Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C>[CH3:21][NH:22][C:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:24]
Reactant: CN=C=O
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Solvent: CCN(CC)CC
Product: CNC(=O)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Yield: 91.6 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was reacted with methyl isocyanate (500 mg, 8.8 mmoles) in the presence of triethylamine in the same manner as Example 9 to give 1-methylaminocarbonyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (2.2 g) (Compound Id-24) as an oil. This compound forms a crystalline salt of oxalic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:16]1[C:24]2[N:23]=[C:22]([Cl:25])[NH:21][C:20]=2[C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[NH:34])[NH:32]O)[C:17]1=[O:35])[CH2:13][CH2:14][CH3:15]>CS(C)=O>[CH2:12]([N:16]1[C:24]2[N:23]=[C:22]([Cl:25])[NH:21][C:20]=2[C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[N:32]=[C:4]([C:3]3[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=3[F:1])[O:6][N:34]=2)[C:17]1=[O:35])[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CCCCn1c(=O)n(CCCCC(=N)NO)c(=O)c2[nH]c(Cl)nc21
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3ccc(O)cc3F)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
CDl (45 mg, 0.28 mmol) in anhydrous DMSO (0.5 ml) was added to 2-fluoro-4-hydroxybenzoic acid (40 mg, 0.25 mmol) and stirred at rt for 2 h. 5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) in DMSO (0.4 ml) was added and the resulting mixture heated at 90° C. for 18 h. Purification by MDAP afforded the title compound as a solid (38 mg, 28%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])(=[O:21])=[O:20])=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:30](N)[CH2:31][NH2:32].[S]>O>[Cl:29][C:23]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([CH2:18][NH:17][CH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:32][CH2:31][CH2:30][N:2]=2)=[CH:8][CH:7]=1)(=[O:21])=[O:20]
Reactant: NCCN
Reactant: N#Cc1ccc(CCC(=O)NCCCNCS(=O)(=O)c2cccc(Cl)c2Cl)cc1
Agent: [S]
Solvent: O
Product: O=C(CCc1ccc(C2=NCCN2)cc1)NCCCNCS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
A solution of 0.7 g (1.54 mmol) of 3-(4-cyanophenyl)-N-{3-[(2,3-dichloro-benzenesulphonyl)methylamino]propyl}propionamide, 3 ml of ethylenediamine and 0.10 g (3.12 mmol) of sulphur was stirred at 100° C. for 15 minutes. Water was then added, and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on alumina (mobile phase: dichloromethane/methanol 100:1) and then crystallized from ethyl acetate/diethyl ether.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:13])=[CH:8][CH:7]=2)([OH:3])=O.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:40][C@H:41]([C:49]1[O:53][CH:52]=[N:51][C:50]=1[C:54]([O:56][CH3:57])=[O:55])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([C:1]([NH:40][C@H:41]([C:49]1[O:53][CH:52]=[N:51][C:50]=1[C:54]([O:56][CH3:57])=[O:55])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:3])=[CH:12]2
Reactant: COC(=O)c1ncoc1[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ncoc1[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Carboxy-5-chloro-indole (146 mg, 0.75 mmol) was dissolved in DCM (5 ml) containing HOBT (126 mg, 0.93 mmol), DIPEA (290 mg, 2.25 mmol) and methyl (S)-5-(1-amino-2-phenylethyl)oxazole-4-carboxylate trifluoroacetate (Method 1; 360 mg, 0.75 mmol). EDAC (178 mg, 0.93 mmol) was added and the mixture stirred at ambient temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (30 ml), washed with dilute citric acid, water and brine, dried over magnesium sulphate and concentrated. The crude material was purified by trituration with diethyl ether to give the title compound as a white solid. (227 mg, 65%)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CS(C)=O.Br[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=1>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:47]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Cc2ccc(C(F)(F)F)cc2)c2ccc3c(c2)OCO3)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 28.5 %

Procedure:
To a suspension of 0.992 g (0.27 mmol) of the product of Example 1 in 0.5 mL of anhydrous THF was added 825 μL (0.82 mmol) of a 1.0M solution of lithium bis(trimethylsilyl)amide in THF at -78° C. under a nitrogen atmosphere. After stirring at -78° C. for 10 minutes, the starting material had not fully dissolved. The reaction mixture was then warmed to 0° C. (ice-water bath) and 300 μL of DMSO was added which resulted in a clear yellow solution, then 0.131 g (0.55 mmol) of α'-bromo-α,α,α-trifluoro-p-xylene was added as a solid. Stirring was maintained for 1 hour, then the reaction mixture was partitioned between EtOAc and water and extracted. The organic layer was washed with saturated brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 2.5% MeOH--CHCl3. Evaporation of the product fractions and drying in vacuo afforded 0.040 g (28%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:58][N:59]2[CH:63]=[N:62][CH:61]=[N:60]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:56])[CH:40]([NH:42][CH:43]6[CH2:48][CH2:47][N:46]([CH2:49]C7C=CC=CC=7)[CH2:45][CH2:44]6)[CH3:41])[C:35]5=[O:57])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.C=O.S1C=CC=C1>C1COCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:58][N:59]2[CH:63]=[N:62][CH:61]=[N:60]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:56])[CH:40]([NH:42][CH:43]6[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]6)[CH3:41])[C:35]5=[O:57])=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1
Reactant: CC(NC1CCN(Cc2ccccc2)CC1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Agent: [Pd]
Agent: C=O
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: CC(NC1CCN(C)CC1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O

Procedure:
A mixture of [2S-[2α,4α(R*,S*)]]+[2S-[2α,4α(S*,R*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (0.006 mol) in THF (250 ml) was hydrogenated for 3 days with Pd on activated carbon 10% (2 g) as a catalyst. Then paraformaldehyde (0.006 mol) and thiophene solution 4% (2 ml) were added. Hydrogenation was continued at 50° C. After uptake of H2, the mixture was cooled. The catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried, yielding 3.2 g (68%) of [2S-[2α,4α(R*,S*)]]+[2S-[2α,4α(S*,R*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(1-methyl-4-piperidinyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (compound 64).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Mg]Cl.Cl>O1CCCC1>[O:6]=[C:5]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH3:9])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)CCCC(=O)O
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of glutaric anhydride (22.82 g) in dry tetrahydrofuran (300 mL) at −78° C. is treated with a solution of 2-methylphenyl magnesium chloride in tetrahydrofuran (200 mL, 0.1 M) over 45 minutes. The mixture is stirred at −78° C. for 2.5 hours and the grey suspension is poured into 1 N hydrochloric acid (300 mL). The mixture is extracted with ethyl acetate (300 mL). The organic phase is dried over magnesium sulphate and evaporated to give 5-oxo-5-(2-methylphenyl)pentanoic acid (36.74 g) as a red-brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[ClH:21].O1CCOCC1>>[ClH:21].[NH2:13][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:10][CH2:11][OH:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](CCO)Cc1ccc(Br)cc1
Reaction time: 2 h
Yield: 94 %

Procedure:
1,1-Dimethylethyl {(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}carbamate (4.4 g, 12.8 mmol) was dissolved in 4N HCl/dioxane (20 mL). After 2 h, the reaction mixture was concentrated in vacuo to give 3.69 g (94%) of the title compound as a white solid. LC/MS (ES) m/e 244.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].N1CCOCC1>O1CCCC1.C(OCC)C>[C:29]1([O:28][C:26](=[O:27])[NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
2-Amino-4-(4-nitrophenoxy)pyridine (600 mg) was dissolved in tetrahydrofuran (12 ml) under a nitrogen atmosphere, and then triethylamine (1.09 ml) and phenyl chloroformate (0.979 ml) were added dropwise thereto, followed by stirring for 20 min. To the reaction mixture was added morpholine (1.81 ml), followed by stirring for 25 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then suspended in diethyl ether. The solid was filtered off, and dried under aeration to provide the titled compound (854 mg, 93.8%) as a brown solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH2:14])[C:8]([OH:21])=[C:7]([CH3:22])[C:6]=1[CH3:23])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[I:29](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1.CO>[C:1]([O:4][C:5]1[C:6]([CH3:23])=[C:7]([CH3:22])[C:8]2[O:21][CH:13]([CH2:14][I:29])[CH:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]=2[C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: O=I(=O)Cl
Reactant: C=CC(c1ccccc1)c1c(C)c(OC(C)=O)c(C)c(C)c1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(c1ccccc1)C(CI)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a suspension of 4-hydroxy-2,3,6-trimethyl-5-(1-phenyl-2-propenyl)phenyl acetate (5.10 g, 16.4 mmol) and calcium carbonate (2.13 g, 21.3 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added benzyltrimethylammonium dichloroiodate (6.28 g, 18.0 mmol) slowly. The mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with 10% aqueous sodium hydrogen sulfite, water, an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, treated with activated carbon, filtrated and the filtrate was concentrated in vacuo to provide 5.30 g of 2-iodomethyl-4,6,7-trimethyl-3-phenyl-2,3-dihydrobenzofuran-5-yl acetate. A mixture of this compound (5.30 g, 12.1 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (9.0 m, 60.0 mmol) in toluene (20 mL) was stirred under an argon atmosphere at 100° C. for 3 hours. To that mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with 2N hydrochloric acid, and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain the title compound (4.0 g, yield 79%). This was oily.
Reaction SMILES: C[O:2][C:3]([C:5]1([N:8]2[C:12]3[N:13]=[CH:14][N:15]=[CH:16][C:11]=3[CH:10]=[CH:9]2)[CH2:7][CH2:6]1)=O.[BH4-].[Na+]>C(O)C>[N:13]1[C:12]2[N:8]([C:5]3([CH2:3][OH:2])[CH2:6][CH2:7]3)[CH:9]=[CH:10][C:11]=2[CH:16]=[N:15][CH:14]=1
Reactant: COC(=O)C1(n2ccc3cncnc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC1(n2ccc3cncnc32)CC1
Yield: 47 %

Procedure:
To a stirred solution of 1-Pyrrolo[2,3-d]pyrimidin-7-yl-cyclopropanecarboxylic acid methyl ester (Preparation 246, 610 mg, 2.80 mmol) in ethanol (15 mL) was added sodium borohydride (318.7 mg, 8.42 mmol) and the mixture heated to reflux for 16 hours. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM:methanol 100:0 to 98:2) to afford the title compound as a light yellow solid in 47% yield, 250 mg.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH:17](OCC)=[O:18].Cl>C1C=CC=CC=1.C[O-].[Na+].CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]([CH:17]=[O:18])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: C[O-]
Agent: Cl
Agent: [H-]
Solvent: c1ccccc1
Solvent: CO
Product: CC1(C)CC(C=O)C(=O)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A solution of 7-bromo-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydronaphthalene (2.0 g, 7.9 mmol) in benzene (34 ml) was added to a cold (0° C.) suspension of sodium hydride (60% in oil, 2.28 g, 57 mmol) and sodium methoxide (24 mgs) in benzene (34 ml). Ethyl formate (2.74 ml, 33.9 mmol) was then added dropwise and the mixture was stirred at 0° C. for 2 hours and then at room temperature for 3 hours. Wet methanol was then added and the aqueous phase was acidified with 4M hydrochloric acid and extracted with ethyl acetate (3×). The combined organic phases were washed with 2M sodium carbonate and the sodium carbonate phases were combined, acidified and reextracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel chromatography (ethyl acetate/hexane 10:90) to give the title material (2.1 g, 95%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]([N:29]4[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]4)=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Reactant: OC1CCNCC1
Product: O=C(N1CCC(O)CC1)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Yield: 16 %

Procedure:
The title compound (200 mg, 16%) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarboxylic acid and 4-hydroxypiperidine similarly to the procedure used for example 149. HRMS ESI+ m/z 415.2943 [MH]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:14][N:15](CCO)[CH3:16]>>[N:1]1([CH2:6][C:7]([O:9][CH2:10][CH2:11][N:15]([CH3:16])[CH3:14])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCCC1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOC(=O)CN1CCCC1
Temperature: 150 °C

Procedure:
To a mixture of 80 g (0.51 mol) of ethyl 1-pyrrolidineacetate and 0.5 g of sodium hydride (in the form of a 60% by weight suspension in mineral oil) was added 48 g (0.54 mol) of 2-(N,N-dimethylamino)ethanol. The mixture was purged with nitrogen gas, heated gradually and then maintained at about 150° C. while collecting the ethanol by-product in a Dean-Stark trap. The liquid reaction product was distilled at 85° C. at a pressure of 100 μmHg to provide 2-(N,N-dimethylamino)-ethyl 1-pyrrolidineacetate. The structure of the product was confirmed by nuclear magnetic resonance and infrared spectral analysis.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29]([C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=4)=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29]([C:31]4[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=4)=[O:30])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)N2CC[C@@H]3[C@H](c4ccccc4)Nc4ccccc4[C@@H]32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)N2CC[C@@H]3[C@H](c4ccccc4)Nc4ccccc4[C@@H]32)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of methyl 4-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)amino]carbonyl}benzoate (77 mg, 0.14 mmol) in tetrahydrofuran (4 ml) and methanol (1 ml) was added 2N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at 60° C. for 16 hrs. The reaction mixture was neutralized (pH 7) by adding 3N hydrochloric acid under ice-cooling. The mixture was concentrated under reduced pressure and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (2:1, v/v). The extract was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The obtained solid was washed with isopropyl ether-hexane (1:2, v/v) to give the title compound (51 mg, 68%) as a white solid.
Reaction SMILES: Br/[CH:2]=[CH:3]/[C:4]([CH3:16])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:5].CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[CH3:16][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:2]
Reactant: CC(C)(/C=C/Br)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 40.9 grams (0.14 mole) of cis/trans-1-bromo-3-methyl-3-(4-trifluoromethylphenyl)-1-butene and 47.0 grams (0.42 mole) of potassium tert.-butoxide in 300 mL of tert.-butanol was heated at reflux for about three hours. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. The reaction mixture was then poured into 300 mL of water and extracted with one 200 mL portion of diethyl ether. The extract was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel using petroleum ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 25.2 grams of 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne. The NMR spectrum was consistent with the proposed structure.