:40]([O:39][C:37]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([N:18]([CH2:27][C@H:28]([O:29][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[C:19]([O:21][CH2:22][C:23]([Cl:25])([Cl:24])[Cl:26])=[O:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:38])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a -78° C. solution of 3.75 g (5.47 mmol) (R,R)-5-{2-[[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester and 60 mL of CH2Cl2 was added 1.27 mL (1.17 g, 10.94 mmol) of 2,6-lutidene followed by 1.38 mL (1.59 g, 6.03 mmol) of TBSOTf. After stirring at -78° C. for 1.5 h, the reaction mixture was quenched with 50 mL sat. aq. NaHCO3 and warmed to room temperature. After extraction with 3×150 mL Et2O, the combined organics were washed with 1×200 mL sat. CuSO4, 1×200 mL brine, dried over MgSO4, filtered and evaporated to a cloudy white oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (8/1 to 4/1) gave 3.42 g (4.46 mmol, an 82% yield) of the title compound (Rf =0.31; 4/1 hexanes/EtOAc) as a gummy colorless solid; 1H NMR (300 MHz, CDCl3): δ-0.13-(-0.08) (m, 3H), 0.00-0.06 (m, 3H), 0.85-0.91 (m, 9H), 1.05 (d, J=6.7 Hz, 3H), 1.33 (t, J=7.1 Hz, 6H), 2.60-2.75 (m, 1H), 2.77-2.96 (m, 1H), 3.00-3.31 (m, 2H), 3.77-4.00 (m, 1H), 4.35 (q, J=7.1 Hz, 4H), 4.65-4.88 (m, 2H), 5.02-5.20 (m, 1H), 6.60-6.85 (m, 4H), 7.15-7.37 (m, 3H); MS (ES) m/z (relative intensity): 790 (M+ +Na, 100), 768 (M+ +H, 20).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH3:16].CC(C)=O.[I-:27].[K+]>C(OCC)C>[I:27][CH2:2][CH2:3][C@H:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH3:16]
Reactant: CC(=O)Oc1ccc(O[C@H](CCCl)c2ccccc2)c(C)c1
Reactant: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(O[C@H](CCI)c2ccccc2)c(C)c1
Yield: 70 %

Procedure:
A mixture of (R)-3-chloro-1-phenyl-1-(2-methyl-4-acetoxyphenoxy)propane (0.200 gm, 0.63 mMol) and 15 mL acetone saturated with potassium iodide was stirred at reflux under argon overnight. The reaction mixture was poured into 50 mL diethyl ether and the resulting suspension was filtered. The filtrated was washed with saturated aqueous sodium hydrogen sulfite followed by water. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure to provide 0.18 gm (70%) of the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[N+:11]([O-])([OH:13])=[O:12]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[CH3:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)cc(C)c1Cl
Product: Cc1cc(O)c([N+](=O)[O-])c(C)c1Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
4-Chloro-3,5-dimethyl-phenol (20.0 g, 128 mmol) was dissolved in glacial acid (150 ml) and the solution was cooled to 5° C. Then nitric acid 65% (12.4 g, 128 mmol) was added dropwise while temperature was kept below 20° C. by external cooling. After the addition was complete stirring was continued for 1 hour at ambient temperature. The reaction mixture was poured into ice/water (1:1, 500 g) whereupon an orange solid precipitated. The solid was filtered off, washed with water and dried. Yield: 23.2 g (90.1%). 1H-NMR (DMSO-d6): δ=11.0 (s, 1H); 6.9 (s, 1H); 2.3 (s, 3H); 2.2 ppm (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[OH:37][CH:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][NH:28][C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:25])[CH2:32][CH2:33]1
Reactant: NCCN1CCC(O)CC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCN2CCC(O)CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 57.2 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with 1-(2-amino-ethyl)-piperidin-4-ol (54 mg, 1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 69.8 mg (57%) of the titled compound as a yellow solid.
Reaction SMILES: S(=O)(=O)(O)N.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[CH:24]=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-:26]Cl=O.[Na+]>CC(C)=O.O>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[C:24]([OH:26])=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1c(OCc2ccccc2)ccc2ccccc12
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1c(OCc2ccccc2)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sulfamic acid (17.28 g, 178 mmol) was added to a solution of 9 (21.11 g, 80.5 mmol) in acetone (420 ml) and water (210 ml) at 0° C. Over a period of 20 minutes, 80% NaClO2 (10.42 g, 92.2 mmol) was added at 0° C. The solution was stirred at 0° C. for 30 minutes and then concentrated to about 200 ml. After dilution with water (200 ml), the mixture was extracted with CH2Cl2 (1×200 ml, 2×100 ml). The organic layer was dried (MgSO4) and concentrated. Crystallization from cyclohexane/ethyl acetate (1:1) generated 19.12 g (85%) of 10 as pale yellow crystals, mp 127°-128° C. (lit. mp 128°-130° C.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.O1CCOCC1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(OCC)(=O)C>CO>[N:30]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:21][C:16]4=[N:17][CH:18]=[CH:19][N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=S(=O)(Oc1ccc(-c2cc3nccnc3[nH]2)cc1)C(F)(F)F
Reactant: C1CCNC1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1cnc2[nH]c(-c3ccc(N4CCCC4)cc3)cc2n1
Temperature: 200 °C

Procedure:
A mixture of 6-(4-trifluoromethanesulfonyloxyphenyl)-5H-pyrrolo[2,3-b]pyrazine [20 mg, Reference Example 18(e)], dioxane (3 mL) and pyrrolidine (0.2 mL) was heated at 200° C. in a microwave oven for 1 hour. The reaction mixture was then evaporated and the residue was subjected to chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give, after trituration with a mixture of ethyl acetate and methanol, the title compound (11 mg) as a yellow solid. MS: 265.1 (MH+). RT=2.92 minutes.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:22])[CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].CC(C)=O>ClCCl>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:5]2[C:4](=[O:22])[CH2:3][C@H:2]([NH:1][C:23](=[O:25])[CH3:24])[CH2:6]2)=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
In the reaction flask, (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (7.0 g, 23.3 mmol), prepared as described in the previous example, was charged together with dichloromethane (70 mL). At 40° C., a solution of acetic anhydride (2.97 g, 29.1 mmol) in dichloromethane (10 mL) was added dropwise under stirring over 30 min. After a reaction time of 1.5 h, no starting material was left according to HPLC. Acetone (250 mL) was added and the mixture was concentrated in vacuo to a volume of ˜50 mL. The residue was dissolved in acetone (250 mL) at 60° C. The warm solution was treated with charcoal, the resulting suspension filtered and the charcoal washed with warm acetone. The filtrate was concentrated at 60° C. to a volume of ˜50 mL when the product started to crystallize. At room temperature, tert-butyl methyl ether (100 mL) was added and the suspension was kept at this temperature overnight. The crystals were collected by filtration, washed with tert-butyl methyl ether and dried in vacuo to afford (S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide (7.0 g, 88%) as an off-white powder. The purity of the material by HPLC was 99.4% (area) and the enantiomeric ratio (S):(R) was determined as >99.9:0.1. The result of the elemental analyses (C,H,N,F,O) corresponded to the expected values.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH3:27])=[O:25])[C:12]2=[O:28])=[CH:2]1.CN(C)[C:31](=[O:33])[CH3:32]>C(O)CCO.O.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:32][CH2:31][OH:33])=[O:25])[C:12]2=[O:28])=[CH:2]1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: CC(=O)N(C)C
Agent: [Zn]
Solvent: OCCCO
Solvent: O
Product: O=C(OCCCO)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
A solution of the compound of Example 51 and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0019 g, 0.0020 mmol) in 1,3-propanediol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred at 120° C. for 2 h then at 100° C. for 12 h. Cooled to ambient temperature, the reaction mixture was diluted with water, and the precipitate was collected by filtration. Ethyl acetate was added to the filtrate, and the precipitate was collected by filtration. Those precipitates were combined then purified by preparative HPLC to afford the titled compound as solid (0.0067 g, y. 16%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[C:11]([CH2:13][N:14]3[N:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:10]=[CH:9][N:8]=2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[CH:12]=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([NH:19][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:32])[CH:16]=[N:15]2)[CH:10]=[CH:9][N:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cc(Cn3ncc(N)n3)ccn2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)ccn1

Procedure:
Following general procedure A followed by B, starting from 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-4-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.P(Br)(Br)[Br:11]>C(OCC)C>[Br:11][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1I
Solvent: CCOCC
Product: BrCc1ccccc1I
Yield: 91 %

Procedure:
To a solution of 2-iodobenzyl alcohol (50 g) in diethyl ether (500 mL), cooled in an ice-water bath, was added dropwise phosphorus tribromide (28 mL). The reaction mixture was chilled in a refrigerator for 3.5 h, then quenched by slow addition of methanol (50 mL). The mixture was washed with water, then saturated sodium bicarbonate, then water (100 mL each). The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to a white solid, which was triturated in hexane and collected by filtration to yield 58 g (91%) of the title material of Step A as a solid, mp 55-57° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:17][CH3:18].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(C(O)Cc2ccccc2)ccc1F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1cc(C(=O)Cc2ccccc2)ccc1F
Reaction time: 8 h
Yield: 151.3 %

Procedure:
To a solution of 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanol (23.7 g, 40.6 mmol) in acetone (240 mL) was added Jones reagent (64 mL) at rt. The reaction mixture was stirred overnight, quenched by the addition of isopropanol and diluted with EtOAc. The organic portion was washed with 1 N HCl (2×), dried over Na2SO4, filtered and concentrated under reduced pressure to yield the 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanone (15 g, 66% yield). LCMS: RT=3.250 min [M+H] 245.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); 1H NMR (500 MHz, CDCl3) δ ppm 7.62 (dd, J=8, 1 Hz, 1H), 7.60-7.55 (m, 1 H), 7.35-7.29 (m, 2H), 7.26-7.23 (m, 3H), 7.10 (dd, J=10, 8 Hz, 1H), 4.24 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C@@:26]([OH:30])([C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCc2sc(C(N)=O)nc2-3)no1

Procedure:
Following Procedure F, 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid after purification by reverse-phase HPLC. LCMS: 396.1 [M+H]+; 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=8.5 Hz, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.02 (d, J=10.4 Hz, 1H), 6.52 (s, 1H), 6.35 (s, 1H), 4.39 (t, J=4.8 Hz, 2H), 3.39 (m, 3H), 2.41 (s, 3H), 1.83 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11](Cl)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[C:11]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccc[nH]1
Product: CCCCCCC(=O)c1c[nH]c(C(=O)OCC)c1
Yield: 71.1 %

Procedure:
Starting with 2.0 g of ethyl pyrrole carboxylate (14 mmol) and 4.2 ml (26 mmol) of heptanoylchloride and following a procedure analogous to the one described above, 2.5 g (70% yield) of the desired product is obtained. 1H NMR (δ ppm, CDCl3): 10.07 (s, br, 1H, NH); 7.53 (dd, J=1.60, 3.35 Hz, 1H, α-pyrrolic); 7.27 (dd, J=1.60, 2.47; 1H; β-pyrrolic); 4.32 (q, 2H, J=7.14 Hz, CO2Et); 2.73 (t, 2H, J=7.50, α-CO CH2); 1.67 (m, 2H, β-CO CH2); 1.33 (t, 3H, J=7.14, CO2Et); 1.28 (m, 6H, γ,δ,ε CH2); 0.85 (m, 3H, end-CH3). 13C NMR (δ ppm, CDCl3): 196.32; 161.26; 127.07; 126.24; 124.01; 114.86; 60.99; 39.78; 31.62; 29.05; 24.59; 22.48; 14.30; 13.99. Exact mass calculated for C14H22NO3 (M+H)=252.159969, found=252.159072.