Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:55])([F:54])[C:46]1[N:51]=[CH:50][C:49]([CH2:52][NH2:53])=[CH:48][CH:47]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([NH:53][CH2:52][C:49]3[CH:50]=[N:51][C:46]([C:45]([F:55])([F:44])[F:54])=[CH:47][CH:48]=3)=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (40 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (21 mg, 0.14 mmol), and CH2Cl2 (3 mL) were added C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (36 mg, 0.21 mmol) and N,N-diisopropylethylamine (48 μL, 0.28 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 40-80% MeCN-water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([S:16][CH3:17])=[N:9][C:8]=2[C:7]([C:18]#[N:19])=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(O)(=O)C.[OH2:42].[OH:43]O>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([S:16]([CH3:17])(=[O:43])=[O:42])=[N:9][C:8]=2[C:7]([C:18]#[N:19])=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:21]1
Reactant: OO
Reactant: CSc1nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c(=O)n1C
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Sodium tungstate dihydrate (139 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylthio)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (230 mg) in a mixture of methanol (2 ml), acetic acid (0.7 ml) and water (0.25 ml), and the resulting mixture was heated to 50° C. A 30% aqueous hydrogen peroxide solution (0.29 ml) was added dropwise thereto, followed by stirring at 60° C. for 4 hours. After the reaction mixture was allowed to cool, the precipitate formed was collected by filtration, washed with water and then dried under reduced pressure to obtain the title compound (230 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[K+].[NH2:16][C:17]1[CH:38]=[CH:37][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[C:19]([F:39])[CH:18]=1.CCCCCC>C(#N)C.C(OCC)C>[F:39][C:19]1[CH:18]=[C:17]([NH:16][C:13]([NH:14][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[S:12])[CH:38]=[CH:37][C:20]=1[O:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH:23]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCCCC3)ncn2)c(F)c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCCC3)ncn2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
2-(4-Fluorophenyl)acetyl chloride (92 mg) was dissolved in acetonitrile (5 ml) under a nitrogen atmosphere, and then potassium thiocyanate (104 mg) was added thereto at 60° C., followed by stirring at the same temperature for 1.5 hrs. The reaction mixture was cooled down to room temperature, and then a solution of piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (118 mg) in acetonitrile (3 ml) was added thereto, followed by stirring for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (5 ml)-hexane (5 ml). The solid was filtered off and dried under aeration to provide the titled compound (98.4 mg, 52.5%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH3:15].CO>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH2:15])=[O:14])[CH:6]=[CH:5]2
Reactant: N
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: NC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
6-bromo-2-naphthoic acid (2 g, 7.97 mmol) was stirred in thionyl chloride (13.28 ml) at 70° C. for 16 h. After concentration in vacuo, the residue was rediluted in CH2Cl2 and concentrated again. To the acid chloride intermediate was added ammonia in MeOH (7 M, 13.66 ml, 96 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was then concentrated. The residue was taken up in AcOEt, filtered, rinsed with AcOEt and then dried over MgSO4, filtered and concentrated in vacuo. The title compound (1.802 g, 90%) was isolated as a beige solid. LC-MS (M+1) 251.9, t=1.34 min.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:5][CH2:6]2.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>C(#N)C>[OH:1][C@H:2]1[C@H:7]([S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:3]1
Reactant: Sc1ccccc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC2OC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@@H](Sc2ccccc2)[C@H](O)C1
Temperature: 25 °C

Procedure:
40 g (0.146 mol) of the 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-piperidine obtained according to Example 12 are dissolved, together with 32 g (0.29 mol) of thiophenol and 146 ml (0.29 mol) of 2 N sodium hydroxide solution, in 300 ml of acetonitrile. The reaction mixture is heated under reflux for 4 hours, then cooled to room temperature and concentrated to about 1/3 of the original volume under a water pump vacuum. The solution is then diluted with 900 ml of water and extracted by shaking with 3 times 1,000 ml of methylene chloride; the combined organic phases are washed twice with 0.1 N sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum. The oil which remains is dissolved in 50 ml of benzene and the solution is filtered through a layer of silica gel. Trans-3-hydroxy-4-phenylthio-1-(β,β,β-trichloroethoxycarbonyl)-piperidine is isolated in the form of a slightly orange coloured oil by elution with a benzene/ethyl acetate mixture (4:1).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Oc3ccnc4ccccc34)cc2s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Oc3ccnc4ccccc34)cc2s1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
The reaction mixture of 2-(methylthio)-6-(quinolin-4-yloxy)benzo[d]thiazole (460 mg, 1.415 mmol) was dissolved in 8 ml of DCM and cooled to −5° C. A solution was made of 77% MCPBA (333 mg, 1.486 mmol) and 6 ml of DCM. This solution was added to above cooled reaction mixture dropwise over 3-4 minutes. The reaction was stirred at −5° C. for 10 minutes, stirred at RT. for 90 minutes. The reaction followed by LC indicated 95% completed and stalled. A new solution was made of 77% MCPBA (25 mg, 0.1132 mmol) and 1 ml of DCM. This solution was added to above RT. reaction mixture dropwise. The reaction was stirred for 90 minutes more with LC indicating the reaction was complete. The reaction was worked up by adding 80 ml of DCM and 25 ml of a 10% sodium thiosulfate solution and stirred at RT. for 10 minutes. Aqueous layer was extracted and the DCM layer was washed with 25 ml of saturated NaHCO3, 2×25 ml 5% NaHCO3 solution, 1×25 ml water, 1×25 ml saturated NaCl, dried with sodium sulfate. About 1 gram of Silica gel was added and stirred for 10 minutes. The mixture was filtered and concentrated in vacuo to give 2-(methylsulfinyl)-6-(quinolin-4-yloxy)benzo[d]thiazole as solid (357 mg). ES/MS m/z 341.0 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Cu+]>[CH2:24]([O:23][C:21]([C@H:20]1[C@H:3]2[C@@H:2]1[O:1][C:5]1[CH:6]=[CH:7][C:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])=[CH:9][C:4]=12)=[O:22])[CH3:25]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2occc2c1
Agent: [Cu+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1[C@H]2Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3[C@H]21
Yield: 108 %

Procedure:
Copper (I) triflate (2:1 complex with toluene, 250 mg, 2.4%) and (S,S)-(±)-2,2-isopropylidenebis(4-tert-butyl)-2-oxazoline (205 mg, 3.4%) were stirred in dichloromethane (15 mL) at ambient temperature under N2 atmosphere for 1 hour. A solution of (benzofuran-5-yloxy)(tert-butyl)dimethylsilane (5.0 g, 20.2 mmol) in dichloromethane (85 mL) was added, followed by a slow addition of ethyl diazoethanoate (40 mL, 380 mmol) during a period of 10 hours using a syringe pump. The mixture was concentrated and purified by column chromatography to afford crude compound (7.3 g) which was used for the next step without any further purification.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])O.[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>O.C(OCC)C>[CH3:12][O:11][C:9]([CH:4]1[C:3](=[O:2])[CH2:8][CH2:7][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:5]1)=[O:10]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(=O)C(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
1.94 g of methyl 4-oxo-3-piperidinecarboxylate hydrochloride, 1.68 g of sodium hydrogencarbonate and 1.67 g of ethyl bromoacetate were dissolved in a mixed solvent comprising 32 ml of water and 8 ml of diethyl ether and stirred at room temperature overnight. 50 ml of ethyl acetate was added to the reaction liquid, and the organic layer was separated by liquid-liquid separation. This was dried with sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (using a gradient eluent of chloroform to chloroform/methanol=100/1) to obtain 1.5 g of ethyl 3-methoxycarbonyl-4-oxo-1-piperidineacetate as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.Cl.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30]([Cl:32])=[O:31])[CH2:23]2>CN(C=O)C>[ClH:32].[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:30]([CH:24]3[CH:25]4[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]4)[CH2:23]3)=[O:31])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(Cl)C1CN2CCC1CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2ncccc2c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
172 mg (1.19 mmol) of 6-aminoquinoline are mixed with 461 mg (3.57 mmol) of N,N-diisopropylethylamine in 3 ml of DMF under argon at 0° C. 250 mg (2.57 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride are dissolved in a little dry DMF and added dropwise to the reaction mixture at 0° C. It is then stirred at room temperature overnight. It is worked up by concentrating and taking up in dichloromethane. The crude product is chromatographed on silica gel 60 (mobile phase: dichloromethane/ethyl acetate 10:1, then dichloromethane/methanol 10:1, 3:1). The product fractions are combined and finally purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water, gradient 1:99→30:70).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: COC(=O)c1cncc(O)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
4-Nitrophenyl chloroformate (7.0 g) was added to a dichloromethane (100 ml) solution of methyl 5-hydroxynicotinate (5.3 g) and diisopropylethylamine (6.1 ml), followed by stirring at room temperature for 1 hour. The reaction liquid was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was washed with EtOAc/hexane and dried under reduced pressure to obtain methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (8.4 g).
Reaction SMILES: C[C:2](C)=[O:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]2[C:17]([C:18](=[O:35])[NH:19][CH2:20][CH2:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]([CH3:36])[NH:15][C:14]([CH3:37])=[C:13]2C(O)=O)[CH:9]=[CH:10][CH:11]=1.[N+]([O-])([O-])=[O:42].[NH4+].[Ce]>O>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:17]([C:18](=[O:35])[NH:19][CH2:20][CH2:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]([CH3:36])[NH:15][C:14]([CH3:37])([C:2]([OH:3])=[O:42])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)=O
Reactant: O=[N+]([O-])[O-]
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)=CC(C)(C(=O)O)N1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2 ml of acetone was added to 57.3 mg (0.110 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-5-(3,3-diphenylpropylcarbamoyl)-1,4-dihydropyridine-3-carboxylic acid. 178 mg (0.320 mmol) of cerium ammonium nitrate suspended in 1 ml of water was added and stirred at room temperature for 2.5 hours. After adding water and extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[N:10]O)[CH2:6]2.C(O)(=O)C>[Pt](=O)=O.C(O)C>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([NH2:10])[CH2:6]2
Reactant: CN1C2CCC1CC(=NO)C2
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CN1C2CCC1CC(N)C2
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A 500-mL Parr hydrogenation vessel was purged with nitrogen and charged with platinum (IV) oxide (1.28 g, 5.64 mmol), 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one oxime (4.00 g, 26.0 mmol), acetic acid (11 mL) and ethanol (110 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 24 h on a Parr hydrogenation apparatus. The hydrogen was then evacuated and nitrogen charged to the bottle. The reaction mixture was then mixed with Celite 521 (5.0 g), filtered, and the filtrate evaporated to a solid residue. This residue was dissolved in methanol (100 mL) and this solution treated with sodium carbonate (10 g). The resulting suspension was added diethyl ether (50 mL) and filtered. Evaporation of the filtrate to dryness afforded 3.64 g (100%) of 8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine as a white solid: 1H NMR (300 MHz, CD3OD) δ 5.18 (br s, 2H), 3.35 (br s, 2H), 3.21 (t, J=6.6 Hz, 1H), 2.40 (s, 3H), 2.26-2.00 (m, 6H), 1.68-1.58 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][C@H:36]1[C@H:41]2[CH2:42][C@H:38]([CH:39]=[CH:40]2)[C@H:37]1[C:43]([NH2:45])=[O:44]>>[NH2:45][C:43]([C@@H:37]1[C@@H:38]2[CH2:42][C@@H:41]([CH:40]=[CH:39]2)[C@@H:36]1[NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][CH:21]=1)(=[O:27])=[O:26])=[O:18])=[O:44]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(=O)[C@H]1[C@@H](N)[C@@H]2C=C[C@H]1C2
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2[C@H](C(N)=O)[C@H]3C=C[C@@H]2C3)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 83% purity by HPLC. MS(ESI+): m/z=509.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[O:11][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(COCc1ccccc1)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
1-O-benzyl-3-O-t-butyldimethylsilylglycerol (1.63 g) was added to pyridine (6 ml), and the mixture was cooled to 5° C., and mesyl chloride (0.5 ml) was added dropwise thereto, and the resultant mixture was stirred overnight at room temperature. Upon confirming the completion of the reaction, the reaction liquid was cooled to 5° C., water (0.5 ml) was added thereto and the mixture stirred at the same temperature for 30 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]([CH3:15])=O.[Si]([C:20]#[N:21])(C)(C)C>CCO.CCOC(C)=O>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][C:13]([C:20]#[N:21])([CH3:15])[CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C#N)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
(2-Aminoethyl)carbamic acid tert-butyl ester (25.07 g, 156.5 mmol) was dissolved in EtOH (500 mL), treated with acetone (13.75 mL, 187 mmol), and the stirred solution was cooled in an ice bath. After stirring for 30 min, TMS-CN (62 mL, 465 mmol; CAUTION—toxic) was added dropwise over 1 h. The solution was stirred for 16 h, allowing to warm gradually to room temperature. The solution was concentrated in vacuo [caution: HCN gas evolved: a dry pump venting to the back of the fume hood was used] resulting in a pale yellow solid. This was dissolved in EtOAc (100 mL) and concentrated to a viscous oil. Hexane (500 mL) was added rapidly and the resulting mixture was swirled vigorously until a thick white crystalline precipitate formed. The mixture was allowed to stand for 30 min, and the crystallized product (30.0 g) was collected by filtration, washing with a small amount of hexane to give a white crystalline solid. The filtrate was concentrated in vacuo to give a viscous gum (5 g). This was quickly purified by flash chromatography eluting with EtOAc [N.B. the product is somewhat unstable to silica gel and decomposes if allowed to stay on the column for a long time] resulting in an additional 1.7 g of product, which was combined with the recrystallized material. Total yield=31.7 g, 89%. 1H NMR: δ (d6-DMSO, 400 MHz) 6.64 (1 H, t), 2.83 (2 H, m), 2.60 (1 H, t), 2.41 (2 H, m), 1.21 (9 H, s), 1.17 (6 H, s).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:18])=[C:4]([CH2:11][CH2:12]OS(C)(=O)=O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[F:1][C:2]1[C:3]2[O:18][CH2:12][CH2:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CS(=O)(=O)OCCc1cc([N+](=O)[O-])cc(F)c1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)c2c(c1)CCO2
Yield: 61 %

Procedure:
A suspension of 6 (3.5 g, 12.53 mmol) in ethyl acetate (45 mL) and triethyl amine (4.37 mL, 31.33 mmol) was refluxed overnight. Water was added and the crude was extracted with ethyl acetate. The organic layer was concentrated, purified by column chromatography eluted with 15% ethyl acetate/hexane, to yield the desired compound 7 (1.4 g, yield 61%).
Reaction SMILES: C([Li])(CC)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:22])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[CH:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=1>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:22][CH:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:33]([F:35])([F:34])[F:36])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: COc1ccc(N=CC(F)(F)F)cc1
Reactant: Cc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)OC(C)(C)C)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
sec-Butyl-lithium (1.3 M in cyclohexane, 21.72 mL) was added to a stirred solution of tert-butyl 5-chloro-2-methylbenzylcarbamate (3.61 g, 14.12 mmol) in THF (30 mL) at −78° C. under nitrogen to give a deep red solution. After 10 min N-(4-methoxyphenyl)-N-(2,2,2-trifluoroethylidene)amine (3.01 g, 14.12 mmol) was added and after a further 5 min the solution was quenched with excess saturated aqueous NH4Cl and warmed to ambient temperature. The solution was partitioned between EtOAc and brine. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-20% ethyl acetate/hexanes gradient) to give tert-butyl 5-chloro-2-{2-[(4-methoxyphenyl)amino]-3,3,3-trifluoropropyl}benzylcarbamate (2.69 g) as a gum; 1H NMR (CDCl3 400 MHz) δ 1.47 (s, 9H), 2.90 (dd, J=10.7 and 14.7 Hz, 1H), 3.16 (dd, J=3.4 and 14.7 Hz, 1H), 3.62 (br d, J=8.2 Hz, 1H), 3.71 (s, 3H), 4.03 (br m, 1H), 4.29 (dd, J=5.6 and 14.7 Hz, 1H), 4.34 (br dd, 1H), 4.87 (br s, 1H), 6.47 (d, J=8.9 Hz, 2H), 6.69 (d, J=8.9 Hz, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2 and 2.0 Hz, 1H), 7.23 (s, 1H).