Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15]C(OC(C)(C)C)=O)[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:38][C@@H:37]([NH:39]C(OC(C)(C)C)=O)[CH2:36][C@@H:35]([NH:47]C(OC(C)(C)C)=O)[CH2:34]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([N+:55]([O-])=O)[CH:29]=3)[N:24]=2)[CH2:10]1)=O)(C)(C)C.Cl>C(O)(C(F)(F)F)=O.CO>[NH2:15][C@@H:13]1[CH2:14][C@H:9]([NH2:8])[CH2:10][N:11]([C:23]2[C:32]([N:33]3[CH2:34][C@@H:35]([NH2:47])[CH2:36][C@@H:37]([NH2:39])[CH2:38]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:55])[CH:29]=3)[N:24]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc([N+](=O)[O-])cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ccc2nc(N3C[C@H](N)C[C@H](N)C3)c(N3C[C@H](N)C[C@H](N)C3)nc2c1
Reaction time: 0.01 h
Yield: 31.1 %

Procedure:
2,3-Bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-6-nitro-quinoxaline (245) (0.05 g, 0.135 mmol) was dissolved in TFA (3 mL) and the mixture was shaken at room temperature in a Teflon septum capped vial for 3 hours. LC-MS indicated complete de-protection at this point. The solution was concentrated to give an orange oil. The oil was dissolved in MeOH (1 mL) and HCl (1 mL, 4.0 M in dioxane) was added and the mixture was vortexed for 20 seconds. A fine suspension was observed. The mixture was concentrated to an orange powder. Ethyl ether (5 mL) was added to the powder and vortexed for 2 minutes. The solid was collected by filtration and dried under high vacuum for 16 hours to give the desired product (255) as an orange powder (0.023 g, 0.042 mmol, 31% yield, assumed 4 HCl salt). LC-MS (ESI): (exact mass: 401.23) m/e=402.2 [M+1]+. 1H NMR (400 MHz, D2O): δ 1.72 (q, 2H, J=12 Hz), 2.49 (d, 2H, J=10 Hz), 2.94 (q, 4H, J=12 Hz), 3.51–3.67 (m, 4H), 4.44 (dd, 2H, J1=12 Hz, J2=4.4 Hz), 4.57 (dd, 2H, J1=12.8 Hz, J2=3.6 Hz), 7.71 (d, 1H, J=9.2 Hz), 8.10 (dd, 1H, J1=9.2 Hz, J2=2.8 Hz), 8.44 (d, 1H, J=2.4 Hz).
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[C:50]1(O)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(Cl)Cl.O1CCOCC1.N1C=CC=CC=1>[O:1]([C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: Oc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(Oc5ccccc5)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 0 °C
Yield: 15.1 %

Procedure:
To a solution of 60 mg of 8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 13a) (0.167 mmol) in CH2Cl2 (2 ml) was added 27 μL of pyridine and the reaction mixture cooled to 0° C. To this was added 40 μL of triflic anhydride (0.24 mmol) in CH2Cl2 (1 ml). Maintained at 10° C. overnight. The reaction mixture was diluted with CH2Cl2 (5 ml) and washed with cold 1N HCl, sat'd NaHCO3 and brine. Dried over sodium sulfate and concentrated in vacuo to afford a yellow oil. The crude triflate was dissolved in 1,4-dioxane (3 ml) and 100 mg of phenol (1.08 mmol was added followed by heating at 80° C. overnight. The reaction mixture was concentrated down and the residue taken up in ethyl acetate (10 ml) washed with 1N KOH (5 ml), sat'd NaHCO3 (5 ml), 1N HCl (5 ml) and brine. The organic layer was dried over NaSO4 and concentrated in vacuo to a colorless oil which was purified by column chromatography (SiO2, 1:1 hexanes/EtOAc) to afford 11 mg of title compound as a white solid (MH+=437.29). The following compounds were prepared in an analogous manner after saponification of the methyl ester.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].Cl>C1COCC1.O>[S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3])(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCOCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an oven dried 12 L three-necked roundbottom flask, equipped with a magnetic stir bar and a 1000 mL pressure-equalizing dropping funnel, a solution of NaOH (440.0 g, 11.0 mol) is added to 1800 mL water and the mixture is cooled to approximately 0° C. A solution of triethylene glycol monomethyl ether, Formula A, (656.84 g, 4.0 mol) in THF (1000 mL) is added. The clear solution is stirred vigorously at 0° C. for 15 min and a solution of tosyl chloride (915.12, 4.8 mol) in THF (2.0 L) added dropwise over a 1 h period. The reaction mixture is stirred for an additional 1 h at O° C., and 10% HCl (5.0 L) is added to quench the reaction (to pH 5-7). The two-phase mixture is transferred to a 4 L separatory funnel the organic layer removed, and the aqueous layer extracted with t-butylmethyl ether (3×250 mL). The combined organic extracts are washed with brine (2×350 mL), dried (MgSO4), and evaporated under reduced pressure to afford Formula B, 1217.6 g (95%) as a light colored oil. This material is taken to the next step without further purification.
Reaction SMILES: Cl[C:2]1[O:10][C:9]2[C:4](=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[C:3]=1[Cl:12].C([Li])(C)(C)C>C1COCC1>[Cl:12][C:3]1[C:4]2=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=[C:9]2[O:10][CH:2]=1
Reactant: Cc1ccc2oc(Cl)c(Cl)c2n1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc2occ(Cl)c2n1

Procedure:
To a solution of 2,3-dichloro-5-methylfuro[3,2-b]pyridine (0.661 g, 3.27 mmol) (Example 12, Step 2) in 16 mL of THF was added a 1.7M solution of t-butyllithium (4.04 mL, 6.87 mmol). After 30 min the solution was quenched at -78° C. with methanol and a solution of NH4C1. The reaction was brought to room temperature and extracted with EtOAc. The organic solvents were evaporated and the title compound was purified by flash chromatography on silica with EtOAc:hexane 1:4 to yield 0.444 g (81%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21][C@H:12]1OS(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[FH:52].F.F.C(N(CC)CC)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:21][C@@H:12]1[F:52]
Reactant: O=S(=O)(O[C@@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21)C(F)(F)F
Reactant: F
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: F[C@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 57.8 %

Procedure:
22.9 mg (0.0356 mmols) of 6-chloro-9-[2-O-(trifluoromethanesulfonyl)-3-deoxy-5-O-(triphenylmethyl)-β-D-erythro-pentofuranosyl]-9H-purine was dissolved in 2.0 ml of toluene, to which were added 10.8 mg (0.107 mmols) of triethylamine and 34.5 mg (0.214 mmols) of triethylamine trihydrofluoride, and stirred at room temperature for about 5 days. After having been cooled, all the mixture was dissolved in methanol, and analyzed through liquid chromatography. The intended product was obtained at an yield of 57.8%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH2:23][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])[C:6]=2[CH:7]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)[CH2:29][N:30]2CCCCC>>[O:22]=[C:9]1[C:8]2([C:6]3[CH:7]=[C:2]([C:29]#[N:30])[CH:3]=[CH:4][C:5]=3[O:24][CH2:23]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCN1C(=O)C2(COc3ccc(Br)cc32)c2ccccc21
Reactant: CCCCCN1CC2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Product: CCCCCN1C(=O)C2(COc3ccc(C#N)cc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 30, and making non-critical variations using 5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′(1′H)-one, the title compound was obtained (78%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (dt, 1H), 7.34 (dt, 1H), 7.12-6.91 (m, 5H), 5.01 (d, 1H), 4.76 (d, 1H), 3.86-3.63 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.32 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.2, 164.1, 142.6, 134.8, 131.4, 130.8, 129.6, 127.8, 123.9, 123.5, 118.8, 111.5, 109.1, 104.7, 80.6, 57.3, 40.6, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 333.5 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1.[H-].[Na+].[CH3:25][NH:26][C:27](=O)[O:28]C1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[NH2:22][C:18]1[CH:17]=[C:16]([O:15][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]([C:27]([NH:26][CH3:25])=[O:28])[CH:11]=[CH:10]3)[CH:21]=[CH:20][N:19]=1
Reactant: COCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Reactant: CNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OCCOC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
4-((6-(2-Methoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 20-6 (2.60 g, 8.67 mmol) was dissolved in N,N-dimethylformamide (50 mL), then 50-72% oily sodium hydride (499 mg) was added under nitrogen atmosphere at room temperature. Phenyl methylcarbamate described in Production Example 1-7 (1.97 g, 13.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and ethyl acetate and water were added for partition. The aqueous layer was extracted with ethyl acetate twice, sodium chloride was added to the aqueous layer, and the resultant was extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under vacuum, and then the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:4-0:1-ethyl acetate:methanol=49:1-24:1). The target fraction was concentrated under vacuum, and ethyl acetate was added and the precipitate was collected by filteration and washed to obtain the title compound (2.23 g, 72%).
Reaction SMILES: [CH2:1](/[C:4](=[CH:7]\[CH2:8][C@H:9]1[CH2:13][CH:12]=[C:11]([CH3:14])[C:10]1([CH3:16])[CH3:15])/[CH:5]=[O:6])[CH2:2][CH3:3].NCCN.[OH-].[K+]>C(O)(C)C>[CH2:1](/[C:4](=[CH:7]\[CH2:8][C@H:9]1[CH2:13][CH:12]=[C:11]([CH3:14])[C:10]1([CH3:15])[CH3:16])/[CH2:5][OH:6])[CH2:2][CH3:3]
Reactant: CCC/C(C=O)=C\C[C@H]1CC=C(C)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: NCCN
Solvent: CC(C)O
Product: CCC/C(=C\C[C@H]1CC=C(C)C1(C)C)CO

Procedure:
In a 100 ml stainless steel autoclave were charged 6.60 g (0.03 mol) of (E)-(R)-2-propyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al synthesized from (1S)-α-pinene having an optical purity of 97% e.e. in a conventional manner, 28.7 mg (0.03 mmol) of RuCl2 (PPh3)3, 2.4 ml of a 0.1M 1,2-diaminoethane (0.24 mmol) solution in isopropyl alcohol, and 15 ml of a 0.1M potassium hydroxide (1.5 mmol) solution in isopropyl alcohol in a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours under a hydrogen pressure of 50 atm.
Reaction SMILES: [C:1]1([CH:11](O)[CH3:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>C1COCC1>[C:1]1([CH:11]([N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[CH3:12])[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1ccc2cccccc1-2
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(c1ccc2cccccc1-2)N1C(=O)c2ccccc2C1=O

Procedure:
The crude 1-(azulen-1-yl)ethanol prepared in Example 72, Step A was dissolved in dehydrated THF (380 mL), and stirred with cooling on ice under nitrogen atmosphere. This reaction mixture was added with phthalimide (45.0 g, Kanto Kagaku), tri-n-butylphosphine (37.7 mL, Kanto Kagaku), and 1,1′-azobis(N,N′-dimethylformamide) (26.3 g, Midori Kagaku), and stirred at room temperature for 16 hours under nitrogen atmosphere. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was added with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=6:1), to obtain 16.8 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][O:6][CH2:7][C@H:8]([NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[OH-].[Li+].C(OCC)(=O)C>O1CCOCC1.O>[C:21]([O:20][C:18]([CH2:17][NH:16][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][O:6][CH2:5][C:4]([OH:25])=[O:3])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)COC[C@@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CN[C@@H](COCC(=O)O)Cc1ccccc1
Reaction time: 56 h
Yield: 68.7 %

Procedure:
((2R)-2-((tert.-butoxycarbonyl)methylamino)-3-phenylpropoxy)acetic acid ethyl ester (0.60 g, 1.71 mmol) was dissolved in dioxane (5 ml). A solution of lithium hydroxide (0.05 g, 2.20 mmol) in water (2 ml) was added. The solution was stirred at room temp. for 56 h. Ethyl acetate (10 ml) and water (2 ml) were added. The phases were separated. The aqueous phase was extracted with ethyl acetate (10 ml). The combined organic layers were extracted with 1N sodium hydroxide solution (20 ml). The combined aqueous phases were acidified with a 1M sodium hydrogensulfate solution (pH=2) and extracted with ethyl acetate (2×20 ml). These ethyl acetate layers were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 0.38 g of crude ((2R)-2-((tert-butoxycarbonyl)methylamino)-3-phenylpropoxy) acetic acid, that was used for the following steps.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].CS(Cl)(=O)=O.[CH2:30]([N:32](CC)CC)[CH3:31]>O.C(#N)C>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:31][C:30]#[N:32])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
In a 50 ml-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 200 mg (0.69 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2 mL of acetonitrile and 41.5 mg (1.04 mmol) of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0° C. To the chilled mixture were added 0.08 mL (1.03 mmol) of methanesulfonyl chloride and 0.15 mL (1.08 mmol) of triethylamine, and the mixture was stirred for 3 hours at the same temperature. Subsequently, to the mixture was added 5 mL of chilled water, and the mixture was extracted with three portions of ethyl acetate (15 mL) which were previously chilled in an ice bath. The mixture was dried over anhydrous magnesium sulfate. The organic portion was then filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 180 mg (yield: 83%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][CH:6]([CH:8]1[NH:12][CH2:11][C:10](=[O:13])[N:9]1[CH2:14][C:15]([O-:17])=[O:16])[CH3:7].[Na+].[CH2:19](O)[CH3:20]>>[CH3:7][CH:6]([CH:8]1[NH:12][CH2:11][C:10](=[O:13])[N:9]1[CH2:14][C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH3:5]
Reactant: CC(C)C1NCC(=O)N1CC(=O)[O-]
Reactant: CCO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN1C(=O)CNC1C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To 50 ml of anhydrous ethanol stirred at 0°-5° C., 2 ml thionyl chloride were added. At the same temperature 2.1 g (0.01 mol) of sodium 2-(1-methylethyl)-5-oxo-1imidazolidineacetate were added. The suspension obtained was stirred at 0° C. for 1 hour and at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue taken up with ethyl acetate. The solid residue was filtered off and the solvent evaporated. The residue was dissolved in a saturated solution of sodium hydrogen carbonate and extracted with 3×50 ml of dichloromethane. The organic layers were dried and evaporated to give ethyl 2-(1-methylethyl)-5-oxo-1imidazolidineacetate (0.9 g) as a pale-yellow oil (42%) (Rf 0.6, ethyl acetate/dichloromethane 6:4; silica gel plates). Hydrochloride salt, m.p. 148°-149° C. (methanol/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9]Cl.[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][N:26]1[CH2:25][CH2:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Solvent: Cc1ccccc1
Product: Cc1nc2ccccn2c(=O)c1CCN1CCN(c2cccc(Cl)c2)CC1
Yield: 39.7 %

Procedure:
A mixture of 1.1 g of 2-methyl-3-(2-chloroethyl)-4H-pyrido[1,2-a)pyrimidin-4-one, 2.95 g of 1-(m-chlorophenyl)piperazine and 15 ml of toluene was refluxed with heating for 30 hours. After completion of the reaction, the reaction mixture was filtered while hot. The filtrate was concentrated under reduced pressure, and the residue was purified by means of column chromatography using alumina. The product was then recrystallized from a mixture of benzene - n-hexane to give 0.75 g of the desired compound as colorless needles, m.p. 112° - 113°C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)[CH2:3][OH:4].CO[C:18](OC)([CH3:20])[CH3:19].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(C)=O>[CH3:19][C:18]1([CH3:20])[O:1][CH:2]([C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:15])[CH2:10][CH2:11][O:12]3)=[CH:7][CH:6]=2)[CH2:3][O:4]1
Reactant: COC(C)(C)OC
Reactant: O=C1CCOc2cc(C(O)CO)ccc21
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc3c(c2)OCCC3=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a mixture of 7-(1,2-dihydroxyethyl)chroman-4-one (Preparation 60A, 0.950 g, 4.56 mmol) and 2,2-dimethoxypropane (1.68 mL, 13.7 mmol) in acetone (20 mL) at room temperature was added (1R)-(−)-camphorsulfonic acid (0.212 g, 0.913 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and concentrated under reduced pressure. The aqueous residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, and brine. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product as a dark oil, which was purified by flash silica gel chromatography using a 20% mixture of ethyl acetate and hexane to afford 7-(2,2-dimethyl-1,3-dioxolan-4-yl)chroman-4-one (0.657 g, 2.65 mmol, 58% yield) as a clear, colorless oil. The product had an HPLC ret. time=2.14 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=248.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14].Cl>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[Cl:10][CH2:11][CH2:12][C:13]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: Clc1cccc([Mg]Br)c1
Reactant: O=C(Cl)CCCl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(CCCl)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.3 %

Procedure:
To a solution of zinc chloride (0.5 M in THF, 20.40 mL, 10.20 mmol) was added a solution of (3-chlorophenyl) magnesium bromide (0.5 M in THF, 20.00 mL, 10 mmol) and the mixture was stirred at ambient temperature for 20 min. Pd(PPh3)4 (578 mg, 0.500 mmol) was added to the above mixture and the reaction was then cooled to 0° C. A solution of 3-chloropropanoyl chloride (1.008 mL, 10.50 mmol) in THF (anhydrous) (10 mL) was added and the reaction was stirred at 0° C. for 2 h. After this time, the mixture was acidified with 3 N HCl and extracted with Et2O (3×). The combined organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and evaporated to an oil which was purified using silica gel chromatography to give the desired product (635 mg, 31%). MS (ESI) m/z: 202.9 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[C:12]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH:22]=[C:21](Br)[N:20]=[CH:19]2)[CH:13]=1.CN1C(=O)CCC1>[Cl-].[Na+].O.[Cu]I.C(OCC)(=O)C.O>[C:12]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH:22]=[C:21]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)[N:20]=[CH:19]2)[CH:13]=1
Reactant: c1cn[nH]c1
Reactant: Brc1cn(-c2cccc(-c3ccccc3)c2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(-c2cccc(-n3cnc(-n4cccn4)c3)c2)cc1
Temperature: 180 °C
Yield: 32.8 %

Procedure:
Pyrazole (68.3 mg, 1.0 mmol), K2CO3 (139 mg, 1.0 mmol), CuI (9.5 mg, 5 mol %) and 11 (150 mg, 0.5 mmol) were added to vial and added NMP (1 mL). The slurry was heated in micro wave (emrys optimiser; fixed hold time) to 180° C. for 1 h after which after it was added NMP (1 mL) and heated to 195° C. for 3 h. The reaction mixture was then added another 6.5 mg CuI and 40 mg pyrazole, and heated for another 4 h after by which LC-MS analysis showed full conversion. The rx was added dropwise to H2O (10 mL) followed by ethyl acetate (30 mL) and brine (10 mL). The phases were separated and the aqueous phase extracted with THF (2×5 mL). The combined organic phases was washed with H2O (2×5 mL), dried (MgSO4), decanted and evaporated onto Celite and purified by CombiFlash sq16 to yield 47 mg (32%) the title compound as a white solid. HRMS (ESI+): m/z=286.3366 [M+H]