Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].[Mg].II.BrCBr.[Br-].[Li+].N1C=CC=NC1=O.[F:23][C@H:24]1[CH2:41][C@@:39]2([CH3:40])[C@@H:35]([CH2:36][CH2:37][C:38]2=[O:42])[C@H:34]2[C@H:25]1[C@@H:26]1[C:31]([CH:32]=[CH:33]2)=[CH:30][C:29](=[O:43])[CH2:28][CH2:27]1>C1COCC1.CN1CCCN(C)C1=O.C[Si](C)(C)Cl.[Cu]I.C(O)(=O)C>[Cl:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C@@H:33]1[CH2:32][C:31]2[C@H:26]([CH2:27][CH2:28][C:29](=[O:43])[CH:30]=2)[C@@H:25]2[C@@H:34]1[C@H:35]1[C@@:39]([CH2:41][C@@H:24]2[F:23])([CH3:40])[C:38](=[O:42])[CH2:37][CH2:36]1
Reactant: ClCCCCCBr
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: II
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN1CCCN(C)C1=O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
First, 20% of a solution of 39 ml of 1-bromo-5-chloropentane in 300 ml of THF is added to a suspension of 7.2 g of magnesium chips in 100 ml of THF under nitrogen. After the reaction starts, which can be achieved by adding iodine and dibromomethane, the remaining solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 51.2 g of lithium bromide is added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-1H)-pyrimidin-2-one is now added and stirred for 15 minutes at 40° C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -50° C. Then, it is stirred for 15 more minutes at -30° C. and mixed at -70° C. drop by drop with a solution of 25 g of 11β-fluoro-estra-4,6-diene-3,17-dione in 260 ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 59 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -65° C. It is stirred for 30 minutes cold, then 34.7 ml of glacial acetic acid is added in drops, the cooling bath is removed, and it is stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.51 of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 22.1 g of 7α-(5-chloropentyl)-11β-fluoro-estr-4-ene-3,17-dione is obtained.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:29][CH:28]=3)=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)C=C.CCN([C:46]1[CH:47]=CC=C[CH:51]=1)CC>>[OH:4][C:5]1[C:14]([CH2:47][CH:46]=[CH2:51])=[C:13]2[C:8]([C:9]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:31][CH:32]=3)=[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Product: C=CCc1c(O)ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc12
Temperature: 190 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
7-Prop-2-enyloxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl) Phenyl)-2H-chromen-2-one (0.150 g.) was dissolved in diethylaniline (4 mL) and allowed to stir at 190° C. for two hours. The resultant solution was extracted with methylene chloride (3×) and 1M hydrochloric acid. The organic layers were dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure to afford a crude brown solid. The solid was purified via preparative-HPLC (40–100% acetonitrile/water, 20 mL/min.) to afford the title compound (0.027 g, 18% yield). 1H-NMR (CDCl3) δ 7.63 (d, 2H), 7.38 (d, 2H), 7.25 (d, 1H), 6.92 (d, 2H), 6.75 (d, 2H), 6.70 (d, 1H), 6.0 (m, 1H), 5.13 (dd, 2H), 4.12 (t, 2H), 3.94 (s, 2H), 3.66 (d, 2H), 3.05 (bs, 2H), 2.8 (bs, 4H), 1.25 (s, 2H). MS (m/z) 550 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:38]=[CH:37][C:17]([O:18][CH:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[C:26]([O:34][CH2:35][CH3:36])[CH:25]=2)[C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:38]=[CH:37][C:17]([O:18][CH:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:32])[CH3:33])=[C:26]([O:34][CH2:35][CH3:36])[CH:25]=2)[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(Oc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(Oc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To 9D (570 mg, 1.09 mmol) in THF (6.0 mL) and MeOH (0.5 mL) was added LiOH (1.0 M, 1.92 mL, 1.92 mmol). The mixture was stirred at rt for 1.0 h before it was acidified with 1.0 N HCl (5.0 mL). The mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. After removal of solvent, 9E (500 mg, 90% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.16 Hz, 6H) 1.30 (t, J=7.03 Hz, 3H) 4.00 (q, J=7.03 Hz, 2H) 4.49 (m, 1H) 5.09 (s, 2H) 5.85 (s, 1H) 6.90-7.38 (m, 11H) 7.95 (d, J=9.20 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17].C(=O)=O.[OH-].[K+]>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Temperature: -30 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (500 mg, 2.3 mmol) in dry CH3CN (40 mL) was added 2-amino-N-methylbenzamide (350 mg, 2.3 mmol) at room temperature. The reaction mixture was cooled to −30° C. using dry ice. Powdered KOH (1.0 g, 17.8 mmol) was added and the reaction mixture was stirred at −30° C. for 1 h, and then warmed to −10° C. to −5° C. and stirred for another 2 h, then quenched with water (200 mL). The mixture was extracted with EtOAc (3×100 mL), the combined organic layer was dried over MgSO4, concentrated, and residue was purified by column chromatography to give 213 mg of the title compound (yield: 28%). 1H NMR (DMSO, 400 MHz): δ=2.75 (d, J=4.4 Hz, 3 H), 7.20-7.24 (m, 1 H), 7.53-7.58 (m, 1 H), 7.74 (dd, J=2.0, 8.0 Hz, 1 H), 8.33 (dd, J=1.2, 8.4 Hz, 1 H), 8.85 (s, br, 1 H), 12.0 (s, br, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][CH2:10]1)C.C1COCC1.[OH-].[Li+]>CO.O>[C:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])[CH2:14][CH2:13]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)CCCCN1CCN(CCCCNC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCN1CCN(CCCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-[4-(4-tert-butoxycarbonylaminobutyl)piperazin-1-yl]pentanoic acid ethyl ester (18) (1.62 g, 4.20 mmol) in methanol (12 mL)/THF (10 mL) was added a solution of lithium hydroxide (0.35 g, 8.40 mmol) in water (4 mL). The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo. The resulting residue was diluted with water (5 mL) and acidified to pH ˜5 with 1 N aqueous HCl. The aqueous solution was extracted with chloroform/2-propanol (3:1, 3×10 mL). The combined extracts were concentrated under vacuum to dryness. The resulting residue was further co-evaporated with toluene and dried under high vacuum to give the desired acid 19 as a colorless, thick oil (1.42 g, 95%): 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.63 (m, 8H), 2.30 (m, 2H), 2.58 (m, 2H), 2.68 (m, 2H), 2.92 (m, 8H), 3.12 (m, 2H), 4.92 (br, 1H); ESI MS m/z 358 [C18H35N3O4+H]+.
Reaction SMILES: CC1(C)CCN(C2C=CC(SC(F)(F)F)=CC=2)C(=O)N1CC1C2C(=NC=CC=2)NC=1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34].[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[O:48])=[CH:42][CH:41]=1>>[OH:34][CH2:33][C:32]([NH:31][C:47]([NH:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][C:38]([F:37])([F:49])[F:50])=[CH:41][CH:42]=1)=[O:48])([CH3:36])[CH3:35]
Reactant: CC(C)(N)CO
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1c[nH]c2ncccc12
Product: CC(C)(CO)NC(=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
1-(1-hydroxy-2-methylpropan-2-yl)-3-[4-(trifluoromethoxy)phenyl]urea was prepared similar to compound 5, but the following reagents were used: 2-amino-2-methyl-1-propanol and 4-(trifluoromethoxy)phenylisocyanate. LCMS [M+H]+=293.1.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7]OCC1N=CNC=1)=[S:4].N[C:16]1[S:17][C:18]([CH2:21]O)=NN=1>>[CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:16][S:17][CH2:18][C:21]1[N:5]=[CH:3][NH:2][CH:1]=1)=[S:4]
Reactant: Nc1nnc(CO)s1
Reactant: CNC(=S)NCCOCc1c[nH]cn1
Product: CNC(=S)NCCCSCc1c[nH]cn1

Procedure:
By the method of Example 58 (i) and (ii) 4(5)-hydroxymethylimidazole was converted first to the intermediate 4(5)-[(3-aminopropyl)thiomethyl]-imidazole dihydrobromide and thence to the title compound (m.p. 118°-120° C, after recrystallisation from water).
Reaction SMILES: [H-].[Na+].[C:3](OC)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[C:16]1([CH2:22][CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[OH:6][C:5]1[CH2:7][C:24]([CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:33][C:3](=[O:8])[CH:4]=1
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccccc2)(CCc2ccccc2)O1
Reaction time: 0.17 h

Procedure:
Freshly distilled THF (25 mL) was cooled in an ice bath under a nitrogen atmosphere, then charged with 660 mg (16.5 mmol) sodium hydride (60% dispersion). This suspension was treated with 1.89 g (16.3 mmol) methyl acetoacetate dropwise, and the reaction was stirred for 10 minutes. n-Butyllithium (10.3 mL of 1.6M in hexanes; 16.5 mmol) was dripped in and the reaction was stirred 30 minutes. At this time 3.10 g (13 mmol) of 1,5-diphenyl-3-pentanone (Ram and Spicer, Tetrahedrom Lett., 1988, 29 (31), 3741) in 20 mL THF was added dropwise over 15 minutes. After 4 hours 100 mL H2O was added and the reaction stirred overnight. The reaction was extracted with diethyl ether, and the organics set aside. The aqueous layer was chilled, treated with 50% HOAc until a precipitate formed, and then extracted with EtOAc. These organics were washed with saturated brine, dried (Na2SO4), and concentrated. 1H NMR (DMSO-d6) δ 2.0 (d of d, 4 H), 2.65 (m, 6 H), 5.0 (s, 1 H), 7.15-7.35 (m, 10 H), 11.4 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][O:27][NH2:28])=[CH:24][CH:23]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:28][O:27][CH2:26][C:25]2[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:17][CH3:18])[CH:3]=1
Reactant: NOCc1ccc(Cl)cc1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOCc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 0.1 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (1.75 g, 5.54 mmol), O-(4-chlorobenzyl)hydroxylamine hydrochloride (1.13 g, 5.82 mmol) and anhydrous NaOAc (477 mg, 5.82 mmol) in EtOH (80 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-{4-chloro-2-[1-(4-chlorobenzyloxyimino)propyl]phenyl}trifluoromethanesulfonamide 11 (1.74 mg, 69%), as a white solid. M.p. 54-55° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.55, br s, 1H, 7.63, d, J=8.8 Hz, 1H, 7.47, d, J=2.2 Hz, 1H, 7.39-7.29, m, 5H; 5.17, s, 2H, 2.84, q, J=7.6 Hz, 2H, 1.18, t, J=7.6 Hz, 3H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.[H-].[Na+].[C:13]([O:17][C:18](=[O:56])[CH:19]([N:24]1[C:30](=[O:31])[CH:29]([NH:32][C:33](=[O:51])[CH:34](Br)[CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])[CH2:28][C:27]2[CH:52]=[CH:53][CH:54]=[CH:55][C:26]=2[CH2:25]1)[CH2:20][CH:21]([CH3:23])[CH3:22])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]([O:17][C:18](=[O:56])[CH:19]([N:24]1[C:30](=[O:31])[CH:29]([NH:32][C:33](=[O:51])[CH:34]([S:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:40](=[O:49])[C:41]3=[CH:48][CH:47]=[CH:46][CH:45]=[C:42]3[C:43]2=[O:44])[CH2:28][C:27]2[CH:52]=[CH:53][CH:54]=[CH:55][C:26]=2[CH2:25]1)[CH2:20][CH:21]([CH3:23])[CH3:22])([CH3:15])([CH3:16])[CH3:14]
Reactant: COc1ccc(CS)cc1
Reactant: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(NC(=O)C(Br)CCCCN2C(=O)c3ccccc3C2=O)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(CSC(CCCCN2C(=O)c3ccccc3C2=O)C(=O)NC2Cc3ccccc3CN(C(CC(C)C)C(=O)OC(C)(C)C)C2=O)cc1
Reaction time: 1 h

Procedure:
Combine p-methoxybenzylmercaptan (0.08 mL, 0.57 mmol) and-sodium hydride (17 mg, 60% oil dispersion, 0.42 mmol) in degassed dimethylformamide (3 mL). After 1 hour, tetra-n-butylammonium iodide (about 5 mg) and 2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid t-butyl ester (0.27 mmol). After 20 hours, quench be the addition of a saturated aqueous ammonium chloride solution and dilute with water (about 5 mL). Extract with ethyl acetate (about 75 mL). Separate the layers and extract the orgainc layer with brine, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].CN1CCCC1=O.[H-].[Na+].Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33]>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:22]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[O:23][CH2:18][CH2:19][CH2:20]1)=[O:33]
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C)CCCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Reaction time: 0.08 h
Yield: 69.3 %

Procedure:
3-Dimethylamino-propan-1-ol (346 uL, 2.92 mmol) was dissolved in N-methylpyrrolidinone (25.0 mL, 259 mmol) and sodium hydride 60% dispersion in mineral oil (93.5 mg) was added. The reaction was stirred for 5 minutes and then 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one (500 mg, 1.95 mmol) was added. The reaction was stirred at room temperature for 4 hours and then partitioned between ethyl ether (100 mL) and water (50 mL). The layers were separated and the organic layer was washed twice with water (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 3-nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester as a yellow oil (437 mg, 69%). LCMS (m/e) 324 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89-7.80 (m, 2H), 7.53-7.36 (m, 1H), 4.29-4.17 (m, 4H), 3.89-3.77 (m, 2H), 2.39-2.08 (m, 4H), 2.19 (s, 6H), 1.88-1.73 (m, 2H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(-c2csc(Br)n2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Yield: 25 %

Procedure:
A solution of 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole (6.89 g, 22.3 mmol), tert-butyl piperazine-1-carboxylate (8.31 g, 44.6 mmol) and potassium carbonate (3.08 g, 22.3 mmol) in dimethylformamide (70 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.31 g (25.0%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([C:5](=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[O:7])[CH2:2][CH2:3][CH3:4].[C:14](#[N:17])[CH:15]=[CH2:16]>>[C:14]([CH2:15][CH2:16][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[O:7])#[N:17]
Reactant: CCCCCC=C(C=O)CCCC
Reactant: C=CC#N
Product: CCCCC=CC(C=O)(CCC#N)CCCC

Procedure:
2-(Beta-cyanoethyl)-2-butyl-3- octenal was prepared from 2-butyl-2-octenal and acrylonitrile analogously to the preparation of 2-(beta-cyanoethyl)2-methylpentanal as described in Example 1. Yield 38% of the product boiling at 143°-148° C. at 0.6 mm.; nD20 1.4754. Saponification and reduction as described in Example 1 gave γ-butyl-γ-1-hexenyl-δ-valerolactone boiling at 125°-127° C. at 0.4 mm. Yield 54%; nD20 1.4754. Odor description: fatty, greenishlike butyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-])=O)=[C:5]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)[CH:4]=1.CO>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:4]=1
Reactant: COc1cc(C2=CC(C)(C)CC(C)(C)C2)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)c(C2CC(C)(C)CC(C)(C)C2)cc1OC
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 4,5-dimethoxy-1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1.0 g, 3.13 mmol) produced in Example (87b), 10% palladium on carbon (500 mg, wet), methanol (8 mL) and tetrahydrofuran (2 mL) was stirred for 13 hours at room temperature and atmospheric pressure under a hydrogen atmosphere. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. A crude product of the title compound was obtained as a yellow oil. The crude product was used without purification for the following reaction.
Reaction SMILES: [CH2:1]([C:3]1([N:16]2[CH2:25][C:24]3=[CH:26][NH:27][C:22]4[C:23]3=[C:18]([CH:19]=[CH:20][N:21]=4)[C:17]2=[O:28])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:1]([C:3]1([N:16]2[CH2:25][C:24]3=[CH:26][NH:27][C:22]4[C:23]3=[C:18]([CH:19]=[CH:20][N:21]=4)[C:17]2=[O:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
tert-Butyl 4-ethyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate (50 mg, 0.124 mmol), HATU (94 mg, 0.248 mmol), and 4-dimethylaminopyridine (46 mg, 0.373 mmol) were stirred in DMF (3 mL) at room temperature for 1 h. The solution was concentrated in vacuo and dissolved in DCM (3 mL) and TFA (1 mL) and allowed to stir at room temperature for 1 h. The solution was concentrated in vacuo and was purified via preparative HPLC 10% to 30% B in A and gave 28 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.36 (m, 1H), 7.27 (m, 1H), 5.04 (s, 2H), 3.22-3.34 (m, 2H), 3.19-3.21 (m, 2H), 2.95-2.98 (m, 2H), 2.13-2.23 (m, 4H), 0.97 (t, 3H, J=7.6 Hz). [M+H] found 285.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=2)[CH:10]=[C:9]([CH3:33])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].I[CH3:37]>CN(C=O)C>[CH3:37][O:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=2)[CH:10]=[C:9]([CH3:33])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CI
Reactant: CCOC(=O)c1c(C)cc(OCc2cccc(OCc3ccc4ccccc4n3)c2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(OCc2cccc(OCc3ccc4ccccc4n3)c2)cc1OC
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-hydroxy-6-methyl-4-[3-(quinolin-2-ylmethoxy)-benzyloxy]-benzoate (150 mg, 0.34 mmol, example 65) in DMF (5 mL) is added sodium hydride (60%, 14 mg, 0.34 mmol) and the reaction is stirred 20 min. Iodomethane (0.03 mL, 0.5 mmol) is added and the reaction is heated at 50° C. for 7 h. The reaction is concentrated in vacuo and the residue is partioned between dichloromethane and aqueous ammonium chloride. The water layer is back-extracted with dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered and concentrated to yield crude product. The residue is purified by column chromatography (silica, 10 to 20% ethyl acetate in hexanes to provide the title compound; MS (ESI) 458 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][C:16]([CH2:20][OH:21])([CH3:19])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH3:29]>>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][C:16]([CH2:20][OH:21])([CH3:19])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: Cn1c(CN2CCC(C)(CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C)(CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, (1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-4-methylpiperidin-4-yl)methanol and 2-ethyl-1H-benzo[d]imidazole were reacted to give 385. LCMS m/z: 505.3 (MH+)