Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([CH3:19])[C:9]=1[C:10]([NH2:12])=[O:11].[CH3:20][N:21]([CH3:35])[CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([C:29]#N)=[CH:27][C:26]=1[CH3:34]>C1COCC1>[CH3:20][N:21]([CH3:35])[CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([C:29]2[NH:12][C:10](=[O:11])[C:9]3[C:13]([CH:19]=2)=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=3[O:7][CH3:6])=[CH:27][C:26]=1[CH3:34]
Reactant: COc1cc(C)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C#N)cc(C)c1OCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN(C)C)c(C)c3)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.9 %

Procedure:
n-Butyl lithium (4.2 mL, 10.54 mmol, 2.5 M solution in hexane) was added slowly to a solution of 2,4-dimethoxy-6-methyl benzamide (958 mg, 4.58 mmol) in THF (30 mL) under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. After completion of the addition, the mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-(2-dimethylamino ethoxy)-3,5-dimethyl benzonitrile (1.1 g, 5.04 mmol) (the B-ring building block) in THF (10 mL) was added quickly. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 16 h at room temperature. A saturated NH4Cl solution was added with cooling and the layers' were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give crude product. The crude product was purified by chromatography to give 3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (162 mg, 8%) as a hydrochloride. Selected data: MS (ES) m/z: 397.06; MP 261-263° C. at decomposition (HCl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=O)=[C:4]([F:15])[CH:3]=1.[NH:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH2:17].C(O)(=O)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:17][NH:16][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(c1ccc(Br)cc1F)C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C(c1ccc(Br)cc1F)C1CCOC1
Yield: 91.3 %

Procedure:
A mixture of ((4-bromo-2-fluorophenyl)(tetrahydro-3-furanyl)methanone (Intermediate 7, 850 mg) 1,1-dimethylethyl hydrazinecarboxylate (616 mg) and acetic acid (1 mL) in methanol (5 mL) was stirred at reflux under nitrogen for 20 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with sodium bicarbonate (1M, 10 mL), dried using a hydrophobic filter tube and concentrated under vacuum to give the title compound as a brown oil (1.1 g).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:33][C:32]([F:34])([F:35])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24][N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7]
Reactant: CN1CCNCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCCO)CN2c1ccccc1
Product: CN1CCN(CCCN2CN(c3ccccc3)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)CC1

Procedure:
The title compound, MS: m/e=612.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy-propyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-methylpiperazine.
Reaction SMILES: [OH-:1].[Na+].[C:3]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]3[C:15]=2[CH2:16][CH2:17][C@H:18]3[O:24][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)=[C:9]([CH3:39])[CH:8]=1)#N.[CH3:40][OH:41]>>[F:23][C:20]1[CH:21]=[CH:22][C:14]([C:10]2[C:9]([CH3:39])=[CH:8][C:7]([O:6][CH2:5][C:3]([O:41][CH3:40])=[O:1])=[CH:12][C:11]=2[CH3:13])=[C:15]2[C:19]=1[C@H:18]([O:24][C:25]1[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=1)[CH2:17][CH2:16]2
Reactant: CO
Reactant: [OH-]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC#N)cc5C)ccc(F)c43)ccc21
Agent: [Na+]
Product: COC(=O)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 1 M aqueous NaOH solution (400 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(4-(cyanomethoxy)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (120 mg) in methanol (4 mL). The mixture is stirred for 12 hours at room temperature. Methanol is evaporated off in vacuo and the residue is diluted with water. 1 M hydrochloric acid (400 μL) is added and the aqueous phase is extracted twice with dichloromethane The combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (petrole ether/ethyl acetate 60:40→0:100). The product thus obtained is crystallized from n-hexane to give the title compound. Yield: 75 mg; LC (method 7): tR=0.99 min; Mass spectrum (ESI+): m/z=521 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].N12CCCN=C1CCCC[CH2:13]2.IC.C(OCC)(=O)C>C(#N)C>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:13])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CI
Product: C=Cc1ccc(C(=O)OC)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-vinylbenzoic acid (Aldrich, 2.18 g, 14.7 mmol) in anhydrous acetonitrile (14.0 mL) was added 1.8-diazabicyclo [5.4.0]undec-7-ene (Aldrich, 2.46 g, 16.2 mmol) and iodomethane (Aldrich, 3.13g, 22.1 mmol) at 0° C. The reaction mixture was then warmed to room temperatue and allowed to stir for 3 h. Ethyl acetate (100 mL) was added to the mixture and the solution was washed with brine (50 mL). The organic phase was then separated and concentrated in vacuo. The residue was chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to give 1.05 g (Y: 44%) of the title product. 1H-NMR (CDCl3): δ8.00 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.76 (m, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.38 (d, J=11.0 Hz, 1H), 3.91 (s, 3H); MS (DCI)m/e: 163 (MH+).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([N:10]=[C:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: S=C(Nc1ccccc1)NC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C(=Nc1ccccc1)=NC1CCCCC1
Yield: 99.3 %

Procedure:
A solution containing 2.0 g (8.55 mmol) of N-cyclohexyl-N'-phenylthiourea, 2.9 g (11.1 mmol) of triphenyl phosphine and 1.16 cm3 (12 mmol) of carbon tetrachloride in 12 cm3 of methylene chloride, is treated with 1.19 cm3 (8.55 mmol) of triethylamine. The solution is heated for 2 hours, the precipitate which forms is eliminated by filtration and the filtrate is concentrated to dryness. The residue obtained is extracted with hexane and then filtered. The filtrates are then concentrated to dryness and 1.7 g (yield 100%) of the desired carbodiimide is obtained in the form of an oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:24]1([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:6][CH:7]=2)=[C:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(C(=C(c2ccccc2)c2ccc(OCCBr)cc2)C(F)(F)F)cc1
Product: Fc1ccc(C(=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2)C(F)(F)F)cc1
Yield: 75.7 %

Procedure:
3.25 g (7 mmoles) of 1-[4-(2-bromoethoxy)-phenyl]-1-phenyl-3,3,3-trifluoro-2-(4-fluorophenyl)-propene, prepared as described in Example 15, are reacted with morpholine as described in Example 1. The product is crystallized from hexane. 2.5 g (75.7%) of the aimed compound are obtained; m.p.: 67°-69° C.
Reaction SMILES: C(#N)CC.[OH-:5].[Ca+2:6].[OH-].O.[C:9](N)(=[O:12])[CH2:10][CH3:11]>>[C:9]([O-:12])(=[O:5])[CH2:10][CH3:11].[Ca+2:6].[C:9]([O-:12])(=[O:5])[CH2:10][CH3:11]
Reactant: [OH-]
Reactant: CCC(N)=O
Agent: [Ca+2]
Solvent: CCC#N
Solvent: O
Product: CCC(=O)[O-]
Temperature: 200 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Propionitrile (311.5 g, 5.66 mol, supplied by Solutia Inc., refined: 99.6% min) was charged into a one gallon 316 stainless steel autoclave through a funnel. Calcium hydroxide (229.3 g, 3.09 mol, supplied by Mississippi Lime, CODEX Hydrated Lime), and deionized water (1007.2 g, 55.9 mol) were mixed to produce a slurry and charged to the autoclave through the same funnel. A second portion of deionized water (345.1 g, 19.2 mol) was used to rinse the calcium hydroxide slurry container and was charged to the autoclave through the funnel. The autoclave was pressurized with nitrogen to 45-55 psig (310.3-379.2 KPa), and the pressure relieved to under 25 psig (172.4 KPa). This cycle was repeated two additional times to purge most of the air from the system. The pressure control valve was set to 260 psig (1792.6 KPa), and a nitrogen flow (100 std cm3/min) through the reactor vapor space was started. The autoclave agitator was started and the contents were heated to 200° C. with a mixture of steam and water under pressure in an internal coil. After the autoclave contents had been at 200° C. for one hour, the nitrogen flow was increased to 200 cm3/min to improve the control of the autoclave pressure. After the autoclave contents had been at 200° C. for a total of two hours, the steam was turned off and the reactor pressure was released through a vapor line heated to over 200° C. over a period of 40 minutes. The water and ammonia that flashed from the autoclave was trapped by passing it into a scrubber containing 4862.6 grams of ice water. This scrubber solution weighed 5414.9 grams after all of the autoclave pressure had been released. After the autoclave contents had cooled to less than 60° C. they were drained and weighed (925.1 g). Deionized water (237.2 g) was added to dissolve all of the calcium propionate. This diluted product was analyzed by the HPLC method described in Example 1 and found to contain 28.0% calcium propionate (326 g, 1.75 mol, 62% yield), 119 ppm of propionamide, and no detectable propionitrile. The scrubber solution was found to contain 0.34% calcium propionate and 1.58% ammonia. From the amount of calcium propionate in the scrubber, it was concluded that approximately 66.4 grams of the product was carried into the scrubber by entrainment and that 400 grams of water and 85.5 grams of ammonia were flashed from the autoclave. This represents 90% of the ammonia that would be expected from complete hydrolysis of the propionitrile charged to the autoclave. No attempt was made to quantify the amount of calcium propionate remaining in the reactor after the product was drained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][C:38]([CH:42]([O:45][Si](C)(C)C)[C:43]#N)=[C:39]([CH3:41])[N:40]=2)=[CH:32][CH:31]=1.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH2:60][CH:59](CI)[CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51].Cl>O1CCCC1>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH2:60][CH:59]([CH2:43][C:42]([C:38]2[S:37][C:36]([C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=3)=[N:40][C:39]=2[CH3:41])=[O:45])[CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(C#N)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(CI)C1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)CC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
In an argon atmosphere, a solution of 1.8 mol/L lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (1.22 mL, 2.19 mmol), chilled to −78° C., was added to 2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]-2-(trimethylsilyloxy)acetonitrile (669 mg, 1.99 mmol) in tetrahydrofuran (2 mL). The mixture was stirred for 20 min, followed by addition of 1-(tert-butoxycarbonyl)-3-iodomethylpiperidine (647 mg, 1.99 mmol) in tetrahydrofuran (2 mL). The mixture was further stirred for 1 hour as it warmed from −78° C. to room temperature. 0.5 mol/L ice-chilled hydrochloric acid was then added and the mixture was further stirred for 10 min. Subsequently, the mixture was extracted with ethyl acetate and washed sequentially with a saturated aqueous sodium bicarbonate solution and brine. The washed product was dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 429 mg (50%) of the desired compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[C:7]=1[CH3:8]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c(Cl)ncnc1Nc1ccc(OC(F)(F)F)cc1
Yield: 84 %

Procedure:
4,6-Dichloro-5-methylpyrimidine (534.6 mg, 3.3 mmol) and 4-trifluoromethoxy aniline (661 mg, 3.6 mmol) were dissolved in EtOH and DIEA (625 uL, 3.6 mmol) was added and the mixture was refluxed for 4 h. It was then cooled, concentrated and work-up with ethyl acetate. The organic layer was separated and dried (Na2SO4). Concentrated and purified by silica-gel column chromatography (Ethyl acetate/hexane). 800 mg (84% Yield), MS m/z 304.14 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[O:8][CH2:9][O:10][C:3]=12.C([Li])CCC.C[O:17][B:18](OC)[O:19]C>C1COCC1>[F:1][C:2]1([B:18]([OH:19])[OH:17])[CH:7]=[CH:6][CH:5]=[C:4]2[O:8][CH2:9][O:10][CH:3]12
Reactant: COB(OC)OC
Reactant: Fc1cccc2c1OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)C1(F)C=CC=C2OCOC21
Temperature: -65 °C
Yield: 21.3 %

Procedure:
1-Fluoro-2,3-methylenedioxybenzene (5.0 g, 35.7 mmol) was dissolved in THF (70 mL) and the solution cooled to −65° C. in a dry ice acetone bath. n-Butyl lithium (2.5 g, 15.7 mL, 39.3 mmol) was added to the solution via syringe with stirring. The reaction was allowed to warm to −35° C. over 1 hour then re-cooled to −65° C. and treated with trimethylborate (4.1 g, 39.3 mmol) via syringe. The reaction was allowed to warm slowly to room temperature then quenched with 1N HCl (50 mL), stirred for 15 minutes then diluted with ether and the layers separated. The organic layer was extracted with 1N sodium hydroxide and this extract separated from the ether and acidified with 1N hydrochloric acid. The acidic aqueous layer was extracted with two portions of ether and these combined ether extracts were dried (sodium sulfate), filtered and concentrated to a oily solid which was triturated with methylene dichloride. The resulting solid was collected by filtration, washed with methylene dichloride and dried to give 1-fluoro-2,3-methylenedioxyphenylboronic acid (1.4 g, 7.6 mmol) as a tan solid: 1H NMR (DMSO-d6): δ 8.05 (bs, 2H), 7.08 (dd, 1H), 6.76 (d, 1H), 6.08 (s, 2H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10](=[O:23])[N:11]2[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16]
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A mixture of (R)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.1 mmol), 4-aminobutyric acid (670 mg, 6.5 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 472.34 (M+1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:11]=[C:12]([N:17]2[C:21](=[O:22])[C@H:20]3[CH2:23][C@@H:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=4)[CH2:25][N:19]3[C:18]2=[O:35])[CH:13]=[C:14]([Cl:16])[CH:15]=1.Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>C1COCC1.O.CCOC(C)=O>[CH3:41][O:40][C:38](=[O:39])[CH2:37][C@:20]12[CH2:23][C@@H:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)[CH2:25][N:19]1[C:18](=[O:35])[N:17]([C:12]1[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=1)[C:21]2=[O:22]
Reactant: O=C1[C@H]2C[C@@H](OCc3ccc(Br)cc3)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C[C@]12C[C@@H](OCc3ccc(Br)cc3)CN1C(=O)N(c1cc(Cl)cc(Cl)c1)C2=O
Temperature: -65 °C
Reaction time: 1 h
Yield: 4.8 %

Procedure:
The compound of formula (Io), wherein Z is methoxycarbonylmethyl and the bonds depicted as wavy bonds define the 7aS,6R stereoisomer, was prepared as follows. 1.65 mL of a solution of LDA (1 M) in THF (1.5 eq.) was added to a solution of (7aR,6R)-2-(3,5-dichloro-phenyl)-6-(4-bromobenzyloxy)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (500 mg) (1.1 mmol) (Ex. 6) in 5 mL of dry THF cooled to −65° C. under nitrogen. The reaction mixture was stirred for 1 h then treated with a solution of methyl bromoacetate (340 mg) (2 eq.) in 3 mL of THF. After 1 h at −65° C., the reaction mixture was allowed to warm to −20° C., stirred for 2 h, and then poured in a mixture of water/EtOAc (1:1, 20 mL). The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting oily residue was purified over SiO2 column (25 g) (eluent: EtOAc/cyclohexane 3/7) to afford the above-titled compound (28.8 mg) as a foam. NMR (CDCl3, 200 MHz): 7.43 (2H, d), 7.35 (1H, m), 7.15-7.0 (4H, m), 4.4-4.2 (3H, dd+m), 4.15 (1H, m), 3.7 (3H, s), 3.2-3.0 (2H, dd+d), 2.75 (1H, d), 2.52 (1H, dd), 2.05 (1H, dd).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13](C)[CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:18]([N:25]1[CH2:30][CH2:29]C[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:45]1([N:51]2CCNCC2)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:45][N:51]3[CH2:29][CH2:30][N:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(CC=O)c1cc(-c2ccc(F)cc2)no1
Reactant: c1ccc(CN2CCCCC2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(-c2cc(CCCCN3CCN(Cc4ccccc4)CC3)on2)cc1
Yield: 120.2 %

Procedure:
About 2 min after dissolving 3-[3-(4-fluorophenyl)isoxazol-5-yl]butanal (25 mg, 0.104 mmol) and 1-benzylpiperidine (37.2, 0.214 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (136 mg, 0.642 mmol), cold acetic acid (14.7, 0.257 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 1.5 hr and followed the same processes as in Example 1 to obtain 49.2 mg (58.4%) of the target compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Mg].Br[C:16]1[O:20][CH:19]=[C:18]([CH:21]=[O:22])[CH:17]=1.C([Li])(C)(C)C.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30]>O1CCCC1.CCCCC>[OH:22][CH:21]([C:18]1[CH:17]=[C:16]([Si:29]([CH3:32])([CH3:31])[CH3:30])[O:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCBr
Reactant: O=Cc1coc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
A mixture of 1-bromododecane (3.45 g, 14 mmol) and magnesium turnings (349 mg, 14.5 mmol) in tetrahydrofuran (10 ml) was refluxed under argon for 1 hour. After cooling to 0 degrees, a solution of 5-bromo-3-furaldehyde (2.42 g, 14 mmol) in tetrahydrofuran (3 ml) was added and conditions maintained for 20 minutes. The mixture was further cooled to -78 degrees and tert-butyl lithium (a 1.7M solution in pentane; 9.77 ml, 1.67 mmol) was added dropwise, followed by chlorotrimethylsilane (5.27 ml, 41.5 mmol) after 20 minutes. Stirring was continued overnight (12 hours) while the cooling bath attained room temperature. The mixture was quenched with saturated aqueous ammonium chloride, diluted with water (15 ml) and extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extract gave a brown oil, which was flash chromatographed on silica using 15% ethyl ether/petroleum ether. Fractions with Rf of about 0.25 on evaporation afforded the title trimethylsilylfuran as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.[CH:35](/[S:43](Cl)(=[O:45])=[O:44])=[CH:36]\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[Cl:27][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][S:43](/[CH:35]=[CH:36]/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:45])=[O:44])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNS(=O)(=O)/C=C/c4ccccc4)c3Cl)c2n1
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg) and triethylamine (0.04 ml) in dichloromethane (2 ml) was added a solution of (E)-styrenesulfonyl chloride (48 mg) in dichloromethane (1 ml) in an ice-water bath. After being stirred for 30 minutes under ice-cooling, the reaction mixture was partitioned into dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated in vacua. The residue was purified by preparative thin-layer chromatography (dichloromethane--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-((E)-styrylsulfonylglycyl)amino]benzyloxy]-2-methylquinoline (78 mg) as an amorphous powder.