Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[N:1]1([C:7]2[N:8]=[C:9]3[N:17]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C@H:16]([C:18]([F:20])([F:21])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Ic1ccncc1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1ccncc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 200 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 380 mg of 4-iodopyridine. After purification by silica chromatography (elution gradient from CH2Cl2 to CH2Cl2/MeOH 96/04), 26 mg of (S)-2-morpholin-4-yl-9-pyridin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][CH:15]([O:21][CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[CH3:13][O:14][CH:15]([O:21][CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(CCCCBr)OC
Agent: [K]
Solvent: CN(C)C=O
Product: COC(CCCCN1C(=O)c2ccccc2C1=O)OC
Reaction time: 5 h

Procedure:
A mixture of potassium phthalimide (0.48 g) and 5-bromopentanal dimethyl acetal (0.50 g) in dry dimethylformamide (3 ml) was stirred at 90° for 5 h and then allowed to cool. The resultant yellow suspension was then partitioned between water (30 ml) and ethyl acetate (3×30 ml). The combined organic extracts were then dried (Na2SO4) and concentrated in vauco.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=O)=O)C=CC=CC=1.C(OC(=O)[N:28]([CH2:37][C:38]1[C:39]([O:45][CH3:46])=[N:40][CH:41]=[C:42]([F:44])[CH:43]=1)[C:29]1[N:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][N:30]=1)(C)(C)C>>[F:44][C:42]1[CH:43]=[C:38]([CH2:37][NH:28][C:29]2[N:30]=[CH:31][C:32]([CH2:35][C:12]3[C:13]4[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=4)[NH:10][CH:11]=3)=[CH:33][N:34]=2)[C:39]([O:45][CH3:46])=[N:40][CH:41]=1
Reactant: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ncc(C=O)cn1
Product: COc1cnc2[nH]cc(Cc3cnc(NCc4cc(F)cnc4OC)nc3)c2c1

Procedure:
(5-Fluoro-2-methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine P-1599 is prepared in three steps from 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine 16 and (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-(5-formyl-pyrimidin-2-yl)-carbamic acid tert-butyl ester 123 as shown in Scheme 13.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:15]1(C(O)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:25].[NH4+].[NH4+]>C(#N)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH:15]1([C:2]2[C:3](=[O:14])[C:4]3[C:9]([C:10](=[O:13])[C:11]=2[OH:25])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)C1CCCCC1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1C(O)=C(C2CCCCC2)C(=O)c2ccccc21
Yield: 45.2 %

Procedure:
A mixture of 2,3-dichloro-1,4-naphthoquinone (5gm), cyclohexane carboxylic acid (2.7629 gm) and silver nitrate (2.095 gm) is taken in acetonitrile (60 ml) and the mixture is heated to reflux. Then a solution of ammonium persulphate (12.06 gm) in 77 ml of water is added through a dropping funnel over a period of 1 to 2 hrs. The mixture is refluxed for 4 hrs and cooled in ice for about 1 hr after which it is filtered. Filtrate is kept aside for acetonitrile recovery. The solid is extracted with hot methylene chloride (100 ml×3). Inorganics is kept aside for silver nitrate regeneration. The methylene chloride layer is dried over anhydrous sodium sulphate, concentrated to get light brownish yellow solid. This on crystallization from acetonitrile afforded the title compound as yellow crystals (2.5 gm). 300 MHz NMR of the compound fully agreed with the desired compound
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=O.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N+:28]#[C-:29].Cl(O)(=O)(=O)=O>C(O)C>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][C:29]1[N:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]2=[N:1][C:9]=1[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: [C-]#[N+]c1c(C)cccc1C
Reactant: O=Cc1ccccc1C(=O)O
Reactant: Nc1ccc(F)cn1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)O)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
2.1 0.802 g (6.8 mmol) of 2-amino-5-fluoropyridine and 0.946 g (6.3 mmol) of 2-formylbenzoic acid are dissolved successively in 20 ml of ethanol at RT under inert gas. 0.929 g (6.8 mmol) of 2,6-dimethylphenyl isocyanide are then added, 0.291 ml (3.4 mmol) of 70% perchloric acid is added dropwise, and the mixture is stirred at RT for a further 20 h. 50 ml of petroleum ether are subsequently added, the precipitated solid is filtered off with suction and washed with a little ethyl acetate, giving 1.900 g (74%) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoic acid as solid; MS-FAB (M+H+)=376.6; Rf (HPLC, polar method): 1.61 min. This is employed in the next step without further purification.
Reaction SMILES: [C:1](O)(=O)CCCC(O)=O.C(O)COCCO.[C:17]([OH:19])#[CH:18].C[O:21][C:22]1C=[C:24](/[CH:29]=[CH:30]/[C:31](/O)=[CH:32]/[C:33](/[CH:35]=[CH:36]/C2C=CC(O)=C(OC)C=2)=O)[CH:25]=[CH:26][C:27]=1O>O>[C:17]([O:21][CH2:22][CH2:27][CH2:26][CH2:25][CH2:24][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:35][CH3:36])(=[O:19])[CH:18]=[CH2:1]
Reactant: O=C(O)CCCC(=O)O
Reactant: C#CO
Reactant: COc1cc(/C=C/C(=O)/C=C(O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Solvent: OCCOCCO
Solvent: O
Product: C=CC(=O)OCCCCCCCCCCCC

Procedure:
Glutaric acid (10 parts), diethylene glycol (10 parts), Acetylenol E100 (surfactant produced by Kawaken Fine Chemicals Co., Ltd.) (1 part), and ion exchange water (79 parts) were mixed and thoroughly stirred. Then the mixture was pressure-filtered through a microfilter (produced by FUJIFILM Holdings Corporation) with a 3.0 μm pore size. As a result, a liquid composition was obtained.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[C:38]=3[Cl:47])[CH2:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:12]=2)[CH2:7][CH2:6]1.O.[OH-].[Li+].Cl>C1COCC1.O>[ClH:47].[Cl:47][C:38]1[C:39]([C:43]([F:45])([F:44])[F:46])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:21]([CH2:22][CH:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:3]([OH:48])=[O:2])[CH2:10][CH2:9]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 169.6 %

Procedure:
To a stirring solution of [4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazin-1-yl]-acetic acid methyl ester (99 mg, 0.146 mmol) in a mixture of THF and water (3:1; 12 ml) was added lithium hydroxide monohydrate (8 mg, 0.192 mmol). The resulting mixture was stirred at room temperature for 18 hours and then acidified with 1 M aqueous HCl (0.2 ml). The mixture was concentrated in vacuo, water (5 mL) was added, and the crude material was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over sodium sulfate, and filtered. The organic layer was concentrated, and the crude amine was treated with 1 M HCl (Et2O). The resulting precipitate was dried under vacuum to afford the title compound as a solid (87 mg, 97%). MS(ES) m/e 666.0 (M+).
Reaction SMILES: [CH2:1]([N:3]([CH2:18]C)[CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]1[OH:17])C.N.CCO>CCOCC>[CH3:18][N:3]([CH3:1])[CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:16][C:15]2[CH2:14][CH:13]=[CH:12][CH2:11][C:10]=2[CH2:9][C@H:8]1[OH:17]
Reactant: CCN(CC)CCC[C@@H]1Cc2ccccc2C[C@H]1O
Agent: N
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCC[C@@H]1CC2=C(CC=CC2)C[C@H]1O
Reaction time: 0.5 h

Procedure:
A solution of 14.6 g (66.6 mmol) of trans-3-[3-(diethylamino)propyl]-1,2,3,4-tetrahydro-2-naphthalenol in 125 ml of ether is added to 1 liter of NH3 (liquid). To this stirred solution is added 10 g of Li in pieces over 10 minutes. When the addition is complete, the reaction mixture is stirred for 30 minutes, after which time absolute EtOH (~ 150 ml) is added dropwise until the blue color is discharged. The NH3 is then allowed to evaporate, the residue is diluted with water, and this thoroughly extracted with ether. The combined ether extracts are washed with saturated aqueous NaCl, dried, and concentrated in vacuo to 13.4 g (92%) of the title compound as an oil.
Reaction SMILES: B.CSC.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[CH2:10].[OH-:14].[Na+].OO>C1COCC1.O>[Br:5][C:6]1[CH:7]=[C:8]([CH2:9][CH2:10][OH:14])[CH:11]=[CH:12][CH:13]=1
Reactant: C=Cc1cccc(Br)c1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: OCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Borane-dimethylsulphide complex (2.0M in THF, 49 ml) was added dropwise to a stirred solution of 3-bromostyrene (10 g, 55 mmol) in THF (130 ml) at 0° C. and the solution was stirred for 3 h at room temperature. 10% Aqueous sodium hydroxide was added cautiously, followed by hydrogen peroxide (30% wt. solution in water, 6 ml) dropwise. After a further 16 h, the mixture was diluted with water, extracted twice with ethyl acetate, the combined extracts washed with saturated sodium bisulphite solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated to give a colourless oil. Purification by flash chromatography, eluting with 30% diethyl ether/hexane gave a colourless oil, [M+Si(CH3)3 derivative]+ 272.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:13][O:14][CH3:15].[CH3:16][CH2:17]CCCC.C([Li])CCC.C(I)C>O1CCCC1.O>[CH2:16]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:13][O:14][CH3:15])[CH3:17]
Reactant: CCCCCC
Reactant: COCOc1cccc2c(Br)cccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Solvent: O
Product: CCc1cccc2c(OCOC)cccc12
Temperature: -60 °C
Reaction time: 1 h

Procedure:
6.9 g of 5-bromo-1-methoxymethoxy naphthalene was dissolved in 100 ml of anhydrous tetrahydrofuran and cooled to -60° C. 21.3 ml of a hexane solution containing 1.6M of n-butyl lithium was gradually added to the solution. After stirring at -40° C.--60° C. for one hour, the reaction solution was cooled to -65° C. and 4.2 ml of ethyl iodide was slowly dropped. After the dropping, the temperature was warmed upto the room temperature, water was added and the solution was extracted with ethyl acetate. After washing the extract with an aqueous saturated solution of sodium chloride and drying over anhydrous magnesium sulfate, the solvent was distilled off. When the residue was purified on silica gel column chromatography (7% ethyl acetate/hexane), 5.5 g of the above-captioned compound was obtained as a pale yellow oily product.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[CH:17]=[CH:16][N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][NH:15]1
Reactant: CCCc1ccnc(N)c1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: CCCC1CCNC(=N)C1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-amino-4-(n-propyl)pyridine to the title compound except platinum oxide was used as the catalyst. Product was triturated with EtOAc to give a white solid. The analysis of the product was found to be consistent with the proposed structure. MH+141; 1H NMR (D2O): δ3.35-3.05 (m, 2H); 2.60-2.40 (m, 1H); 2.15-2.00 (m, 1H); 1.80-1.60 (m, 2H); 1.78 (s, 3H); 1.35-1.05 (m, 5H); 075-0.65 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@:9]2([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@:9]2([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:17])[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@]1(NC(=O)[C@@H]2CCCCN2C(=O)OC(C)(C)C)C[C@@H]1c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@]1(C(=O)O)C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-((1R,2R)-2-(4-bromophenyl)-1-(methoxycarbonyl)-cyclopropylcarbamoyl)piperidine-1-carboxylate (3 g) in THF (45 mL) and water (30 mL) was added lithium hydroxide monohydrate (0.298 g). The mixture was stirred at RT for 2 h. The mixture was partitioned between 0.1 N HCl(aq) and ethyl acetate, and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to leave the title compound (2.90 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].O=S(Cl)Cl.C(N(CC)CC)C.[CH3:21][Si:22]([CH3:27])([CH3:26])[CH2:23][CH2:24]O>ClC(Cl)C>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH2:24][CH2:23][Si:22]([CH3:27])([CH3:26])[CH3:21])=[O:8]
Reactant: O=C(O)c1sccc1Br
Reactant: C[Si](C)(C)CCO
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)c1sccc1Br

Procedure:
A solution of 3-bromothiophene-2-carboxylic acid (1 mmol) and SOCl2 (3 mmol) in 1 mL of dichloroethane was heated at 80° C. for 20 h and then the solvents evaporated. The residue was dissolved in 2 mL CH2Cl2 and mixed with triethylamine (3 mmol) and 2-(trimethylsilyl)ethanol (1.3 mmol) at rt for 12 h. Extractive isolation provided 2-(trimethylsilyl)ethyl 3-bromo-2-thiophenecarboxylate as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH2:4][NH2:5].[C:18]1([CH2:24][C:25]([OH:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C.[OH2:40].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:13]([F:16])([F:15])[C:10]([OH:26])=[O:40].[CH3:1][CH:2]([CH3:17])[C@@H:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1)[CH2:4][NH:5][C:25](=[O:27])[CH2:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)[C@H](CN)Nc1ccc(C(F)(F)F)cc1
Reactant: O
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](CNC(=O)Cc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
(2R)-3-Methyl-N2-[4-(trifluoromethyl)phenyl]butane-1,2-diamine (8 mg, 0.033 mmol) obtained in step 2, phenylacetic acid (5 mg, 0.037 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (10 mg, 0.052 mmol), 1-hydroxybenzotriazole monohydrate (8 mg, 0.052 mmol) and triethylamine (9 μl, 0.066 mmol) were mixed in methylene chloride (3 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by purification step A to give the title compound (4.1 mg, 0.009 mmol, 26%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C([Mg]Cl)(C)C.[O:19]=[C:20]1[CH2:26][CH:25]2[CH2:27][CH:21]1[CH2:22][N:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24]2>C1COCC1>[OH:19][C:20]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH2:26][CH:25]2[CH2:27][CH:21]1[CH2:22][N:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24]2
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Reactant: Brc1cncc(-c2ccccc2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cncc(-c3ccccc3)c1)C2
Yield: 14.2 %

Procedure:
To a solution of 3-bromo-5-phenylpyridine (0.23 g, 1.0 mmol) in THF (5 mL) at ambient temperature was added 2.0 M isopropylmagnesium chloride in THF (0.5 mL). The reaction was stirred for an hour under nitrogen. Then a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.21 g, 1.0 mmol) in THF (2 mL) was added. The mixture was stirred at ambient temperature overnight, concentrated and quenched with water (1 mL). The mixture was extracted with chloroform (2×10 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The compound was purified by silica gel column chromatography (1:1 ethyl acetate/hexane) to yield 50 mg of product (13%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:19][O:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][C:24]=1B(O)O.[Li+].[Cl-]>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>[CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1[C:25]1[CH:24]=[C:23]([O:22][CH2:21][O:20][CH3:19])[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][O:31][CH3:32])=[O:4]
Reactant: COCOc1ccc(OCOC)c(B(O)O)c1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@H](C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Product: COCOc1ccc(OCOC)c(C2=C(C(=O)OC)C[C@@H](C)C2)c1
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Prepare a mixture of 4-Methyl-2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid methyl ester 3a (2.5 g, 8.7 mmol), 2,5-Bis-methoxymethoxy phenylboronic acid 7 (2.31 g. 9.5 mmol), tetrakis(triphenylphosphine)palladium (485 mg, 0.435 mmol), and LiCl (1.1 g, 26.1 mmol) in DME (80 mL). Add 2.0 M solution of Na2 CO3 (10 mL, 21.7 mmol) and heat the reaction to reflux and stir for 2 hours. Cool the reaction to room temperature and partitioned between CH2Cl2 and saturated aqueous NaHCO3. Separate and extract the aqueous solution with CH2Cl2 (2×). Combine the organic extracts, dry (Na2SO4), filter and concentrate in vacuo. Purify by flash chromatography (125 g SiO2, 0-30% EtOAc/hexane and 30% EtOAc/hexane) to afford 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylic acid methyl ester 8a (2.4 g, 7.1 mmol, 83%) as a yellow oil. 1H NMR (δ, 400 MHz, CDCl3): 7.02 (d, 1H, J=9.2 Hz), 6.90 (dd, 1H, J=9.2, 3.1 Hz), 6.80 (d, 1H, J=3.1 Hz), 5.10 (s, 2H), 5.03 (s, 2H), 3.56 (s, 3H), 3.48 (s, 3H), 3.44 (s, 3H), 3.01-2.91 (m, 2H), 2.53-2.37 (m, 3H), 1.14 (d, 3H, J=6.6 Hz). HRMS calcd. 337.1651; found (electrospray, M+1) 337.1647.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[C:25](O)(=[O:27])[CH3:26]>O.C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][C:25](=[O:27])[CH3:26])=[CH:18][CH:19]=2)[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)O
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Oc1ccc(C=C(C(=O)O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
p-Nitrophenylacetic acid (0.60 moles, 108.69 grams) is added to a one liter glass beaker containing stirred aqueous sodium hydroxide solution (24.0 grams, 0.06 mole diluted with deionized water to a total volume of 600 mL) followed by heating to 60° C. The resultant solution is rotary evaporated under vacuum until final conditions of 100° C. and one nm Hg are achieved and maintained for 30 minutes. A portion (99.08 g, 0.4877 mole) of the recovered dry, white carboxylic acid sodium salt, p-hydroxybenzaldehyde (59.56 g, 0.4877 mole) and acetic acid (250 g) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at a 145° C. reflux. Refluxing is continued over the next 18 hours after which time, the reactor is cooled to 100° C. and ethanol (300 mL) and deionized water (50 mL) are added. The resultant slurry is boiled at 89° C. for one hour followed by cooling to 50° C. and filtered. The filtrate is added to deionized water (1500 mL) and the resultant precipitate recovered by filtration. The precipitate is exhaustively extracted with deionized water saturated with sodium carbonate. The combined extracts are filtered and neutralized with concentrated aqueous hydrochloric acid inducing formation of a precipitate. The precipitate is recovered by filtration and dried at 50° C. in a forced air, convection type oven. The dried powder is added to a beaker along with carbon tetrachloride (200 mL) and stirred with heating to a boil. Acetic acid (40 mL) is added to the boiling slurry and allowed to boil. Once boiling is achieved, the slurry is allowed to cool to room temperature (23° C.) and then at 4° C. for 16 hours. The product is recovered by filtration and dried at 70° C. under a vacuum of 5 mm Hg to a constant weight of 39.1 grams of brilliant, light yellow colored, crystalline powder.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]([NH:22]C(=O)OC(C)(C)C)[CH2:10][N:11]([CH3:21])[C:12]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:4][CH2:3]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CCOCC.CCO>[NH2:22][C@@H:9]([CH2:8][CH:5]1[CH2:4][CH2:3][C:2]([F:30])([F:1])[CH2:7][CH2:6]1)[CH2:10][N:11]([CH3:21])[C:12](=[O:13])[O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18]
Reactant: CN(C[C@H](CC1CCC(F)(F)CC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CN(C[C@@H](N)CC1CCC(F)(F)CC1)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(S)-tert-Butyl 1-(4,4-difluorocyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (6.25 g, 0.0139 mol) was dissolved in a minimal volume of ether (100 mL) and added to a solution of toluenesulfonic acid (2.71 g, 0.0142 mol) in absolute EtOH (20 mL). This solution was placed on a rotary evaporator and the Et2O was removed at ambient temp. The flask was then lowered into the water bath (temperature: 60° C.) and the selective removal of the Boc group proceeded concurrently with removal of the remainder of solvent. The reaction was completed by 2 h and gave a white solid, which was washed with hexanes:EtOAc (5:1, v/v, 3×10 mL), basified with 1N NaOH (pH>10), and extracted with Et2O (3×50 mL) The combined Et2O extracts were washed with 1N aq NaOH (3×5 mL), brine (3×5 mL), dried, decanted and stripped to give the free base (S)-2-(trimethylsilyl)ethyl 2-amino-3-(4,4-difluorocyclohexyl)propyl(methyl)carbamate (3.68 g, 76%). 1H NMR (400 MHz, CD3OD): 4.17 (t, J=8.4 Hz, 2H), 3.15 (m, 1H), 2.93 (s, 3H), 2.61 (dd, J=12.0 & 4.0 Hz, 1H), 2.36 (dd, J=12.0 & 8.4 Hz, 1H), 2.12-1.16 (m, 11H), 1.00 (t, J=8.4 Hz, 2H), 0.04 (s, 9H); MS (E/Z): 351 (M+H+).