Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH:8]([O:10][C:11]([CH3:46])([CH3:45])[CH2:12][O:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([C:24]1N3C=C([C@@H](N4CC[C@H](N)C4)C(F)(F)F)C=CC3=NN=1)[CH:20]=[CH:19]2)=O.IC>O>[CH3:8][O:10][C:11]([CH3:46])([CH3:45])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([CH3:24])[CH:20]=[CH:19]2
Reactant: CC(C)(COc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12)OC=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)COc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To a mixture of sodium hydride (60% in mineral oil; 0.013 g, 0.32 mmol) in anhydrous dimethylformamide (1.4 mL, 0.22 mmol) was added dropwise a solution of 2-methyl-1-(2-methylquinolin-8-yloxy)propan-2-ol (Example 259; 0.050 g, 0.22 mmol) in anhydrous dimethylformamide (1.4 mL, 0.22 mmol). The mixture was allowed to stir at ambient temperature for 30 minutes before by addition of iodomethane (0.054 mL, 0.86 mmol), and the resultant mixture allowed to stir at ambient temperature for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) providing the title compound (0.038 g, 73%).
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4][CH:3]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.Cl[C:27]1[N:31]([CH3:32])[N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CCO>[F:1][CH:2]1[CH2:8][CH2:7][N:6]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])[CH2:5][CH2:4][CH:3]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCNCCC1F
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(F)C(NC(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Yield: 13.6 %

Procedure:
To a solution of tert-butyl 5-fluoroazepan-4-ylcarbamate (310 mg, 1.34 mmol) in EtOH (4 mL) was added DIPEA (1 ml, 5.7 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (216 mg, 1.34 mmol). The reaction mixture was heated at 130° C. in a microwave for 8 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (30-40% EtOAc/isohexane) to give the two trans (anti) isomers, tert-butyl 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a yellow glass (65 mg) contaminated with some of the cis (syn) isomer.
Reaction SMILES: [F:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[CH:15]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[NH:41])[NH:39]O)=[CH:34][CH:33]=1)[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[N:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[N:17]=1.O.C(O)(=O)C>CO.[Fe]>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([NH:31][CH:15]([C:3]2[CH:4]=[C:5]([O:13][CH3:14])[C:6]3[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]=3[C:2]=2[F:1])[C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[N:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])[N:17]=2)=[CH:33][CH:34]=1)(=[NH:39])[NH2:41]
Reactant: COc1cc(C(Nc2ccc(C(=N)NO)cc2)c2nn(-c3ncccc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCCO2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCCO2
Temperature: 60 °C
Reaction time: 30 h

Procedure:
To a solution of 61 mg of 2-(3-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(N-hydroxycarbamimidoyl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)nicotinic acid in 6 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 60 mg of iron powder, and the mixture was stirred at 60° C. for 30 hours under a nitrogen atmosphere. Upon cooling, the reaction mixture was filtered through celite and purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 2-{3-[(4-carbamimidoylphenylamino)-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}nicotinic acid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][CH3:8])[NH:5][CH:6]=1.[OH-:9].[Na+].[CH2:11]=O>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][CH3:8])[NH:5][C:6]=1[CH2:11][OH:9]
Reactant: [OH-]
Reactant: CCc1nc(Br)c[nH]1
Reactant: C=O
Agent: [Na+]
Solvent: CCO
Product: CCc1nc(Br)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Bromo-2-ethylimidazole (24.4 g) was dissolved in ethanol (244 ml), and 1N aqueous sodium hydroxide solution (105 ml) and 37% formalin (15.6 ml) were added. The mixture was stirred at room temperature for 15 hr. The reaction mixture was neutralized under ice-cooling and concentrated to dryness under reduced pressure. The residue was extracted with chloroform-methanol (4/1) and insoluble matter was filtered off. The residue was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=49:1–19:1) to give 4-bromo-2-ethyl-5-(hydroxymethyl)imidazole (18.9 g) as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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.CCOC(C)=O.O>[Cl:22][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)[CH:21]=[CH:20][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[C:8]1=[O:19]
Reactant: O=C1CCC(N2CCC(Cc3ccc(Br)cc3Cl)C2=O)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(CC3CCN(C4CCC(=O)CC4)C3=O)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Combine 3-(4-Bromo-2-chloro-benzyl)-1-(4-oxo-cyclohexyl)-pyrrolidin-2-one (0.5, 1.3 mmol), 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.814 g, 3.9 mmol), sodium carbonate (0.689 g, 6.5 mmol) in DME (8 mL)/H2O (3 mL) and degas with a stream of nitrogen. Add (Ph3P)4Pd (0.150 g, 0.13 mmol), and stir at 80° C. for 17 hour under nitrogen atmosphere. Cool to ambient temperature and add ethyl acetate (20 mL) and water (10 mL). Extract the aqueous phase with ethyl acetate (2×20 mL), dry (sodium sulfate) and condense under reduced pressure. Chromatography (silica, EtOAc) yields 0.287 g (42%) as a white solid MS (m/z): 386 (M+1).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6](O)=O)[CH:2]=[CH2:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:40][C:41]12[C:54]([CH3:56])([CH3:55])[CH:45]([CH2:46][C:47]3[C:52]([OH:53])=[CH:51][CH:50]=[CH:49][C:48]=31)[NH:44][CH2:43][CH2:42]2.[Cl:57]CCl>>[ClH:57].[CH2:1]([O:4][CH2:5][CH2:6][N:44]1[CH2:43][CH2:42][C:41]2([CH3:40])[C:54]([CH3:56])([CH3:55])[C@H:45]1[CH2:46][C:47]1[C:52]([OH:53])=[CH:51][CH:50]=[CH:49][C:48]=12)[CH:2]=[CH2:3]
Reactant: C=CCOCC(=O)O
Reactant: CC12CCNC(Cc3c(O)cccc31)C2(C)C
Reactant: ClCCl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOCCN1CCC2(C)c3cccc(O)c3C[C@@H]1C2(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.8 g of allyloxyacetic acid are placed in 15 mL dichloromethane, combined with 4.8 g of TBTU and 7.5 mL of ethyldiisopropylamine and stirred for 15 min. at RT. Then the mixture is cooled to −5° C. and 3.1 g of 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol are added. The mixture is stirred for 30 min at 0° C., and for 1 h at RT. Then it is washed once with 100 ml of 2N HCL and 100ml of 10% potassium carbonate solution, dried and evaporated down in vacuo. The residue is taken up in 50 mL of THF and added dropwise under nitrogen to a suspension of 1.0 g of lithium aluminium hydride in 50 ml of THF (temp. increases to 35° C.). Then the mixture is heated to 50° C., stirred for 1 h, cooled and 1 ml of water is added dropwise at 0-10° C., the mixture is stirred for 30 min, 3 ml of NaOH are added and the mixture is stirred for another 30 min. The precipitate is suction filtered, the mother liquor is evaporated down in vacuo and the residue is filtered through a short column (about 75 ml of silica gel; dichloromethane 70, ethyl acetate 20, methanol 10). The appropriate fractions are evaporated down in vacuo, and crystallised from acetone+eth. HCl. Yield 2.8 g (77%), melting point: 236° C.; [α]D20=−78,3° (c=1; methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11]CC)=O)=O)=[CH:4][CH:3]=1.[C:16]([O:19]C(=O)C)(=O)[CH3:17].O.[NH2:24][NH2:25]>C(#N)C>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH2:8][C:9](=[O:11])[NH:25][N:24]=2)=[CH:14][CH:15]=1)(=[O:19])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1ccc(N)cc1
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(C2=NNC(=O)C2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In 440 ml of acetonitrile was dissolved 146 g of ethyl p-aminobenzoylacetate, and 70 ml of acetic anhydride was added dropwise to the solution at 40° C. After reacting at 40° C. for 1 hour, 48.8 g of 80% hydrazine hydrate was added thereto dropwise. After heat generation subsided, the reaction was further continued at a temperature between 55° C. and 60° C. for 1 hour. The reaction mixture was cooled to 5° C., and the precipitated crystals were filtered to yield 148 g of 3-(4-acetylaminophenyl)-2-pyrazolin-5-one as gray crystals having a melting point of 254° to 258° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:15]2[C:6]([C:7]3[CH:8]=[C:9]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:10]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=4)=[N:11][C:12]=3[CH:13]=[CH:14]2)=[N:5][N:4]=1.C(Cl)C[Cl:32].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[N:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][C:61](O)=[O:62])[CH:55]=1>CN(C)C=O>[Cl-:32].[CH3:2][C:3]1[N:15]2[C:6]([C:7]3[CH:8]=[C:9]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:10]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][NH:23][C:61](=[O:62])[CH2:60][C:56]5[CH:55]=[NH+:54][CH:59]=[CH:58][CH:57]=5)=[CH:20][CH:21]=4)=[N:11][C:12]=3[CH:13]=[CH:14]2)=[N:5][N:4]=1
Reactant: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CN)cc4)nc3ccn12
Reactant: O=C(O)Cc1cccnc1
Reactant: ClCCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CNC(=O)Cc5ccc[nH+]c5)cc4)nc3ccn12
Product: [Cl-]
Temperature: 100 °C

Procedure:
To 1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methanamine hydrochloride (5-3, 20 mg, 0.050 mmol)), EDC (12 mg, 0.065 mmol), HOBT (10 mg, 0.0650 mmol), DIPEA (0.033 ml, 0.199 mmol), and pyridin-3-ylacetic acid hydrochloride (11 mg, 0.0650 mmol) was added 0.6 mL anhydrous dimethylformamide. The reaction mixture was then heated under microwave irradiation at 100° C. for 5 minutes. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 1% acetonitrile/0.1% trifluoroacetic acid/water→95% acetonitrile/0.1% trifluoroacetic acid/water) & conversion to HCl salt (addition of saturated solution of HCl in ethyl acetate (˜4N) & concentration) gave the title compound as yellow solid. HRMS (M+H+): calculated=243.1079, observed=243.1083.
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[O:19]=[C:20]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)[CH2:21][CH2:22][C@@H:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C(#N)C.C(OCC)(=O)C.O>[CH:1]1([S:7][CH2:8][CH2:9][N:26]2[CH2:27][CH2:28][C@@H:23]([CH2:22][CH2:21][C:20](=[O:19])[C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=4)[N:37]=[CH:36][CH:35]=3)[C@@H:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:25]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C
Yield: 68.5 %

Procedure:
2.06 g of 2-chloroethyl cyclohexyl sulfide in 50 cm3 of acetonitrile, followed by 1.78 g of potassium iodide and 7.25 g of potassium carbonate, were added with stirring, at a temperature in the region of 20° C. and under an inert atmosphere, to a solution of 3.9 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate in 50 cm3 of acetonitrile. The mixture was heated for 18 hours at a temperature in the region of 80° C. After cooling to approximately 20° C., the mixture had 100 cm3 of water and 100 cm3 of ethyl acetate added. The organic phase was separated by settling, while the aqueous phase was extracted with 200 cm3 of ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 45° C. An oil was obtained, which product was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μ; diameter 3.5 cm; height 46 cm), elution was carried out with. a dichloromethane/methanol (95/5 by volume) mixture, and 50-cm3 fractions were collected. Fractions 18 to 37 were combined and concentrated as above. A product was obtained, which product was purified a second time by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μ; diameter 4 cm; height 40 cm), elution was carried out with an ethyl acetate/cyclohexane (7/3 by volume) mixture, and 100-cm3 fractions were collected. Fractions 24 to 54 were combined and then concentrated under the same conditions as above. 3.7 g of methyl (3R,4R)-1-[2-(cyclohexylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate were obtained in the form of an oil with a brown color.
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=[O:8])C.Cl.C1(C)C=CC=CC=1>O.[Cl-].[Zn+2].[Cl-]>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=[O:8]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 72.7 %

Procedure:
A mixture of 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (20.0 g), zinc chloride (60.0 g) and hydrochloric acid (37%, 15 mL) was stirred at 90° C. for 17 h. The mixture was diluted with water (100 mL) and then cooled to 3° C. After 1 h the product was filtered and washed with cold water. The product was dried in vacuo at 100° C. to give 16.5 g (95.1%) of crude product. The crude product was mixed with toluene (275 mL) and activated carbon (2,0 g) and the resulting mixture was refluxed for 45 min. The hot solution was filtered and then cooled to 3° C. After 1 h the product was filtered and washed with cold toluene. It was dried in vacuo at 50° C. to give 12.6 g (72.6%) of pure 3,4-dihydroxy-5-nitrobenzaldehyde (mp. 146°-8° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23](C#N)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].[F:35]C1C=CC(B(O)O)=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([F:11])([F:12])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:35])=[CH:26][CH:27]=2)=[CH:17][N:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccc(F)cc2)cn1
Yield: 42.4 %

Procedure:
Compound 6 was prepared in a similar manner to compound 5 from (4-fluorophenyl)boronic acid to afford a solid 6 (0.1 g, 0.22 mmol, 42.4%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.20 (d, J=2.5 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.43-7.38 (m, 2H), 7.27 (d, J=2.5 Hz, 1H), 7.26-7.03 (m, 4H), 6.79-6.70 (m, 2H), 5.49 (d, J=14.5 Hz, 1H), 5.15 (d, J=14.5 Hz, 1H). MS (ESI): m/z 494.1 [M++1]. HPLC: 99.43%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:29]=[CH:28][C:27](C4C=CC=CC=4)=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1CCC[C@H]1C(O)=O>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 839.2 %

Procedure:
Using the procedure described for example 97f 0.125 g of 1-(2-(R)-acetylamino-3-phenyl)-propionyl)-pyrrolidine-2-(S)-carboxylic acid was converted into 0.90 g (47%) of the title compound. (+)-APCI-MS: 460 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(CC1C(=O)C=C(C)CC1)(OCC)=O>C1COCC1>[C:22]([CH2:21][CH:8]1[C:7](=[O:11])[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]1)([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCCCC1=CC(=O)CCC1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: CCOC(=O)CC1CCC(C)=CC1=O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1=CC(=O)C(CC(=O)OCC)CC1
Yield: 83.5 %

Procedure:
The reaction of 3-n-butyl-2-cyclohexen-1-one (3.0 g, 19.7 mmoles) in 10 ml of THF with lithium diisopropylamide (2.17 mmoles) followed by ethyl bromoacetate (3.96 g, 23.6 mmoles) in 10 ml of THF, at -78° C. under argon, was conducted in a similar manner to the synthesis of 6-(carbethoxymethyl)-3-methyl-2-cyclohexen-1-one described in Example II, and a yield of 3.92 g (83%) of 6-(carbethoxymethyl)-3-n-butyl-2-cyclohexen-1-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:14])=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.C(O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:12][C:10]([CH:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([CH3:14])[CH2:17][N:18]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:19]1)=[O:11]
Reactant: COC(=O)/C=C(\C)c1ccc(Cl)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccccc2)CC1(C)c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A mixture of 11.7 g (55 5 mmol) (E)-methyl 3-(4-chlorophenyl)but-2-enoate (Organic Letters 2008, 2131-2134), 16.5 g (69 4 mmol) N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine and 0.63 g (5.5 mmol) TFA in 30 mL DCM was stirred at 0-5° C. for 1 h and then at room temperature over night. The mixture was neutralised with NEt3 and evaporated. The residue was taken up on isolute and purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. After evaporation of the product containing fractions 9.6 g (50%) of the title compounds was isolated as colorless oil. MS m/e: 344.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:29])[N:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]=2)[NH:12][C:11]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:21]([N:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[C:10]2[CH2:9][CH2:8][NH2:7])=[O:29])[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCN)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of {2-[5-diisobutylcarbamoyl-2-(3,5-dimethyl-phenyl)-1H-indol-3-yl]-ethyl}carbamic acid tert-butyl ester (230 mg in 12 mL methylene chloride) at 0° C. was added 0.55 mL anisole followed by 3.4 mL trifluoroacetic acid and the mixture stirred at 0° C. After 1 hour, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:8:1) gave the title compound (173 mg).
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:21][C:22]1[CH2:26][CH2:25][CH2:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:21]=[C:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:2]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC1=NCCC1
Reactant: CSc1ccc(C(=O)C(Cl)c2ccc(SC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2nc3n(c2-c2ccc(SC)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 9.0 g (0.028 mol) of 2-chloro-1,2-di(4-methylthiophenyl)ethanone in 50 ml of dry N,N-dimethylformamide was added 7.0 g (0.084 mol) of 2-amino-4,5-dihydro-3H-pyrrole. The mixture was stirred for 48 hours at ambient temperature, then poured into 1 liter of ice containing 300 ml of 5% aqueous sodium carbonate solution. The precipitate was collected by filtration and dissolved in methylene chloride. The solution was washed with water, dried (K2CO3) and evaporated to give a residue which was chromatographed on alumina and eluted with methylene chloride-methanol (95:5) to give the title compound, m.p. 127°-128°.
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].CC([O-])=O.[Na+].I[CH:24]([CH3:26])[CH3:25]>C1COCC1>[Br:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH:24]([CH3:26])[CH3:25])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(C)I
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Agent: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Yield: 7.6 %

Procedure:
Hydrazine hydrate (3.29 ml, 66.9 mmol) was added dropwise to a solution of 2-bromo-5-(chlorosulfonyl) benzoic acid (Preparation 22, 10.0 g, 33.4 mmol) in THF (100 mL) at 0° C. Once the addition was complete the mixture was allowed to warm to room temperature and the solid was collected by filtration. The solid was washed with heptane (3×20 mL) and dried under vacuum at 50° C. for 18 hours. The solid was dissolved in EtOH (100 mL) and NaOAc (16.4 g, 198 mmol) and 2-iodopropane (16.7 mL, 165 mmol) were added. The mixture was heated to reflux for 16 hours, cooled to room temperature and the solvent was evaporated under reduced pressure to leave an off-white solid. The solid was partitioned between EtOAc (50 mL) and 1M NaOH (100 mL). The aqueous layer was separated, acidified to pH=1 with 2M HCl and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried over MgSO4 and the solvent was evaporated under reduced pressure to leave an orange oil. The oil was purified by silica gel column chromatography eluting with MeOH/CH2Cl2/AcOH 5:95.5:0.5 followed by a further chromatography eluting with heptanes/EtOAc 4:1 to give the title compound as a white solid 8% yield, 0.78 g.