Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:16][CH2:15][CH2:14][C:5]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:20]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][N:16]1[C:2](=[O:1])[CH2:3][CH2:4][C:5]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:14][CH2:15]1
Reactant: O=C1CCC2(CCN1)COc1ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC2(CCC1=O)COc1ccccc12
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
1,2,3,5,6,7-Hexahydro-7-oxospiro[4H-azepine-4,3'(2H)-benzofuran] (D25, 0.42 g, 1.9 mmol) was dissolved in dry DMF (10 ml) and added under Ar to sodium hydride (80% in mineral oil, 0.09 g, 3 mmol) in dry DMF (1 ml). After stirring for 5 min, iodomethane (0.24 ml, 3.8 mmol) was added. The mixture was stirred for 1 h, diluted with ethyl acetate (150 ml), washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (0.36 g, 79%) as yellow semi-solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>>[CH3:44][N:45]([CH3:49])[C:46]([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[O:47]
Reactant: CN(C)C(=O)Cl
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)N(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and dimethylcarbamoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:15])[CH2:10][CH2:11][N:12]([CH3:14])C.[Br:16][C:17]1[CH:18]=C([CH:21]=[CH:22][CH:23]=1)N>C(O)C.O>[Br:16][C:17]1[CH:18]=[C:14]([NH:12][CH2:11][CH2:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)CCC(=O)c1ccccc1Cl
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(CCNc1cccc(Br)c1)c1ccccc1Cl
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 1-(2-chlorophenyl)-3-(dimethylamino)propan-1-one HCl salt (5.17 g, 20.85 mmol) and 3-bromoaniline (2.27 mL, 1 equiv) in 1:1 ethanol/water (21 mL, 1.0M) was heated at reflux overnight. LC-MS found the starting material was gone. The reaction mixture was cooled to rt. The ethanol was removed in vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with 1% aq HCl (2×30 mL), satd aq NaHCO3 solution (20 mL), brine (20 mL), and dried over Na2SO4. After filtration and concentration, the residue (6.08 g) was purified by chromatography on a 120-g silica cartridge to afford 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-one (2.75 g, 40% yield) as an orange oil. LC-MS (3 min) tR=2.03 min, m/z=340, 341(M+1); 1H NMR (CDCl3) δ 7.47(d, 1H), 7.44-7.38 (m, 2H), 7.33 (td, 1H), 7.00 (m, 1H), 6.84 (m, 1H), 6.77 (s, 1H), 6.56 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:19][C:17]1[CH:18]=[C:13]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:9])[CH3:10])=[CH:6][N:7]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(O)c1ccc(N)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(Br)cc(Nc2ccc(C(C)(C)O)cn2)c1=O
Temperature: 120 °C
Reaction time: 6 h
Yield: 60.3 %

Procedure:
In a flame-dried seal tube reaction vial, dissolve 2-(6-Amino-pyridin-3-yl)-propan-2-ol (530 mg, 3.484 mmol) in anhydrous Dioxane (13 mL). Then add 3,5-Dibromo-1-methyl-1H-pyridin-2-one (1.022 g, 3.83 mmol), Cs2CO3 (3.4 g, 10.45 mmol) and Xantphos (0.2 g, 0.3482 mmol). Bubble argon through for 15 min before adding Pd(OAc)2 (39 mg, 0.1742 mmol). The tube as sealed and heated to 120° C. Reaction was kept at that temperature for 6 hrs. Reaction was then diluted with EtOAc (10 mL) and filtered through celite. Filter cake was washed with EtOAc (3×10 mL). The combined filtrate was concentrated and purified on ISCO column with 5-10% MeOH in 1/1 EtOAC/Hexane to afford 5-Bromo-3-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-1H-pyridin-2-one (710 mg, yield 60%) as green solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCI
Reactant: CCCCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OCCCCCC)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 32.5 %

Procedure:
To a solution of 0.40 g (1.10 mM) of 2-(4-octylphenyl)-5-(4-hydroxyphenyl)thiazole in 20 ml of N,N-dimethylformamide (DMF), 0.40 g (1.10 mM) of potassium hydroxide was added, followed by stirring for 45 minutes at 100° C. To the mixture, 0.36 g (1.70 mM) of hexyl iodide was added at 100° C. under stirring, followed by further stirring for 6 hours and 16 minutes at 120° C. After the reaction, the reaction mixture was poured into 100 ml of water and extracted with ethyl acetate. The organic layer was washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from ethanol to obtain 0.16 g of 2-(4-octylphenyl)-5-(4-hexyloxyphenyl)thiazole (Yield: 32.3%). ##STR43##
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([C:32]4[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[C:34]([O:35][CH3:36])[CH:33]=4)[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3cccc(I)c3)n2)s1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2cccc(Nc3nccc(-c4sc(N)nc4-c4ccccc4)n3)c2)cc1OC

Procedure:
A solution of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-iodo-phenyl)-amine (300 mg, 0.64 mmol) and 3,4-dimethoxyphenylboronic acid (122 mg, 0.66 mmol) in dimethoxyethane (8 ml) and aqueous potassium carbonate (13 ml) are stirred in the presence of tetrakis triphenylphosphine palladium (15 mg) under a nitrogen atmosphere at reflux for 1 hour. After an aqueous work-up the residue is purified by chromatography (eluent: 2:1 mixture of ethyl acetate/hexane) to give the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3′,4′-dimethoxy-biphenyl-3-yl)-amine, m.p. 236–237° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([Si:17]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:18]1[O:19][CH:20]=[C:21]([CH:23]=[O:24])[CH:22]=1)[CH3:16]>C1COCC1>[OH:24][CH:23]([C:21]1[CH:22]=[C:18]([Si:17]([CH2:25][CH3:26])([CH2:15][CH3:16])[CH2:27][CH3:28])[O:19][CH:20]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dodecylmagnesium bromide (a 1M solution in tetrahydrofuran 14.3 ml, 14.3 mmol) was added dropwise to a solution of 2-triethylsilyl-4-furaldehyde (2.0 g, 9.52 mmol) in THF (20 ml) at 0 degrees C under argon. After stirring at room temperature for 2 hours, the mixture was quenched with dilute HCl and extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 30% ethyl ether/hexane to give the titled alcohol.
Reaction SMILES: [Na].[C:2]1([CH2:8][C:9](=O)[CH2:10][C:11]([O:13]CC)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]([NH2:20])=[S:19].Cl>C(O)C.O>[OH:13][C:11]1[CH:10]=[C:9]([CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:20]=[C:18]([SH:19])[N:17]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Oc1cc(Cc2ccccc2)nc(S)n1

Procedure:
Sodium (11.5 g, 0.5 mol) was dissolved in ethanol (700 ml) and ethyl 4-phenylacetoacetate added with mechanical stirring. Further ethanol (350 ml) and thiourea (22.8 g, 0.3 mol) were added and the reaction mixture heated under reflux for 24 hours. The reaction mixture was then cooled, poured into water (2 liters) and acidified with concentrated hydrochloric acid to approximately pH5. The resulting precipitate was filtered off, washed with water (3×500 ml) and diethyl ether (2×300 ml) and dried under vacuum to afford 41.5 g 4-hydroxy-6-phenylmethyl-2-mercaptopyrimidine as a beige solid, m.pt., 215°-220° C. with decomposition. M+ found: 218.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O>CC(O)=O.CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1cc(CCOc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(CCOc2ccc(N)c3ccccc23)ccn1

Procedure:
A solution of N-(4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide (570 mg, 1.62 mmol) in a mixture of AcOH: MeOH (6:1 v/v, 54 mL) was subjected to hydrogenation by passage through a Thales H-cube (1 mLmin−1, 30 mm, 10% Pt/C Cat-Cart, full H2, 45° C.). The solvent was removed by evaporation in vacuo, and, the residue was subjected to SCX capture and release to furnish the title compound, Intermediate B, (550 mg, 100%): m/z 322 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:23]([O+](CC)CC)[CH3:24].C(Cl)Cl.CO>C(Cl)Cl>[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](=[NH:14])[O:13][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1cccc(OCc2ccccc2)c1
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOC(=N)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under an atmosphere of argon 11.36 g of 3-benzyloxybenzamide were suspended in CH2Cl2 (200 ml) and 9.5 g triethyloxonium fluoroborate in CH2Cl2 (100 ml) were added dropwise on ice cooling. The reaction mixture was then stirred further 20 h at RT until completion of reaction according to TLC analysis (CH2Cl2/MeOH: 15/1). The solid which had formed was filtered off, washed with ether to give the desired ethyl m-benzyloxybenzimidate tetrafluoroborate as white crystals, mp 152°-154° C., which was used without further purification in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CC(C)CCBr
Product: CC(C)CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 47.2 %

Procedure:
The title compound (0.030 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 1-bromo-3-methyl-butane (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C18H24ClN3, 317.17; found, m/z 318.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.56-7.54 (m, 4H), 4.34 (s, 2H), 3.57-3.55 (br m, 2H), 3.44-3.42 (br m, 2H), 3.40-3.38 (br m, 2H), 3.29-3.27 (br m, 2H), 1.79-1.77 (br m, 1H), 1.02 (d, J=4.5 Hz, 6H).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.C[Si]([C:26]#[N:27])(C)C>[I-].[Zn+2].[I-].CCOCC>[C:26]([C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:27]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: N#CC1=CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reaction time: 15 h
Yield: 43.6 %

Procedure:
N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide (4.21 g, 14 mmol), trimethylsilyl cyanide (10.0 g, 100 mmol) and Zinc Iodide (0.25 g) were combined and stirred under nitrogen for 15 hours. The reaction mixture was then diluted by addition of 200 mL of Et2O, washed with cold water, and the organic layer was dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in 250 mL of toluene, and 0.5 g of paratoluene sulfonic acid was added. The reaction mixture was refluxed for three hours, cooled, and the the solvent was removed under reduced pressure. The crude product was eluted through silica under medium pressure with 5% EtOAc in hexanes to yield 1.89 g (6.1 mmol, 44%) of N-(5-Cyano-7,8-dihydro-naphthalen-2-yl)-bezenesulfonamide as an oil. MS: 311 (M+H)+.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C1(=O)[O:14][CH2:13][CH2:12]O1>[Br-].C([N+](CC)(CC)CC)C.CN(C=O)C>[OH:2][CH2:1][CH2:3][O:2][C:1]1[CH:9]=[C:7]([O:8][CH2:6][CH2:4][OH:5])[CH:6]=[C:4]([O:5][CH2:12][CH2:13][OH:14])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CN(C)C=O
Product: OCCOc1cc(OCCO)cc(OCCO)c1
Temperature: 150 °C
Yield: 74.3 %

Procedure:
A mixture of phloroglucinol (12.60 g, 0.10 mol), ethylene carbonate (35 g, 0.39 mol), and tetraethylammonium bromide (8 g, 0.04 mol) in DMF (20 mL) was heated at 150° C. for 14 hr. After evaporating the solvent, the residue was purified on a silica gel chromatography column using a mixture of methylene chloride and acetonitrile: 1/1, 1/2, 1/3 and 1/4 as eluents to give 9.6 g of 1,3,5-tris(2-hydroxyethoxy)benzene (37% yield). The product was purified further by recrystallization from cold methylene chloride and THF to afford 5.5 g (21%). 1H NMR (DMSO-d6): δ 6.08 (s, aromatic protons, 3H), 4.83 (s, OH, 3H), 3.92 (t, —OCH2—, 6H), 3.69 (m, —CH2OH, 8H). 13C NMR (DMSO-d6): δ 160.54 (aromatic C—O—), 93.81(aromatic C—H), 69.53 (—CH2O—), 59.55 (—CH2OH). FT-IR (KBr, m−1): 3255 (OH), 2947, 2371, 1596, 1462, 1377, 1167, 1071, 1024, 902, 745.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[CH3:18][C:19](=[CH:21][CH2:22][CH2:23][CH:24]([CH2:26][CH:27]=O)[CH3:25])[CH3:20].CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH3:25][CH:24]([CH2:23][CH2:22][CH:21]=[C:19]([CH3:20])[CH3:18])[CH2:26][CH2:27][NH:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NCCC(C)CCC=C(C)C
Yield: 73.8 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-leucine methyl ester hydrochloride (2.0 gm, 11.0 mmol), THF (30 mL), MgSO4 (2.24 gm, 18.7 mmol), (±) citronellal (3.95 mL, 22.0 mmol), Et3N (1.54 mL, 11.0 mmol), sodium borohydride (832 mg, 22.0 mmol), and methanol (20 mL) to give 11m (2.3 gm, 74%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.86 (3H, d, J=6.34 Hz), 0.9 (3H, d, J=6.59 Hz), 0.92 (3H d, J=6.83 Hz), 1.1-1.2 (1H, m), 1.24-1.36 (3H, m), 1.42-1.54 (4H, m), 1.59 (3H, m), 1.67 (4H, m), 1.9-2.08 (2H, m), 2.4-2.62 (2H, m), 3.27 (1H, t, J=7.32 Hz), 3.71 (3H, s), 5.08 (1H, t, J=7.32 Hz). ESI-MS: 306.3 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([OH:17])([CH2:12][C:13]([CH2:15]Br)=[CH2:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].C1COCC1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2([O:17][CH2:14][C:13](=[CH2:15])[CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=C(CBr)CC1(O)CCN(C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=C1COC2(CCN(C(=O)OCC)CC2)C1
Reaction time: 8 h

Procedure:
The product of step b) (1.50 g, 0.0066 mmol), 50% NaOH (15 ml) and THF (20 ml) were mixed and stirred overnight. The reaction mixture was diluted with CH2Cl2 /H2O and separated. The aqueous layer was further extracted with CH2Cl2 (50 ml×2) and worked-up to give 1.42 g of a tan oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:13][C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(Br)cnc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2ncc(Br)cc21
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A suspension of 5-bromo-pyridine-2,3-dicarboxylic acid (700 mg, 2.85 mmol) in acetic anhydride (0.88 ml, 9.39 mmol, 3.3 equiv.) was heated at 80° C. for 10 min and then refluxed for 1 h. Acetic anhydride was evaporated off in vacuo. The resulting solid was triturated with hexane to afford 3-bromo-furo[3,4-b]pyridine-5,7-dione (510 mg, 79%) as off white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[C:13]1=[O:26])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[C:13]1=[O:26]
Reactant: COC(=O)c1ccc2ccn(CCCNC(=O)OC(C)(C)C)c(=O)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccn(CCCN)c(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.90 g, 2.5 mmol) in methylene chloride (20 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (10.0 mL, 40 mmol). The reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated to dryness to afford methyl 2-(3-aminopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.74 g, quant.). LC-MS: (FA) ES+ 261.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH:14]=2)[NH:9][C:8]([CH3:25])([CH3:24])[CH:7]=1)[CH:2]=[CH2:3].Br[CH2:27][C:28]1C2C(=CC=C(C3C=CC=CC=3OC)C=2)NC(C)(C)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(N)C=C>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:25])([CH3:24])[CH:7]=[C:6]2[CH2:5][NH:4][C:1]1[CH:29]=[CH:28][CH:27]=[CH:3][CH:2]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: C=CCNCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCN
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
Allyl-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]amine 54 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 28 μL of allyl amine reacted to give 8 mg of the title compound as a foam.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]1)=[O:14])(C)(C)C.C1(=O)O[C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.CO>ClCCl>[O:30]=[C:29]1[C:28]2[C:27](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13](=[O:14])[N:15]1[C@H:16]1[CH2:17][CH2:18][C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:21]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)O)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (44.6 mL, 583.0 mmol, 30.0 eq) is added at room temperature to a stirred solution of (trans-4-tert-butoxycarbonylamino-cyclohexyl)-acetic acid (5.0 g, 19.4 mmol, 1.0 eq) in dichloromethane (50 mL). After 3 hours stirring at room temperature, the reaction mixture is concentrated, the resulting residue is dissolved in pyridine (150 mL) and phthalic anhydride (5.0 g, 33.0 mmol, 1.7 eq) is added at room temperature. The reaction mixture is heated to reflux for 4 hours, pyridine is then removed and acetic anhydride (40 mL) is added. The resulting mixture is heated to reflux for 3 hours, then extracted with ethyl acetate (3×200 mL) and water (200 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 50:1 to 10:1, v/v) to afford [trans-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexyl]-acetic acid as a white solid (4.82 g, 86% yield).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C@H:17]1([C:26]([OH:28])=O)[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:26]([C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:25])[CH2:21][CH2:22]1)=[O:28])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)CC1

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) trans-cyclohexane-1,4-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.67 g (76%) of the title compound as a colorless oil. MS m/e (%): 547 (M+H+, 100).