Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 63.9 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140°-142° C. ANALYSIS: Calculated for C15H19FN2O2 : 64.73%C 6.88%H 10.06%N Found: 64.79%C 6.97%H 10.03%N
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:9][C:8](=[O:18])[N:7]([CH2:19][CH3:20])[C:6]=2[CH:21]=1.Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:34][C:33]=2[O:44][CH3:45])[C:28]([Cl:46])=[CH:27][N:26]=1>>[Cl:46][C:28]1[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:34][C:33]=2[O:44][CH3:45])=[N:30][C:25]([NH:1][C:2]2[C:3]([O:22][CH3:23])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH2:9][C:8](=[O:18])[N:7]([CH2:19][CH3:20])[C:6]=3[CH:21]=2)=[N:26][CH:27]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CN(CC(=O)N(C)C)Cc2cc(OC)c(N)cc21
Product: CCN1C(=O)CN(CC(=O)N(C)C)Cc2cc(OC)c(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc21

Procedure:
The title compound was prepared from 2-(8-Amino-1-ethyl-7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to example 724. Product was isolated as a tan solid (0.017 g, 18%). Mp 98-101° C.; LCMS (m/e) 639 (M); 1H-NMR (DMSO, 400 MHz) δ 8.10 (s, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.54-7.52 (d, 1H, J=8.84 Hz, 6.99 (s, 1H), 6.61 (d, 1H), 6.37-6.34 (d, 1H, J=10.61 Hz), 3.86 (s, 3H), 3.80-3.74 (m, 8H), 3.53 (s, 3H), 3.12-3.11 (t, 4H, J=4.8 Hz), 3.02 (s, 3H), 2.97 (s, 2H), 2.83 (s, 4H), 1.19-1.18 (d, 1H, J=6.32 Hz), 0.90-0.86 (t, 3H, J=7.33 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[CH3:10][S-:11].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11][CH3:10])=[CH:4][C:3]=1[Cl:9]
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(Br)c(Cl)c1
Yield: 109.2 %

Procedure:
A solution of 1-bromo-2-chloro-4-fluorobenzene (7, 0.50 g, 2.39 mmol) and sodium thiomethoxide (0.17 g, 2.42 mmol) in DMSO (2.5 mL) was stirred at 100° C. for 1 h. The reaction mixture was added to 20 mL water with stirring, the aqueous mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The title compound (0.62 g) was obtained as a colorless oil and was used in the next step without further purification.
Reaction SMILES: C([CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]1=[O:10])(OC(C)(C)C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O1CCOCC1>[Cl:26][CH:15]1[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8]1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C1CCCCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C1CC(Cl)CCCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
Example 228 B) To a solution of 1 g (0.0047 mol) of this Boc-caprolactam product of Example 228 A in 10 mL of anhydrous THF at -78° C. was added 0.005 mol of LiHMDS. After stirring for 30 minutes, 1.2 g (0.005 mol) of hexachloroethane in 5 ml of anhydrous THF was added. The mixture was allowed to warm to 0° C. and was quenched with dilute HCl. The mixture was extracted with EtOAc and the organic layer was washed with 5% HCl, dried (MgSO4), filtered and concentrated to afford a yellow oil. The residue oil was dissolved in 40 mL of 1,4-dioxane (satd. with anhydrous HCl), stirred for 40 minutes, concentrated to afford 0.9 g of 3-chlorocaprolactam as an off-white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23](Cl)(=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27].CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CCCCC(=O)Cl
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and pentanoyl chloride (0.36 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O for 18 h. The product was dried in vacuo to give pentanoic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.77 g, 35% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.71 min (95.58%); mp: 184-186° C.; 1H NMR (DMSO-d6) δ 0.81-0.95 (m, 3H, CH3), 1.28 (dq, J=7.3, 14.8 Hz, 2H, CH2), 1.41-1.64 (m, 2H, CH2), 1.97-2.13 (m, 1H, CHH), 2.17 (t, J=7.5 Hz, 2H, CH2), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-2.99 (m, 1H, CHH), 4.43 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.67-7.81 (m, 2H, Ar), 7.88 (d, J=7.7 Hz, 1H, Ar), 8.50 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.68, 21.79, 21.99, 27.37, 30.93, 34.98, 41.87, 48.99, 121.78, 123.48, 129.71, 131.59, 133.28, 147.84, 166.97, 167.12, 169.82, 172.47, 172.73; LCMS: MH=372; Anal Calcd for C19H21N3O5: C, 61.45; H, 5.70; N, 11.31. Found: C, 61.12; H, 5.54; N, 11.15.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].Br[CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OC)c(OCCCC(F)(F)F)c1
Reaction time: 8 h

Procedure:
A suspension of 3-hydroxy-4-methoxy-benzoic acid ethyl ester (1.00 g, 5.10 mmol), 1-bromo-4,4,4-trifluorobutane (1.12 g, 5.86 mmol) and anhydrous K2CO3 (2.14 g, 15.3 mmol) in MeCN (10 mL) is refluxed with stirring overnight. After cooling, the mixture is filtered, and the filtrates are evaporated to drying to give the title compound as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.62. MS: 307.0 [M+H]+. 1H-NMR (CDCl3): δ 1.42 (m, 3H), 2.1-2. (m, 2H), 2.3-2.45 (m, 2H), 3.95 (s, 3H), 4.14 (m, 2H), 4.39 (m, 2H), 6.93 (dd, 1H), 7.58 (d, 1H), 7.74 (dd, 1H) ppm.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:5]([OH:7])=O)([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.[NH2:27][C@@H:28]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1.[CH2:49]([N-:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH:50]([CH3:52])[CH3:51]>C(Cl)Cl>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:5]([NH:27][C@@H:28]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:7])([CH3:3])[CH3:4].[CH2:49]([N-:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH:50]([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)C[N-]CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 18 h

Procedure:
In a 100 ml round bottom flask, 0.50 mmol of Boc-Aib (Aib=α-aminoisobutyric acid) was dissolved in 30 ml dry CH2Cl2 and then 0.51 mmol of 1-hydroxybenzotrizole was added while stirring under N2 atmosphere in an ice-bath, 0.55 mmol of 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide HCl was added in 20 ml dry CH2Cl2 at a fast drop rate and the reaction was stirred for 1 hour at 0° C. 0.51 mmol of (2) in 15 ml of CH2Cl2 was added dropwise and stirring was continued for a further 18 h at ambient temperature. The reaction mixture was washed with 20 ml of 20% citric acid aqueous solution, 20 ml of saturated NaCHO3 aqueous solution, and 20 ml of saturated sodium chloride aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Further purification was done by flash column chromatography (CHCl3/MeOH, 95:5) to afford white solid of Boc-Aib-DTrp-DPro-diisobutylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:4][CH:3]=1.[O:20]([C:22]#[N:23])[Na]>O.C(O)(=O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:22]([NH2:23])=[O:20])=[CH:7][CH:6]=3)=[C:9]([CH2:18][CH3:19])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: N#CO[Na]
Solvent: CC(=O)O
Solvent: O
Product: CCc1sc2ncnc(N)c2c1-c1ccc(NC(N)=O)cc1
Yield: 95.7 %

Procedure:
A mixture of Example 78A (0.27 g, 1 mmol) and NaOCN (0.13 g, 2 mmol) in water (1.5 mL) and acetic acid (1.5 mL) was stirred overnight at room temperature and partitioned between water and ethyl acetate. The organic extract was washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to provide 0.3 g of the desired product. MS (ESI(+)) m/e 314 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.15 (t, J=7.46 Hz, 3H); 2.63 (q, J=7.57 Hz, 2H); 5.94 (m, 2H); 7.24 (d, J=8.48 Hz, 2H); 7.56 (d, J=8.48 Hz, 2H); 8.25 (s, 1H); 8.75 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22](I)[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]>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.CN(C=O)C.CCN(CC)CC>[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22]([C:5]#[C:4][CH2:3][NH:2][CH3:1])[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: C#CCNC
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1cc(C(C)=O)c[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (43.6 mg, 0.66 mmol) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (100 mg, 0.25 mmol) (Example 90B) using (Ph3P)4Pd (30.1 mg) and Cul (6.0 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 89° C. for 5 h to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=1)[CH2:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=1)[CH2:13][C:14]1[C:19]([O:20][S:33](=[O:35])(=[O:34])[N:32]([CH3:37])[CH3:31])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2O)c(C)c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2OS(=O)(=O)N(C)C)c(C)c1
Reaction time: 48 h
Yield: 22.5 %

Procedure:
To a solution of {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-hydroxy-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.190 g, 0.46 mmol) in CH2Cl2 (4 mL) was added dimethylsulfamoylchloride (0.160 mL, 1.49 mmol), NEt3 (0.300 g, 2.16 mmol) and DMAP (catalytic) and the reaction mixture stirred for 48 h. The mixture was diluted with CH2Cl2 (30 mL) and the organic layer was washed with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4), and concentrated. Purification by column chromatography on silica gel with saturated NH4OH in Et2O afforded {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-dimethylsulfamoyloxy-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.054 g, 23%) 1H NMR (CDCl3) δ 1.30-1.53 (m, 13H), 2.11 (s, 3H), 2.25 (s, 3H), 2.50-2.54 (m, 2H), 2.94-3.00 (m, 8H), 3.74 (s, 2H), 3.91 (s, 2H), 5.11 (br s, 1H), 7.16 (s, 1H), 7.23 (dd, 1H, J=6.6, 4.8 Hz), 7.72 (d, 1H, J=8.3 Hz), 8.—(s, 1H), 8.51 (d, 1H, J=4.1 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>CCOCC>[N:21]([CH2:13][C:12](=[O:15])[CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CC(C(=O)CBr)C(F)(F)F)OCc1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)C(CC(=O)OCc1ccccc1)C(F)(F)F
Yield: 81.2 %

Procedure:
Stir a mixture of 290 mg (0.82 mmol) of the bromo-ketoester of Example 5, 91 mg (1.4 mmol) of NaN3, and 4 ml of dry DMF at 25° C. for 1 hour. Dilute the mixture with ether, wash several times with water and then brine, dry over MgSO4, and remove the solvent in vacuo to give 210 mg of the desired azide (VII, R=CF3, R1,R2 =H, R3 =C6H5CH2) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7](Br)[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[C:26]1([S:40]([OH:43])(=[O:42])=[O:41])[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36]([OH:39])(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1>C(#N)C.CC(C)=O>[C:26]1([S:40]([OH:43])(=[O:42])=[O:41])[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36]([OH:39])(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1.[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC#N
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 54.8 %

Procedure:
145 g (0.4 mol) of 4-bromo-4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester were dissolved in 800 ml of acetonitrile. 100 g (1.45 mol) of imidazole were added and the mixture was heated for 20 hours under reflux. The solvent was then distilled off in vacuo, the residue was taken up in 500 ml of methylene chloride and the solution was washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated. The oil which remained was dissolved in 800 ml of acetone and 100 g (0.35 mol) of 1,5-naphthalenedisulphonic acid in 300 ml of acetone were added. The resulting crystalline precipitate was filtered off and dried. 122.5 g (62% of theory) of 4-(4-chlorophenoxy)-2,2-dimethyl-4-(imidazol-1-yl)-3-keto-butanoic acid ethyl ester 1,5-naphthalenedisulphonate of melting point 194° C. were obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.[CH3:8][C:9]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C=O)C>[Si:12]([O:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)([C:9]([CH3:11])([CH3:10])[CH3:8])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H](O)CN1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a suspension of (R)-4-hydroxypyrrolidin-2-one (purchased from Asta Tech or Aldrich) (5.030 g, 48.26 mmol) in DMF (24 mL) at 0° C. was added TBDMS-Cl (7.637 g, 50.67 mmol) followed by imidazole (4.978 g, 72.39 mmol). The resulting mixture was warmed to ambient temperature and stirred for 1 hour, then poured into 100 mL of water with stirring. The resulting suspension was filtered and the solids were washed with water and dried under reduced pressure to afford (R)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one (10.14 g, 97.56% yield) that was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1csc2c(F)cccc12
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)NCc1csc2c(F)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluorothiophenol (4.14 g, 32.6 mmol) was dissolved in anhydrous THF (100 mL). Potassium tert-butoxide (1.0 M in THF, 35.8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde dimethyl acetal was added and the mixture was stirred for 3 days. Water (100 mL) was added and the solution was extracted with diethyl ether (3×100 mL). The extracts were concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to yield 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene (6.42 g) as a colorless oil. Chlorobenzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. The 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene was then added slowly turning the solution dark. After 3 hours of heating, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophenyl (0.77 g). The 7-fluorobenzothiophenyl (0.77 g, 5.1 mmol) and dichloromethyl methyl ether (0.872 g, 7.6 mmol) were dissolved in anhydrous DCM (25 mL). Titanium tetrachloride (1.0 M in DCM, 7.6 mL, 7.6 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g). The 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g, 3.77 mmol) and sulfamide (1.7 g, 18 mmol) were combined in anhydrous ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.148 g, 3.92 mmol) was added. After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([O:18][CH2:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:11]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Clc1cc(COCc2ccccc2)ncn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1

Procedure:
To a solution of 5-hydroxy indole (1.33 g, 10 mmol) and 4-benzyloxymethyl-6-chloro-pyrimidine (2.35 g, 10 mmol) in acetonitrile (20 mL) is added DBU. After 16 h at rt the solution is concentrated under reduced pressure. The residue is purified by FCC (EtOAc/Heptane from 0% to 40%) to give 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole. MS (ESI) m/z 447.0 (M+1).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:11]([O:23][C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=CC=Cc1ccccc1
Reactant: CCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C=Cc1ccccc1
Yield: 87 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), SeO2 (11.3 mmol), dodecanol (5 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of neutral alumina (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Dodecylcinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C12H25) is isolated in 87% yield. 1H-NMR (CDCl3, 300 MHz) δ7.51 (1H, d), 7.28 (2H, m), 7.14 (3H, m), 6.26 (1H, d), 4.02 (2H, t), 1.50 (2H, t), 1.11 (18H, m), 0.73 (3H, d); 13C-NMR (CDCl3, 75.4 MHz) δ166.4, 144.2, 134.4, 129.6, 128.6, 127.9, 118.2, 64.3, 31.9, 29.7, 29.6, 29.4, 28.7, 26.0, 22.7, 14.0.