Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COc1ccc(NNC(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
10 g of 4-methoxyphenylhydrazine hydrochloride are dissolved in water and then triethylamine is added until the salt has been neutralized. Extraction is carried out with AcOEt and then the extract is evaporated to dryness to produce 8 g of precipitate composed of 4-methoxyphenylhydrazine. This compound is dissolved in 30 ml of ether and then a solution of 13 ml of acetic anhydride dissolved in 30 ml of ether is added dropwise. The mixture is stirred at 0° C. for 15 minutes and then the white precipitate formed is filtered off to produce 7.4 g of the expected compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[N:9]=[C:10]([N:13](C(OC(C)(C)C)=O)CC2C=CC(OC)=CC=2)[S:11][CH:12]=1)([CH3:7])[CH3:6])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)c1csc(N)n1
Yield: 94.7 %

Procedure:
2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4-yl}-2-methyl-propionic acid ethyl ester (1.5 g, 3.45 mmol) was refluxed in 15 mL of trifluoroacetic acid for 18 hrs. Trifluoroacetic acid was removed in vacuo and the residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the solid product (0.7 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([O:20][C:21](=[O:23])[CH3:22])[CH2:8][NH:7]1.CCN(CC)CC.[C:31](Cl)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>ClCCl>[CH2:34]([O:33][C:31]([N:7]1[CH2:8][C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CN[C@@H]1c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CN(C(=O)OCc2ccccc2)[C@@H]1c1ccco1
Temperature: 0 °C
Yield: 51.8 %

Procedure:
To the solution of the product of Example 37 (189 mg, 0.58 mmol) in dichloromethane (2.5 mL) was added Et3N (0.10 mL, 0.72 mmol), and the mixture was cooled to 0° C. CbzCl (0.11 mL, 0.73 mmol) was added dropwise, and the solution was warmed up room temperature for 2 h. The reaction was quenched with aqueous NaCl, extracted with dichloromethane several times. The combined organic layer was dried over MgSO4. After the removal of volatiles, the residue was chromatographed on silica gel using hexanes-EtOAc (3:1) and hexanes-EtOAc (1:1) to yield pure product (138 mg) and starting material (5.81) (75 mg), 86% yield based on the consumed (5.81). Contain two rotamers at rt. 1H NMR (360 MHz, MeOD-d4) δ 7.55-7.48 (m, 1H), 7.38-7.21 (m, 5H), 6.50-6.33 (m, 2H), 5.90 (d, J2,3=5.7 Hz, 0.5H, H2), 5.87 (d, J2,3=5.7 Hz, 0.5H, H2), 5.76 (t, J4,3=J4,5=9.6 Hz, 0.5H, H4), 5.74 (t, J4,3=J4,5=9.6 Hz, 0.5H, H4), 4.99 (ddd, J5,6b=10.9 Hz, J5,4=9.6 Hz, J5,6a=5.6 Hz, H5), 4.39 (dd, J6a,6b=13.0 Hz, J6a,5=5.6 Hz, 0.5H, H6a), 4.35 (dd, J6a,6b=13.0 Hz, J6a,5=5.6 Hz, 0.5H, H6a), 3.07 (dd, J6b,6a=13.0 Hz, J6b,5=10.9 Hz, 0.5H, H6b) 2.97 (dd, J6b,6a=13.0 Hz, J6b,5=10.9 Hz, 0.5H, H6b), 2.00 (s, 3H), 1.99 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[S:17][C:18](=[CH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=4[C:38]([F:41])([F:40])[F:39])=[C:25]([O:42][CH3:43])[CH:24]=3)[C:19](=[O:21])[N:20]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:43][O:42][C:25]1[CH:24]=[C:23]([CH:22]=[C:18]2[S:17][C:16]([NH:15][CH2:14][CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[N:20][C:19]2=[O:21])[CH:28]=[CH:27][C:26]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=1[C:38]([F:40])([F:39])[F:41]
Reactant: COc1cc(C=C2SC(NCC3CN(C(=O)OC(C)(C)C)CCO3)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C=C2SC(NCC3CNCCO3)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
LC/MS (m/z) [M+1]+618.8 (calculated for C29H29F3N4O6S, 618.63). 2-({5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-methyl)-morpholine-4-carboxylic acid tert-butyl ester (0.1 g, 0.16 mmol) was dissolved in dry dichloromethane (6 mL). To the reaction mixture was then added at 0° C. trifluoroacetic acid (2 mL). The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The reaction mixture was then partitioned with saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (6% ammonia 2.0 M methanol/dichloromethane) to yield the compound as a solid (0.052 g, 63%).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:29]=[C:28]5[C:23]([CH:24]=[CH:25][CH:26]=[N:27]5)=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[N:39]1([C:45]([N:2]2[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]3[N:9]([C:14]4[CH:15]=[CH:16][C:17]([C:20]5[CH:29]=[C:28]6[C:23]([CH:24]=[CH:25][CH:26]=[N:27]6)=[CH:22][CH:21]=5)=[CH:18][CH:19]=4)[C:10](=[O:13])[NH:11][N:12]=3)[CH2:3]2)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCOCC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 4 mL vial was placed 5-[(3S)-3-pyrrolidinylmethyl]-4-[4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.147 mmol). Added in succession was dichloromethane (2 mL), N,N-diisopropylethylamine (0.458 mmol), and 4-morpholinecarbonyl chloride (0.157 mmol). The vial was capped and the solution was stirred at room temperature for 30 min. The solution was concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (23 mg, 31%). MS(ES)+ m/e 485.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].C(OCC)C>O1CCCC1>[CH3:23][Si:22]([CH3:25])([CH3:24])[O:1][CH2:2][CH2:3][N:4]([CH2:12][CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1
Reactant: CCN(CCO)c1ccc(I)cc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCN(CCO[Si](C)(C)C)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A solution of 14.5 g, that is 50 mmole of 4-[(2-hydroxyethyl)ethylamino]iodobenzene and 6.0 g, that is 60 mmole triethylamine, from Aldrich Chemical Co. in 90 ml tetrahydrofuran ("THF") was stirred in an ice-water bath under nitrogen. Next, 5.5 g, 51 mmole chlorotrimethylsilane, from Aldrich Chemical Co. was added slowly while maintaining the reaction temperature below 10° C. The mixture was stirred for 30 minutes then warmed to room temperature for 1 hour. Ethyl ether was added and extracted with brine. The organic layer was separated and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was flash column chromatographed on silica gel with 2% ethyl acetate-hexane to give 16.63 g of a clear viscous oil at a 92% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:14])[CH:3]=1.[ClH:15]>CCO.[OH-].[OH-].[Pd+2]>[ClH:15].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1cnccn1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(F)ccc1C1CNCCN1

Procedure:
Meanwhile, 2-chloropyrazine (4.75 mL) was dissolved in anh. THF (30 mL) and [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) (510 mg) was added. To this suspension the solution of Grignard was added dropwise, at 0° C., under N2. After the addition was complete, the reaction mixture was heated at reflux for 2 hr. The THF was evaporated, the residue poured in sat. aq. NaCl and the aqueous phase was extracted with DCM (3×). The organic extracts were dried, the solids were filtered and the solvent evaporated. The crude oil was purified by flash chromatography (CH/AcOEt 85:15) and then through a small column of Florisil (eluant: DCM) to eliminate the nickel residue (6.0 g): 2-(4-fluoro-2-methyl-phenyl)-pyrazine (6.0 g) was obtained as a pale yellow solid. 2-(4-Fluoro-2-methyl-phenyl)-pyrazine (0.3 g) dissolved in EtOH 95% (20 mL) and 37% HCl (0.2 mL) was hydrogenated at 5 atm. for 4 hr, in the presence of 20% Pd(OH)2/C (30 mg) as catalyst. The catalyst was filtered off and the solvent was evaporated. The crude residue was triturated in MeOH/AcOEt (5 mL/5 mL) to obtain the title compound (0.08 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:13]([C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1)#[N:14]
Reactant: CN(C)C=O
Reactant: CC(=O)N(C)c1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(=O)N(C)c1ncc(C#N)cn1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a sealed tube was added N-(5-bromo-pyrimidin-2-yl)-N-methyl-acetamide (0.70 g, 3.04 mmol), Zn(CN)2 (0.59 g, 5.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.30 mmol) in anhydrous DMF was degassed with Argon for 5 minutes and then warmed at 120° C. After 5 hours, the mixture was cooled and diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford N-(5-cyano-pyrimidin-2-yl)-N-methyl-acetamide.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:18][CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1OCCN1CCC(O)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[2-(2-nitrophenoxy)ethyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[2-(2-nitrophenoxy)ethyl]piperidine.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].Br[CH2:15][CH2:16][CH:17]1[O:22][CH2:21][CH2:20][CH2:19][O:18]1>O.C(OCC)(=O)C.C(O)(=O)C>[C:3]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:15][CH2:16][CH:17]1[O:22][CH2:21][CH2:20][CH2:19][O:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCCC1OCCCO1
Reactant: CC(C)(C)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(OCCC2OCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (3.46 g, 1.3 eq) was taken up in water (20 mL) and stirred for about 30 minutes. Then 3-tert-butyl phenol (10.0 g, 66.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. Next, 2-(2-bromoethyl)-[1,3]dioxane (9.9 mL, 1.1 eq) was added ant the resulting mixture was heated at reflux for 40 hours. The reaction mixture was cooled to room temperature and then added ethyl acetate (150 mL) and with stirring acetic acid was added to pH=4, followed by dilution with water (100 mL) and ethyl acetate (150 mL). After partitioning, the layers were separated and then washed the organic layer with water (3×100 mL) and the ethyl acetate layers were dried over magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil (16.91 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)(=O)=O.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:25]([C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)#[N:26]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)cc(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Zinc cyanide (1.1 g) and Pd(PPh3)4 (281 mg) were added to a DMF (45 mL) solution of methyl 5-{[(trifluoromethyl)sulfonyl]oxy}biphenyl-3-carboxylate (1.68 g), and stirred at 90° C. for 1 hour and 30 minutes. The reaction liquid was filtered through Celite, the solvent was partly evaporated away, and the residue was diluted with ethyl acetate, aqueous ammonia was added to it, and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated away. The residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a white powder.
Reaction SMILES: [CH2:1](N1CCC(NC2C=CC=C(F)C=2)(C#N)CC1)[C:2]1C=CC=CC=1.C(C(C(Cl)=O)C(Cl)=O)C.N1C(C)=CC=CC=1C.[CH2:41]([N:48]1[CH2:53][CH2:52][C:51]([N:56]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[CH:64]=2)[C:57](=[O:62])[CH2:58][C:59]([OH:61])=[O:60])([C:54]#[N:55])[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:41]([N:48]1[CH2:53][CH2:52][C:51]([N:56]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[CH:64]=2)[C:57](=[O:62])[CH2:58][C:59]([O:61][CH2:1][CH3:2])=[O:60])([C:54]#[N:55])[CH2:50][CH2:49]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: N#CC1(N(C(=O)CC(=O)O)c2cccc(F)c2)CCN(Cc2ccccc2)CC1
Reactant: N#CC1(Nc2cccc(F)c2)CCN(Cc2ccccc2)CC1
Agent: CCC(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CC(=O)N(c1cccc(F)c1)C1(C#N)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-benzyl-4-[(3-fluorophenyl)amino]piperidine-4-carbonitrile (Intermediate 1A.1-1, 9.0 g, 29.1 mmol) in dichloromethane (150 ml) were added ethyl malonyl chloride (4.9 ml, 37.8 mmol) and 2,6-lutidine (5.1 ml, 43.6 mmol). The reaction was allowed to stir at rt for 2.5 h. Additional ethyl malonyl chloride (1.1 ml, 8.7 mmol) was added, and the reaction was allowed to stir for 30 min. The reaction was diluted with dichloromethane and washed with water and brine. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to yield a 1:1 mixture of desired ester ethyl 3-[(1-benzyl-4-cyanopiperidin-4-yl)(3-fluorophenyl)amino]-3-oxopropanoate and its acid 3-[(1-benzyl-4-cyanopiperidin-4-yl)(3-fluorophenyl)amino]-3-oxopropanoic acid (quant).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH:12]([CH3:16])[CH2:13]2)[C@H:9]1[CH2:17][NH2:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]2[N:26]([C:27]=1[C:28](O)=[O:29])[CH:25]=[CH:24][S:23]2>>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH:12]([CH3:16])[CH2:13]2)[C@H:9]1[CH2:17][NH:18][C:28]([C:27]1[N:26]2[C:22]([S:23][CH:24]=[CH:25]2)=[N:21][C:20]=1[CH3:19])=[O:29])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc2sccn2c1C(=O)O
Reactant: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CN)[C@H]2C1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CC(C)C[C@H]2CN1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester with commercially available 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[C:20](OCC)=[O:21].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=1[CH2:20][OH:21]
Reactant: CCOC(=O)C1=C(c2ccccc2F)CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCC1=C(c2ccccc2F)CCCC1
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (1.90 g) was added to a recovery flask, and THF (300 mL) was added thereto in an ice bath. A solution of ethyl 2-(2-fluorophenyl)cyclohex-1-enecarboxylate obtained in Preparation Example 1-(2) (10.3 g) in THF (100 mL) was added dropwise to the reaction solution at the same temperature, and the mixture was stirred for one hour. Water (1.90 mL), a 5 N sodium hydroxide solution (1.90 mL) and water (5.70 mL) were sequentially added to the reaction solution. Anhydrous magnesium sulfate was further added, followed by extraction with ethyl acetate. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (8.88 g).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C@@:7]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1)[CH:5]=C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C@:7]2([CH2:4][CH:5]=[O:1])[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH3:15])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: O=[O+][O-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(F)cc2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(F)cc1)N1CC[C@](CC=O)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h

Procedure:
Ozone was passed into a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-fluorophenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.40 mmol) in anhydrous CH2Cl2 (20 mL) at −78° C. until a blue color appeared. Then Ph3P (920 mg, 3.5 mmol) was added at −78° C. The formed mixture was stirred overnight. The mixture was concentrated to give crude 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-fluorophenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetaldehyde, which was used for the next step without purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:19][CH3:20])=[CH:9][CH:10]=[C:11]3[C:16]=2[O:15][C:14](=[O:17])[CH:13]=[C:12]3O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:25]>C1(C)C=CC=C(C)C=1>[NH2:25][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([O:19][CH3:20])=[CH:9][CH:10]=2)[O:15][C:14](=[O:17])[CH:13]=1
Reactant: COc1ccc2c(O)cc(=O)oc2c1OC1CCCC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1cccc(C)c1
Product: COc1ccc2c(N)cc(=O)oc2c1OC1CCCC1
Reaction time: 3 h

Procedure:
A mixture of 8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one (450 mg, 1.63 mmol, Example 1, Step 2), ammonium acetate (3.0 g, 39 mmol), and anhydrous m-xylene (8 mL) was refluxed under N2. After 3 h, the reaction was concentrated and purified by silica gel chromatography (3:2→0:1; hexanes:ethyl acetate) to give 4-amino-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: MS (ESI): 275.9.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([N+:15]([O-])=O)[CH:11]=[CH:10][CH:9]=2)[CH3:2]>C(O)C.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]=[CH:7]2
Reactant: CCOCc1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Pd]
Solvent: CCO
Product: CCOCc1cc2c(N)cccc2cn1
Yield: 78.9 %

Procedure:
A catalyst (3% palladium-on-charcoal; 3.5 g) is added to a solution of 3-ethoxymethyl-5-nitroisoquinoline (24 g) in ethanol (350 cc). A stream of hydrogen is bubbled through for 4 hours, whilst keeping the temperature at about 25° C. with the aid of a bath of cold water. The suspension is filtered and the filtrate is evaporated to dryness at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized from diisopropyl ether (200 cc). 5-Amino-3-ethoxymethylisoquinoline (16.5 g), melting at 95° C., is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=O)=[CH:6][CH:5]=1)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>C1COCC1>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](=[S:16])[NH2:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C(N)=O)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C(N)=S)cc1
Temperature: 55 °C
Yield: 20.1 %

Procedure:
To a solution of 4-(diethylamino)benzamide (5.66 g, 29.43 mmol) in THF (80 mL) was added P2S5 (9.81 g, 44.14 mmol) at 50° C. over a period of 1 h. The mixture was heated at 55° C. for 8 h, then cooled to rt, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (1.23 g, 20%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1
Reactant: OCc1ccc(CCc2ccco2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
To an ethyl acetate (50 mL) solution of (4-(2-furan-2-yl-ethyl)phenyl)-methanol (580 mg, 2.87 mmol) described in Manufacturing Example 80-1-3 was added activated manganese dioxide (8 g, 92 mmol), which was stirred for 12 hours at room temperature. The reaction solution was suction filtered through a Celite pad, and washed with ethyl acetate (50 mL). The filtrate was concentrated under a reduced pressure to obtain the title compound (480 mg, 83.5%).