Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[N:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]=2)[O:7][C:6]([CH3:30])([CH3:29])[CH2:5]1)=[N+]=[N-].O.CP(C)C>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[C:13]3[C@H:4]([NH2:1])[CH2:5][C:6]([CH3:30])([CH3:29])[O:7][C:8]3=[N:9][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[CH:19][CH:18]=1
Reactant: CC1(C)C[C@@H](N=[N+]=[N-])c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C[C@@H](N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Step A (9.5 g, 20.7 mmol) in 50 mL of THF was added 2.5 mL of H2O and 31.0 mL of trimethylphosphine in THF (1.0 M, 31.0 mmol). After stirring at rt for 3 h, the solvent was evaporated. Chromatography on a Biotage 40+M cartridge using 1:19 v/v CH3OH/CH2Cl2 as the eluant afforded the product: 1H NMR δ 1.42 (s, 3H), 1.54 (s, 3H), 1.78 (t, J=12.5, 1H), 2.18 (dd, J=5.9, 13.4, 1H), 4.16 (dd, J=6.0, 11.7, 1H), 7.04 (d, J=8.5, 2H), 7.17-7.26 (m, 5H), 7.93 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[Cl:10][C:4]1[N:3]=[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Cl)nc(Cl)c1
Reactant: C1COCCN1
Product: COc1cc(Cl)nc(N2CCOCC2)c1
Temperature: 130 °C
Yield: 43 %

Procedure:
A mixture of 2,6-dichloro-4-methoxypyridine (1.0 equiv.) and morpholine (20 equiv.) were heated to 130° C. for 40 min in the microwave. The reaction mixture was centrifuged and the soluble portion was removed from solids. Water was added to the soluble portion which resulted in precipitation of product. This mixture was centrifuged and the soluble portion was discarded. The remaining solids were partitioned between water and EtOAc. The organic phase was washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuo to give 4-(6-chloro-4-methoxypyridin-2-yl)morpholine in 43% yield. LCMS (m/z) (M+H)=229.1, Rt=0.76 min.
Reaction SMILES: [CH3:1][C:2]([N+:5]([O-:7])=O)([CH3:4])[CH3:3].C(O)(=O)C.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>C(O)C.[Zn]>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[N+:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[O-:7]
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1ccccn1
Temperature: 5 °C

Procedure:
To a suspension of 1,1-dimethylnitroethane (545.5 mg, 5.29 mmol) and zinc (516.6 mg, 7.90 mmol) in ethanol (3.0 ml) was added acetic acid (950.1 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 20 minutes. After cooling the mixture to 5° C. again, 2-pyridinecarbaldehyde (283.9 mg, 2.65 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (ethyl acetate).
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[CH3:23]>C(O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])=[CH:17][C:16]=1[CH3:23]
Reactant: COc1ccc(C=O)cc1C
Reactant: NN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: COc1ccc(C=NN2C(=O)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Yield: 85 %

Procedure:
N-aminophthalimide (1.62 g) and 4-methoxy-3-methylbenzaldehyde (1.50 g) were added to ethanol (20 ml), the mixture was stirred under heat reflux overnight. The mixture was allowed to cool to a room temperature, and then the precipitate was separated by filtration, washed with ethanol, and dried under a reduced pressure to give the title compound (2.50 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](/[CH:17]=[CH:18]\[N+:19]([O-])=O)=[CH:9]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][CH2:18][NH2:19])=[CH:9]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2cc(/C=C\[N+](=O)[O-])c3ccccc32)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(CCN)c3ccccc32)cc1
Yield: 104.4 %

Procedure:
(Z)-1-(4-Methoxybenzyl)-3-(2-nitrovinyl)-1H-indole (5 g, 15.72 mmol) in dry THF (32 mL) was reacted with LAH (2.98 g, 78.61 mmol) in dry THF (32 mL). The resulting mixture was refluxed for 16 hours under nitrogen atmosphere to afford 4.6 g of the product (100% yield).
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]([C:5]2[CH:4]=[C:3]([OH:2])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:6]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
0.5 mmol of Compound 27 prepared in Example C-1 was charged in a 25 mL round-bottom flask and dissolved in methylene chloride (5 mL) to make a solution to which trifluoroacetic acid (TFA, 5 equivalents) was then added, followed by stirring at room temperature for 30 minutes. After completion of the reaction was confirmed by TLC, the reaction liquid was washed three times with distilled water, and the organic layer was dried over anhydrous MgSO4 and concentrated to afford the title compound.
Reaction SMILES: [OH-].[Na+].Cl.[C:4]1([C:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]3[CH:14]([CH2:15][NH:16][CH2:17]3)[C:13](=[O:19])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:26]([OH:36])(=[O:35])[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28].O>C(OCC)(=O)C>[C:26]([OH:36])(=[O:35])[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28].[C:20]1([C:10]2([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C@H:18]3[C@H:14]([CH2:15][NH:16][CH2:17]3)[C:13](=[O:19])[CH2:12][CH2:11]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Yield: 29.6 %

Procedure:
4N aqueous sodium hydroxide (500 cc) is added slowly and with stirring to a suspension of (3aRS,7aRS)-7,7-diphenylperhydro-4-isoindolone hydrochloride (200 g) in ethyl acetate (2000 cc); stirring is continued until the starting material has disappeared. The organic solution is washed with distilled water (250 cc) and with saturated aqueous sodium chloride solution (250 cc), dried over magnesium sulphate and filtered. To the solution thereby obtained, a solution of L(+)-mandelic acid (92.8 g) in ethyl acetate (1000 cc) is added with stirring; after 4 hours' stirring, the crystals obtained are drained, crystals are taken up with distilled water (2000 cc); the mixture is heated to reflux with stirring for 15 minutes; the insoluble crystals are drained, washed with distilled water (2×100 cc) and dried. They are recrystallized in a mixture of acetonitrile (1100 cc) and distilled water (500 cc); the crystals obtained are drained, washed with acetonitrile (3×40 cc) and dried. (3aR,7aR)-7,7-Diphenylperhydro-4-isoindolone L-mandelate (80 g) is obtained; [α]D20 =-164° (c=1, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].C([O-])([O-])=O.[Na+].[Na+].C(N(CC)CC)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH:14]=[CH2:15])=[CH:5][CH:4]=1
Reactant: C=CC(=O)Cl
Reactant: COc1ccc(SCCN)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)NCCSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 1 (1.83 g) in EtOAc (50 mL) was added acryloyl chloride (1.35 g, 1.5 eq.) and Na2CO3 (2.12 g, 2.0 eq.). The reaction mixture was stirred at r.t. overnight and triethylamine was added. After stirring for 20 min, the mixture was washed with H2O (20 mL), 1N HCl (2×20 mL) and sat. NaHCO3 (2×20 mL). The solvents were removed by evaporation under reduced pressure to give product 32 as white solid (one spot on TLC). Yield: 2.2 g, 92.8%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+]>CC(O)=O.[Fe]>[CH:5]1[C:6]([Cl:11])=[C:7]([NH2:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(Cl)ccnc1Cl
Temperature: 40 °C

Procedure:
2.4-Dichloro-3-nitropyridine c (2.058 g, 10.7 mmol) was dissolved in HOAc (10 mL) under nitrogen. Iron powder (1.9191 g, 34.4 mmol) was added. The sample was heated at 40° C. for two hours. The reaction mixture was poured onto ice and then NaHCO3 was added to give a neutral solution. The sample was extracted with EtOAc (3×100 mL). The EtOAc extracts were washed with saturated NaHCO3 (1×100 mL). The combined aqueous layers were back extracted once with 100 mL EtOAc. The combined EtOAc extracts were dried over MgSO4, filtered, and concentrated to give 3-amino-2-4-dichloropyridine d (1.510 g, 9.26 mmol, 87%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([OH:28])([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)(O)CC(=O)O
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, light yellow solid (57 mg, 53%), MS (ISP) m/z=431.5 [(M+H)+], mp 139° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-hydroxy-3-methyl-butanoic acid.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[CH2:23]([NH:27][C:28](=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]1[CH2:56][C:55]2[CH:54]=[C:53]([O:57][CH3:58])[CH:52]=[CH:51][C:50]=2[C@@H:49]2[C@@H:40]1[C@H:41]1[C@@:45]([CH2:47][CH2:48]2)([CH3:46])[C@@H:44]([O:59]C2CCCCO2)[CH2:43][CH2:42]1)[CH2:24][CH2:25][CH3:26]>C1(C)C(C)=CC=CC=1>[CH2:23]([NH:27][C:28](=[S:10])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]1[CH2:56][C:55]2[CH:54]=[C:53]([O:57][CH3:58])[CH:52]=[CH:51][C:50]=2[C@@H:49]2[C@@H:40]1[C@H:41]1[C@@:45]([CH2:47][CH2:48]2)([CH3:46])[C@@H:44]([OH:59])[CH2:43][CH2:42]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCNC(=O)CCCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](OC4CCCCO4)CC[C@H]3[C@H]12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CCCCNC(=S)CCCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 130 °C

Procedure:
2,4-Bis-(p-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's Reagent; 0.375 g.) was added to a stirred solution of N-n-butyl-11-(3-methoxy-17β-tetrahydropyranyloxyoestra-1,3,5(10)-trien-7α-yl)undecanamide (0.25 g.) in xylene (14 ml.) and the mixture was stirred and heated at 130° C. for 5 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran (2 ml.), water (2 ml.) and acetic acid (4 ml.) and the solution was stirred at laboratory temperature for 16 hours and then evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained as an oil N-n-butyl-11-(17β-hydroxy-3-methoxyoestra-1,3,5(10)-trien-7α-yl)thioundecanamide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1n[nH]cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(Cc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Into a 100-mL 3-neck round-bottom flask, was placed a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (1.0 g, 6.5 mmol) in tetrahydrofuran (20 mL). The solution was cooled to 0° C., then sodium hydride (360 mg, 9.00 mmol, 60% dispersion in mineral oil) was added in portions and the mixture was stirred for 20 min. Benzyl bromide (904 μL, 7.60 mmol) was added at 0° C., then the resulting mixture was stirred for 1.5 h at room temperature. The reaction was carefully quenched with by drop-wise addition of water (35 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with of brine (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:20-1:2) as eluent to obtain the title compound as a yellow solid (1.0 g, 63%).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:28][C:27]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:27]2[N:28]=[C:29]([C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(C4(C)CCCCC4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the procedure of Example 74. 1H NMR (400 MHz, CDCl3) δ 7.16-7.13 (m, 3H), 6.79 (d, 2H, J=8.60 Hz), 6.61-6.59 (m, 1H), 6.51-6.48 (m, 1H), 6.46 (t, 1H, J=2.35 Hz), 4.13 (t, 2H, J=6.25 Hz), 3.75 (s, 3H), 3.24 (d, 1H, J=13.68 Hz), 3.12 (d, 1H, J=13.68 Hz), 2.96 (t, 2H, J=6.25 Hz), 2.30 (s, 3H), 2.15-2.08 (m, 2H), 1.61-1.45 (m, 5H), 1.44 (s, 3H), 1.43-1.36 (m, 3H), 1.30 (s, 3H); MS (ES+) calcd for C30H38NO6: Found m/e 508.3 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[F:19][C:20]1([F:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][C:20]([F:26])([F:19])[CH2:21][CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: FC1(F)CCNCC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CCC(F)(F)CC2)cc1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (90 mg, 0.318 mmol) in MeOH (3179 μL), 4,4-difluoropiperidine (115 mg, 0.95 mmol) was added. The reaction was allowed to stir at rt. When the reaction was complete, removed solvent and applied residue to Silica gel. Eluted with EtOAc/Hex to afford the desired 2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (80.8 mg, 0.220 mmol, 69.1% yield). LC-MS (M+H)+=368.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[C:25]=1[F:33].Cl.[OH-].[Na+]>C(O)C>[NH2:30][C:26]1[C:25]([F:33])=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:3]1[C:4]([C:18]([F:20])([F:21])[F:19])=[CH:5][C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:7][C:2]=1[Br:1])=[O:34]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 104.7 %

Procedure:
0.940 g (1.63 mmol) of N-(2-bromo-4-(heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-nitrobenzamide and 0.960 g (5.05 mmol) of stannous chloride (anhydrous) were added to 10 ml of ethanol, and 1.02 ml (9.78 mmol) of concentrated hydrochloric acid was added thereto, followed by stirring at 60° C. for 4 hours. The reaction mixture was adjusted to pH 10 by the addition of an aqueous sodium hydroxide solution, and the precipitated insolubles were removed by filtration using Celite. The filtrate on Celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with a 20% aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=4:1) to prepare 0.930 g (yield 99%) of a target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[O:17][CH2:18][CH:19]2[CH2:21][O:20]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:26][NH:27][CH3:28]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:27]([CH3:28])[CH3:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CNC
Reactant: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Solvent: C1CCOC1
Product: COc1cc(CCCCc2ccccc2OCC(O)CN(C)C)cc(OC)c1
Yield: 62 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 0.42 g of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran was treated with 2 ml of 50% by volume aqueous dimethylamine. After purification, 0.29 g (yield 62%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[CH2:7]([C:1]1[CH:6]=[CH:5][C:4]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of 1-phenyloctane (5.86 g, 30.8 mmol) in CHCl3 (50 mL) was added chlorosulfonic acid (17 mL, 29.8 g, 256 mmol) and the mixture was stirred at rt for 20 h. The mixture was poured on ice (200 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The yellow oily residue (ca 80% yield) was used without further purification in the next reaction; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7 Hz), 1.27-1.32 (m, 10H), 1.64-1.66 (m, 2H), 2.72 (t, 2H, J=8 Hz), 7.42 (d, 2H, J=8 Hz), 7.93 (d, 2H, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:14](=O)[CH3:15].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH2:14][CH3:15])[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCNc1cc(Br)cc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.09 mmol) and acetaldehyde (180 mg, 4.09 mmol) in dichloroethane (10 mL), acetic acid (1.47 g, 24.58 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (2.6 g, 12.29 mmol) was added at 0° C., allowed to attain room temperature and stirring continued for 2 h. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (600 mg, 55%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.CCCCCC.[Li].[C:18]1(=[N:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19]1.B(F)(F)F.CCOCC>O1CCCC1.C1(C)C=CC=CC=1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:18]2([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH2:21][CH2:20][CH2:19]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(CN=C2CCC2)cc1
Reactant: c1cscn1
Agent: FB(F)F
Agent: [Li]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CNC2(c3nccs3)CCC2)cc1
Temperature: 25 °C

Procedure:
A solution of thiazole (2.253 mL, 31.7 mmol) in anhydrous tetrahydrofuran (30 mL) at −78° C. was treated dropwise with 2.5M n-butyllithium in hexane (12.68 mL, 31.7 mmol) via an additional funnel while maintaining the reaction temperature below −70° C. The lithium species was stirred for about 10 minutes and added dropwise via cannula to a −78° C. solution of N-cyclobutylidene-1-(4-methoxyphenyl)methanamine (5.0 g, 26.4 mmol) and boron trifluoride diethyl etherate (6.70 mL, 52.8 mmol) in 4.0 molar anhydrous tetrahydrofuran in anhydrous toluene (100 mL). The reaction was stirred and allowed to warm to ambient temperature over 30 minutes. The reaction was quenched with saturated ammonium chloride, and product was extracted with ethyl acetate. The organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 10% to 20% ethyl acetate in hexanes, to provide the title compound. MS DCI(+) m/z 275.1 [M+H]+.