Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9]2)[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@H](n2cnc(CO)c2)CC1
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1CC[C@H](n2cnc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (1.04 g) obtained in Step 2 of this Reference Example was dissolved in toluene (10 mL). To the solution, a solution of sodium bicarbonate (1.35 g) in water (5 mL), iodine (2.72 g), and 2,2,6,6-tetramethyl-1-piperidinyloxy (84 mg) were added in this order, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, saturated aqueous sodium thiosulfate was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1-1/2) to obtain the title compound (0.900 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][NH2:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=2)[C:27](O)=[O:28])[N:18]=1>>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]3[CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=[N:24][CH:25]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1coc(-c2ccccc2)n1
Product: O=C(NCCc1coc(-c2ccccc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(2-phenyloxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (42 mgs, yield 32%). 1H NMR (CDCl3) δ 9.46 (d, J=2.1 Hz, 1H), 9.32 (d, J=2.1 Hz, 1H), 8.87 (t, J=2.7 Hz, 1H), 8.06-7.96 (m, 3H), 7.57-7.44 (m, 3H), 3.85 (m, 2H), 2.93 (t, J=6.3 Hz, 2H). MS (ESI) m/z: Calculated for C20H14F3N5O3: 429.10. found: 430.1 (M+H)+.
Reaction SMILES: C[C:2]1(C)[O:6][CH2:5][CH2:4][O:3]1.[F:8][C:9]([F:16])([F:15])[C:10]([F:14])=[C:11]([F:13])[F:12]>>[F:12][C:11]([CH:4]1[CH2:5][O:6][CH2:2][O:3]1)([F:13])[CH:10]([F:14])[C:9]([F:16])([F:15])[F:8]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CC1(C)OCCO1
Product: FC(C(F)(F)F)C(F)(F)C1COCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Example 1 was prepared by combining 2,2-dimethyl-1,3-dioxolane (200 g, 1.96 moles, Fluka Chemie GmbH, Deisenhofen, Germany) and Luperox 575 (10 g, 0.041 moles) (Arkema, Oakville, Ontario, Canada) were combined in a 600 mL Parr reactor (Parr Instrument Co., Moline, Ill.). The reactor was warmed to 75° C. and hexafluoropropene (300 g, 2.0 moles) (MDA Manufacturing Inc., Decatur, Ala.) was added at a constant rate. The reactor was allowed to stir at this temperature for 16 h. The crude reaction material was distilled using a ten plate Oldershaw column to afford 4-(1,1,2,3,3,3-hexafluoropropyl)-1,3-dioxolane (boiling point (b.p.) of 144° C.).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]1([N:4]([CH3:17])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a mixture of N-cyclopropyl-2-nitrobenzenesulfonamide (5.63 g), potassium carbonate (4.82 g) and N,N-dimethylformamide (60 mL), methyl iodide (2.17 mL) was added and stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:diethyl ether=1:0-1:1) to give N-cyclopropyl-N-methyl-2-nitrobenzenesulfonamide (5.35 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:19])([CH3:18])[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>ClCCl.C(N(CC)CC)C>[CH3:18][C:7]1([CH3:19])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([O:21][CH3:20])=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=3)=[CH:3][CH:4]=2)[CH2:9][N:8]1[C:12](=[O:17])[C:13]([F:16])([F:14])[F:15]
Reactant: CC1(C)Cc2ccc(N)cc2CN1C(=O)C(F)(F)F
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CN(C(=O)C(F)(F)F)C(C)(C)C3)cc1C(F)(F)F
Yield: 62.1 %

Procedure:
A solution of 7-amino-3,3-dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinoline (408 mg; 1.5 mmol) in dichloromethane (20 ml) and triethylamine (0.6 ml) was treated with 4-methoxy-3-trifluoromethylbenzoyl chloride (358 mg; 1.5 mmol). The resultant solution was stirred at 25° C. for 1 h. The reaction mixture was then washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with 1% methanol in dichloromethane, to give the title compound (442 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH:17]([CH3:19])[CH3:18])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21].[Br:22]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.Br>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6]([Br:22])([CH:17]([CH3:18])[CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c2c(c3cc(C(=O)O)oc3c1C)CC(C(C)C)C2=O
Reactant: BrBr
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c2c(c3cc(C(=O)O)oc3c1C)CC(Br)(C(C)C)C2=O
Temperature: 0 °C

Procedure:
A solution of 4,5-dimethyl-6-oxo-7,8-dihydro-7-isopropyl-6H-indeno[5,4-b]furan-2-carboxylic acid (0.01 mole) in acetic acid (60 ml.) is treated with 48% hydrobromic acid (1 drop) then with bromine (0.01 mole) in acetic acid (10 ml.) during a ten minute period. The solution is poured into ice water (300 ml.) containing sodium bisulfite (1 g.) to afford 4,5-dimethyl-6-oxo-7,8-dihydro-7-bromo-7-isopropyl-6-H-indeno[5,4-b]furan-2-carboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[OH-].[Na+]>CO>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2=CCCCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1CCN(CC2=CCCCC2)CC1
Yield: 95.8 %

Procedure:
A mixture of tert-butyl N-[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamate obtained in Example 4a (7.47 g, 25.4 mmol), a 5 N aqueous hydrochloric acid solution (25 ml, 125 mmol) and methanol (100 ml) was stirred at 70° C. for 1.5 hours. The reaction mixture was ice-cooled, a 5 N aqueous sodium hydroxide solution (25 ml, 125 mmol) was added, and the solvent was distilled off. Water was added to the residue, which was extracted with ethyl acetate twice. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound (4.73 g, yield: 95.8%).
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1.[Si]([O:41][CH2:42][C@H:43]([CH3:59])[C@H:44]([O:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)[CH2:45][C:46]#[C:47][Si](C)(C)C)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:59][C@H:43]([C@H:44]([O:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)[CH2:45][C:46]#[CH:47])[CH2:42][OH:41]
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](CC#C[Si](C)(C)C)OC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC[C@@H](OC1CCCCO1)[C@@H](C)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
A 1M nBu4NF/THF solution (8.8 ml, 8.80 mmol, 4 equivalent) was added to a THF solution (20 ml) of the compound (58) (1.13 g, 2.20 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was extracted with ethyl acetate after the addition of water. The extract was washed with brine, dried over magnesium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (35 g, 20% AcOEt-hexane) to obtain a colorless oily product (59) (450 mg, 96%). 1H-NMR (400 MHz, CDCl3/TMS) δ: 0.99 (3/2H, d, J=6.7 Hz), 1.01 (3/2H, d, J=7.0 Hz), 1.41-1.89 (6H+1/2H, m), 1.99 (1/2H, t, J=2.7 Hz), 2.00 (1/2H, t, J=2.7 Hz), 2.13-2.19 (1/2H, m), 2.33 (1/2H, bs), 2.38 (1/2H, ddd, J=2.4, 6.1, 17.1 Hz), 2.57 (1/2H, ddd, J=2.4, 4.0, 17.1 Hz), 2.63 (1/2H, ddd, J=2.8, 4.0, 17.1 Hz), 2.72 (1/2H, ddd, J=2.8, 7.0, 17.1 Hz), 3.30-3.31 (1/2H, m), 3.41-3.56 (3/2H, m), 3.60-3.81 (2H, m>, 3.95-4.01 (3/2H, m), 4.69-4.71 (1H, m).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].CO>C1COCC1>[O:11]=[C:6]1[N:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: CCOC(=O)CI
Reactant: Oc1nccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cn1ccc2ncccc2c1=O
Temperature: 100 °C
Yield: 95 %

Procedure:
1,6-naphthyridin-5-ol (1.00 g, 6.8 mmol), ethyl iodoacetate (1.6 ml, 14 mmol) and cesium carbonate (4.5 g, 14 mmol) were dissolved in 25 mL of THF then stirred and heated at 100° C. for 2 h until the reaction was complete. The reaction was concentrated and purified via MPLC using a gradient to 90% DCM: 10% MeOH to afford ethyl 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)acetate (1.5 g, 94% yield).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[OH-].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1>S1(CCCC1)(=O)=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([O:4][CH:1]=[CH:2][CH3:3])=[CH:9][CH:10]=1
Reactant: C=CCO
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: CC=COc1ccc(C(F)(F)F)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
174 g of allyl alcohol was added to a mixture of 298 g of 85% flake potassium hydroxide and 750 ml of sulpholane under nitrogen, and the mixture was heated to 125°-135° C. 272 g of 4-chlorobenzotrifluoride was added over 20 minutes at this temperature. After 2 hours, the reaction mixture was cooled to 30° C., and distillation from the solvent gave 207 g of propenyl 4-trifluoromethylphenyl ether b.p.: 84°-88° C. at 15 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]([OH:51])[CH2:9][CH2:10][N:11]([C@@H:23]2[C:40]3=[CH:41][C:36](=[CH:37][C:38]([O:42][CH3:43])=[N:39]3)[C:35]3[C:30](=[CH:31][C:32]([NH:44][C:45](=[O:48])[O:46][CH3:47])=[CH:33][CH:34]=3)[NH:29][C:28](=[O:49])[C@H:27]([CH3:50])[CH2:26][CH2:25][CH2:24]2)[C:12](=[O:22])[CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[F:52].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:51])[CH2:9][CH2:10][N:11]([C@@H:23]2[C:40]3=[CH:41][C:36](=[CH:37][C:38]([O:42][CH3:43])=[N:39]3)[C:35]3[C:30](=[CH:31][C:32]([NH:44][C:45](=[O:48])[O:46][CH3:47])=[CH:33][CH:34]=3)[NH:29][C:28](=[O:49])[C@H:27]([CH3:50])[CH2:26][CH2:25][CH2:24]2)[C:12](=[O:22])[CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[F:52]
Reactant: CCOP(=O)(CC(=O)N(CC[C@@H](O)c1nccc(Cl)c1F)[C@H]1CCC[C@@H](C)C(=O)Nc2cc(NC(=O)OC)ccc2-c2cc(OC)nc1c2)OCC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(CC(=O)N(CCC(=O)c1nccc(Cl)c1F)[C@H]1CCC[C@@H](C)C(=O)Nc2cc(NC(=O)OC)ccc2-c2cc(OC)nc1c2)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 5P (15.5 mg, 0.020 mmol) in anhydrous DCM (4 mL) was added Dess-Martin periodinane (11.18 mg, 0.026 mmol). The mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated to give 5Q (15 mg, 99%). MS (ESI) m/z: 762.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=[O:16])[CH:8]=2)[CH:3]=1.[C:18](O)(=[O:20])[CH3:19].CN(C)C=O.O>C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1.CO>[C:18]([O:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=[O:16])[CH:8]=2)[CH:3]=1)(=[O:20])[CH3:19]
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Oc1cc2ccc(C(=O)O)cc2cc1C(=O)O
Temperature: 50 °C
Yield: 81.2 %

Procedure:
2-Hydroxy-3,6-di-hydroxycarbonylnaphthalene (12.1 g) was suspended in acetic anhydride (39.0 g), acetic acid (60.1 g) and N,N-dimethylformamide (40.0 g) and 4-dimethylaminopyridine (0.2 g) was added, followed by heating to 50° C. After heating for about 20 hours, the reaction solution was poured into a mixed solution of water (400 g) and methanol (100 g). The deposit was filtered and then washed with water to obtain 11.6 g of 2-acetoxy-3,6-di-hydroxycarbonylnaphthalene as grayish white powder (DSC analysis value: 239.2° C.).
Reaction SMILES: CN(C)C=O.C[O-].[Na+].[SH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[C:17]1[C:22]([C:23]#[N:24])=[CH:21][CH:20]=[CH:19][N:18]=1>O>[C:23]([C:22]1[C:17]([S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:18][CH:19]=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1cccnc1Cl
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCSc1ncccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A mixture of anhydrous N,N-dimethylformamide (30 ml), sodium methoxide (0.54 g, 10 mmol), methyl 3-mercaptopropionate (1.20 g, 10 mmol) and 2-chloro-3-cyanopyridine (1.38 g, 10 mmol) was stirred at room temperature for 1 h. The reaction mixture was poured into water (200 ml), the product filtered, washed with water and recrystallized from ethyl acetate/hexanes to yield methyl 3-(3-cyanopyridin-2-ylthio)propanoate (1.60 g). mp 101-102° C. as heavy colorless prisms. 1H NMR (300 MHz, CDCl3): 8.45 (dd, 1H), 7.02 (dd, 1H), 3.68 (s, 3H), 3.49 (t, 2H), 2.78 ppm (t, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Mg].Cl[CH:11]1[CH2:15][CH2:14][CH:13]=[CH:12]1>O1CCCC1>[CH2:2]([CH:15]1[CH2:14][CH2:13][CH:12]=[CH:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClC1C=CCC1
Reactant: CCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCC1C=CCC1
Yield: 51.8 %

Procedure:
The procedure followed is the same as that described in Exmple 8 substituting the starting material, 1-bromoheptane (100 g, 0.56 moles) dissolved in tetrahydrofuran (100 ml), granular magnesium (25 g) in tetrahydrofuran (100 ml), 0.1M solution of Li2CuCl4 (1.7 mmoles), and 3-chlorocyclopentene (57 g, 0.56 moles) dissolved in tetrahydrofuran (200 ml). The crude product is fractionally distilled under vacuum leaving a clear, colorless oil (48 g, 0.29 moles), BP 41° C./0.35 mm.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])(=[O:24])[CH3:23]
Reactant: OCCc1ccc2ccccc2c1Br
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1ccc2ccccc2c1Br
Yield: 101.6 %

Procedure:
A solution of 1-bromo-2-(2-hydroxy-ethyl)-naphthalene (46.5 g, 0.185 mol) in methylene chloride (370 mL) was placed under a nitrogen atmosphere, cooled in an ice bath, and stirred. Triethylamine (32.3 mL, 0.232 mol) was added followed by acetyl chloride (15.8 mL, 0.222 mol) dropwise over 5 minutes. The reaction mixture was removed from the ice bath and stirred at room temperature for 15 minutes. The reaction mixture was washed with water (300 mL), 1N hydrochloric acid (200 mL) and water (250 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to afford the title compound as an oil (55.1 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([CH3:10])[N:4]=1)[CH3:2].[F:11][C:12]1[C:17]([O:18][C:19](=O)[O:20]C2C(F)=C(F)C(F)=C(F)C=2F)=[C:16]([F:33])[C:15]([F:34])=[C:14]([F:35])[C:13]=1[F:36]>C1COCC1>[F:11][C:12]1[C:17]([O:18][C:19](=[O:20])[NH:9][C:7]2[CH:6]=[C:5]([CH3:10])[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=2)=[C:16]([F:33])[C:15]([F:34])=[C:14]([F:35])[C:13]=1[F:36]
Reactant: CCc1cc(N)cc(C)n1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc(C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-ethyl-6-methyl-pyridin-4-ylamine (1.33 g, 9.8 mmol) in THF (25 mL) is slowly added to a solution of bis(pentafluorophenyl)carbonate (3.99 g, 10.1 mmol) in THF (10 mL). The mixture is stirred at r.t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)=[O:8].[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:30]C)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.C(OCC)(=O)C.C(OC(C)C)(C)C>[F:17][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:3]2[N:2]([NH:1][C:27](=[O:28])[C@@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:30])[CH:6]=[CH:5][N:4]=2)=[O:8])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1ccnc1C(=O)Nc1cc(F)cc(F)c1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccnc1C(=O)Nc1cc(F)cc(F)c1
Temperature: 55 °C
Reaction time: 48 h
Yield: 59.7 %

Procedure:
1.60 g (6.18 mmol) of 1-amino-N-(3,5-difluorophenyl)-1H-imidazole-2-carboxamide, 1.64 g (8.65 mmol) of (S)-2-(tert-butoxycarbonylamino)butanoic acid and 1.34 g (8.65 mmol) of EDCHCl were dissolved in 45 mL of THF and stirred at 55° C. overnight and at room temperature for 2 days. Then the solvent was evaporated and the crude residue was taken up in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulphate, filtered and the solvent was evaporated. The solid obtained was redissolved in the minimum amount of ethyl acetate and diisopropylether was added until a solid precipitated, which was filtered to furnish 1.51 g (57% yield) of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:8]([CH2:19][CH3:20])[NH:7][N:6]=1)[CH3:4].Br[CH2:22][CH2:23][O:24][CH3:25]>CN(C)C=O>[CH2:3]([C:5]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:8]([CH2:19][CH3:20])[N:7]([CH2:22][CH2:23][O:24][CH3:25])[N:6]=1)[CH3:4]
Reactant: COCCBr
Reactant: CCc1n[nH]c(CC)c1Oc1cccc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CCOC)c(CC)c1Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 22 mg, 0.54 mmol) was added to a solution of the pyrazole from Example 60 (100 mg, 0.41 mmol) and 1-bromo-2-methoxy-ethane (51 μl, 0.54 mmol) in dimethylformamide (1.5 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and was stirred for 4 hours. The reaction was quenched with water and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and water (10 ml) and the organic phase was washed with water (2×10 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a solvent gradient of 100% pentane changing to 100% ethyl acetate and finally ethyl acetate:methanol (90:10, by volume) to provide the title compound (66 mg) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][CH2:8][CH2:7]2
Reactant: Fc1cccc2c1NCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Fc1cc(Br)cc2c1NCC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
7-Fluoroindoline (1.1 g, 8.0 mmol) was dissolved in acetonitrile (80 mL), cooled to 0° C., and N-bromosuccinimide (1.43 g, 8.0 mmol) was added. The mixture was warmed to 25° C. and stirred for 3 hours. The mixture was concentrated to 10 mL and diluted with ethyl acetate and washed with NaHCO3, water, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-15% ethyl acetate in hexane) afforded 5-bromo-7-fluoroindoline (1.05 g). MS (ES) m/z 215.8; HPLC purity 97.6% at 210-370 nm, 10.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14]([C:16]3([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:25]4[CH2:31][CH2:30][C@@H:29]3[CH2:28][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:26]4)[CH2:13][CH2:12][N:11]([C:14]([C:16]3([NH:21][C:44](=[O:45])[C:43]([CH3:48])([CH3:47])[CH3:42])[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C2(N)CCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C2(NC(=O)C(C)(C)C)CCCC2)CC1
Yield: 53.7 %

Procedure:
N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentyl}-2,2-dimethylpropanamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentyl}carbamate (0.627 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form 1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentanamine (0.528 g, 99%). 1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentanamine (0.050 g, 0.09 mmol), 2,2-Dimethyl-propionyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentyl}-2,2-dimethylpropanamide (0.031 g, 54%) as an oil. ES-LCMS m/z 642 (M+1).