Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Br)C=C>O1CCCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]([CH2:7][CH:5]=[CH2:6])[C:26]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(COCCCOCc1ccccc1)OCCCOCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC(OCCCOCc1ccccc1)C(=O)OCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of diisopropylamine (0.075 ml, 0.53 mmol) in dry tetrahydrofuran (0.5 ml) is cooled to 0° C. and a 2.5M solution of n-butyllithium in hexane is added (0.19 ml, 0.47 mmol). The solution is stirred at 0° C. for 15 minutes and then cooled down to -78° C. A solution of 3-benzyloxypropyl 2-[(3-benzyloxypropyl)oxy]acetate (0.165 g 0.44 mmol) in tetrahydrofuran (1 ml) is added slowly. The mixture is allowed to stir at -78° for 1 hour and then hexamethyl phosphoramide (0.5 ml) is added, followed by allyl bromide (0.23 ml, 2.7 mmol). The mixture is allowed to warm to room temperature over 3 hours and then quenched using saturated aqueous ammonium chloride. The mixture is extracted with ether (3×15 ml) and the combined organic extracts are washed with water (3×45 ml) and brine (30 ml). The organic layer is dried, evaporated and the residue purified by flash chromatography on silica gel using ethyl acetate/hexane (1:4) as eluent to obtain 3-benzyloxypropyl 2-[(3-benzyloxypropyl)oxy]pent-4-enoate. IR (CH2Cl2): 1745, 1644, 1195, 1101 cm-1. Reduction of the ester with diisobutyl aluminum hydride, followed by conversion of the alcohol as previously described yields methyl 4-[(3-benzyloxypropyl)-oxy]-hept-6-enoate. This is in turn converted to methyl 4-[3-(N-t-butoxycarbonyl-p-chlorophenylsulfonamido)-propyloxy]-7-(3-pyridyl)-heptanoate as starting material for compound under (a), or methyl 4-[3-(N-t-butoxycarbonyl-p-chlorophenylsulfonamido)-propyloxy]-6-(3-pyridyloxy)-hexanoate for compound under (b), according to methods described in the previous examples.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C1CCCCC1>N1C=CC=CC=1>[C:20]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(-c2nc3c(O)cccc3s2)cc1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2sc(-c3ccc(C(=O)O)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
The 4-(4-hydroxybenzothiazol-2-yl)benzoic acid (6.9 g) obtained in Example 3 was dissolved in 15 ml of pyridine, and 2.6 g of acetic anhydride was added dropwise. The mixture was stirred at room temperature for 2 hours, and 160 ml of cyclohexane was added. The precipitated crystals were collected by filtration, washed with cyclohexane and then diethyl ether, and recrystallized from acetonitrile to give 4.0 g of 4-(4-acetoxybenzothiazol-2-yl)benzoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C(O)CCC>O1CCOCC1>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C:18]4[CH:19]=[C:20]([S:24]([NH2:27])(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=4)[N:7]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: C1COCCO1
Solvent: CCCCO
Product: NS(=O)(=O)c1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
The mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.64 mmol, 1.0 equiv.), 3-aminobenzenesulfonamide (329 mg, 1.91 mmol, 3.0 equiv.), butan-1-ol (1 mL) and dioxane (0.5 mL) was stirred at 95° C. for 8 h. Then, the reaction mixture was cooled to room temperature and filtered. The residue was crystallized with methane/water/isopropyl ether to afford Compound 82 (7.7 mg, 3%). LC-MS (m/z): 372.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.62-0.63 (m, 2H), 0.88-0.92 (m, 2H), 1.82-1.86 (m, 1H), 6.06 (bs, 1H), 6.49 (bs, 1H), 7.39 (s, 2H), 7.52 (d, J=1.8 Hz, 2H), 7.97 (s, 3H), 10.02 (s, 1H), 10.45 (bs, 1H), 12.27 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.Cl>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(CO)ccc1Br
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
10.55 g of methyl 4-bromo-3-methylbenzoate was dissolved in 110 mL of tetrahydrofuran, to which 1.31 g of lithium aluminium hydride was added dropwise in small portions at −30 to −20° C., and this mixture was stirred for 15 minutes at −20° C. Then a mixed solution of methanol and water (4:1) was added dropwise to the reaction mixture, and this mixture was stirred for 30 minutes at room temperature. The reaction mixture, to which water was added, was adjusted to pH 7 with 6M hydrochloric acid followed by addition of ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 9.20 g of (4-bromo-3-methylphenyl)methanol as brown oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:42]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])=[O:43])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazine (250 mg), 2-methoxyphenylacetic acid (92 mg) and 1-hydroxybenzotriazole (75 mg) in dichloromethane (8 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg) at room temperature. After 3 hours, the reaction mixture was poured into aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using ethyl acetate--n-hexane (1:1.5) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-methoxyphenylmethylcarbonyl)piperazine (290 mg) as a powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]2)=[N:6][CH:7]=1
Reactant: Fc1cc(-c2cncc(NCC3CCOCC3)n2)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (375 mg, 1.162 mmol), DMSO (3.5 ml) and trans-4-aminocyclohexanol (1204 mg, 10.46 mmol) was stirred at 100° C. for 18 hours and the progress was followed by LCMS. The reaction mixture was let cool, added 300 ml of ethyl acetate, washed with saturated sodium bicarbonate solution (3×), water (2×), saturated salt solution (1×), dried with sodium sulfate, filtered and concentrated to crude solid. The crude material was purified by silica gel chromatography using 40 g column, eluting slowly from (80%> ethyl acetate 20% heptane with 2% MeOH) to 100% ethyl acetate with 2% MeOH. The desired fractions are concentrated to a constant mass, lyophilized from 1:1 ACN/water (does not fully dissolve), re-lyophilized from 80 ml of (60/40) ACN/water solution with sonicating to dissolve solid, giving 270 mg of title compound as free base. LCMS (m/z): 418.3 (MH+), retention time=0.52 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.19-1.55 (m, 6H) 1.71 (d, J=12.89 Hz, 2H) 1.85-2.15 (m, 5 H) 3.28-3.32 (dMeOH, 2H App.) 3.40 (td, J=11.72, 1.76 Hz, 2H) 3.50-3.73 (m, 2H) 3.94 (dd, J=11.28, 3.08 Hz, 2 H) 6.66 (s, 1 H) 7.86 (s, 2H) 7.99 (s, 1 H)
Reaction SMILES: Cl[NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[CH3:10][CH2:11][C:12](=S)C>>[Cl:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[NH:2][C:11]([CH3:12])=[CH:10]2
Reactant: CCC(C)=S
Reactant: ClNc1ccc(Cl)cc1
Product: Cc1cc2cc(Cl)ccc2[nH]1
Yield: 72 %

Procedure:
This compound was prepared from N-chloro-4-chloroaniline and methylthioacetone following Method A, which gave 6.68 g (0.032 mol, 72%) of the sub-titled product: mp. 64°-64.5° (recr. from cyclohexane ir (KBr) 3350 cm-1 (NH); pmr (CCl4), 2.42 (1H,s,NH), 2.52 and 3.15 (1 resp. 2H,m,aromatic H), 7.72 and 7.90 (3H, s, CH3 and SCH3).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]2[CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=[C:4]2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]2[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccc(OC)cc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(Cl)cc3nc(C(=O)O)cn3c2c1

Procedure:
800 mg of ethyl 5-chloro-8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate were mixed with 10 ml of methanol and 20 ml of 1 N sodium hydroxide solution. The mixture obtained was refluxed for 1 hour and the solid sodium salt which separated out was filtered off and then was dissolved in 20 ml of water. The solution was acidified with concentrated hydrochloric acid to obtain a white precipitate of 5-chloro-8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylic acid. The precipitate was filtered off and was suspended in 10 ml of methanol and the suspension was acidified with HCl/methanol to obtain a clear solution to which diethyl ether was subsequently added to give 5-chloro-8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylic acid hydrochloride melting at 284°-286° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH2:39][CH2:40][CH2:41][OH:42]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:39][CH2:40][CH2:41][OH:42])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: NCCO
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(NCCO)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting material: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and 2-aminoethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:23])=[CH:8][C:9](=[O:22])[N:10]2[CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[O:24]1[CH2:29][CH2:28][O:27][C:26]2[CH:30]=[C:31]([CH2:34][NH2:35])[CH:32]=[CH:33][C:25]1=2.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C.CO>[O:24]1[C:25]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][CH:18]3[CH2:17][CH2:16][CH:15]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([CH3:23])=[CH:8][C:9]4=[O:22])[CH2:20][CH2:19]3)=[CH:30][C:26]=2[O:27][CH2:28][CH2:29]1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3CCC(=O)CC3)c2c1
Reactant: NCc1ccc2c(c1)OCCO2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To 2 mL of methanol solution containing 45 mg of 7-methoxy-4-methyl-1-(2-(4-oxocyclohexyl)ethyl)quinolin-2(1H)-one and 21 mg of (2,3-dihydrobenzo[b][1,4-]dioxin-6-yl)methylamine, 10 μL of acetic acid and 12 mg of sodium cyanoborohydride were added, and stirred at the same temperature for 30 min. To the reaction mixture, water, chloroform and aqueous saturated sodium hydrogen carbonate solution were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [eluent; chloroform:methanol=20:1], to give (A) 5.4 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)cyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a yellow oil and (B) 17 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)cyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a pale yellow foam.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Si:20]([O:27][CH2:28][CH:29]([OH:40])[C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:40][CH:29]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH2:28][O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (0.5 g, 2.27 mmol) in DMF (10 ml) were added anhydrous cesium carbonate (0.74 g, 2.27 mmol) and 1-tert-butyldimethylsilyloxy 2-hydroxy 2-(4-tertbutylphenyl)ethane (0.7 g, 2.27 mmol). The mixture is stirred for 2 hours at 70° C. and then cooled to room temperature and ethyl acetate is added to it. The solution is then washed with water, dried and concentrated and the residue subjected to purification by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:14][C:15](O)=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].B.[ClH:19]>C1COCC1.C(O)C>[ClH:19].[OH:16][CH2:15][CH2:14][CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][NH:10]1
Reactant: O=C(O)CC1NCCc2ccc([N+](=O)[O-])cc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)C(CCO)NCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a suspension of 7-nitro-1,2,3,4-tetrahydroisoquinolin-1-acetic acid in anhydrous THF (20 ml) at 0° C. was added 1.0M borane in THF (25 ml). The reaction mixture was slowly warmed to ambient temperature and stirring was continued for 4 h. Since the reaction was not proceeding to completion, additional borane (10 ml) was added and the solution heated at reflux for 1 h. Upon cooling to ambient temperature, the reaction was quenched by the addition of methanol (1 ml) and 6M hydrochloric acid (5 ml). The solution was heated at reflux for 2 h to decompose any borate intermediates and the solvent concentrated at the rotoevaporator. The resulting oil was taken up in water, made basic with dilute NaOH, and extracted twice with dichloromethane. The dried (MgSO4) organic extracts were concentrated to give a solid. This solid was dissolved in hot ethanol (75 ml) and hydrochloric acid in ethanol added to give an acidic solution. The product was isolated by filtration of the precipitate to give the title compound as a light yellow solid (2.28 g, 84%), m.p. 238-40° C.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[C:18]([OH:20])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:35][C@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>C(#N)C>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][C@H:36]([NH:35][C:18]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=2)=[O:11])=[O:20])[CH2:37]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(O)C1CCCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)C2CCCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 1-(4-nitrobenzyloxycarbonyl)-2-piperidinecarboxylic acid (1.54 g) in anhydrous acetonitrile (30 ml), N,N-carbonyldiimidazole (851 mg) was added at the room temperature, followed by stirring for one hour. The reaction mixture was allowed to react with a solution of (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (931 mg) in anhydrous acetonitrile (15 ml) under ice cooling in a similar manner to that described in Referential Example 1-(1), whereby 1.81 g of (3S)-1-(tert-butoxycarbonyl)-3-[1-(4-nitrobenzyloxycarbonyl)piperidin-2-ylcarbonylamino]pyrrolidine were obtained as a colorless amorphous substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>C1COCC1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:26]3([OH:29])[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a stirred suspension of 1.54 mmol 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole in 3 ml THF at −78° C. was added dropwise 3.85 mmol butyllithium solution (1.6 M in hexane) and stirring continued at −78° C. for 1 h. To the resulting yellow solution was added dropwise a solution of 3.08 mmol tetrahydro-4H-pyran-4-one in 0.7 ml THF and the mixture was stirred at −78° C. for 30 min and then allowed to warm to room temperature. The reaction was quenched by addition of 1 M aq HCl, diluted with ethyl acetate, and then made basic by addition of 2 M aq NaOH. The phases were separated and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow solid (25% yield). MS (m/e): 310.3 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C(#N)C.CO>[NH2:34][CH:35]1[CH2:38][N:37]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:28])[CH2:36]1
Reactant: NC1CNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(N)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 1 h
Yield: 111.4 %

Procedure:
2.05 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidine carboxylic acid were dissolved in 20 ml of dry acetonitrile, and 0.78 g of N,N'-carbonyldiimidazole was added to the resulting solution, after which the mixture was stirred at for 1 hour. The resulting mixture was then added dropwise to a solution of 1.00 g of 3-aminoazetidine dihydrochloride and 2.40 ml of diisopropylethylamine in 10 ml of methanol, whilst ice-cooling, and the mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 60 9383, manufactured by Merck, 100 g) to give 2.56 g of the title compound, in the form of an amorphous powder, from the fraction obtained by elution with a 65:35 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[N:24]([CH:30]2[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]2=[O:37])[CH2:23]3)=[O:17])=[CH:11][C:10]=1[CH3:38])(C(C)(C)C)(C)C.Cl>C(Cl)Cl.CCOCC>[O:37]=[C:31]1[CH:30]([N:24]2[CH2:23][C:22]3[C:26](=[CH:27][CH:28]=[C:20]([CH2:19][NH:18][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH3:38])[CH:11]=4)=[O:17])[CH:21]=3)[C:25]2=[O:29])[CH2:35][CH2:34][C:33](=[O:36])[NH:32]1
Reactant: Cc1cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.2 %

Procedure:
To a solution of the product from Step 3 (0.5 g, 0.9 mmol) in methylene chloride (20 mL) was added 2N HCl in ether (2 mL). The mixture stirred for 16 h at ambient temperature. The precipitated product was isolated by filtration, and was rinsed with methylene chloride (20 mL) and dried under vacuum, providing 0.4 g of 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-hydroxy-3-methylphenyl)urea as an off-white solid, in quantitative yield; HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 1.88 min (96.94%); mp 210-212 0C; 1H NMR (DMSO-d6) δ 1.94-2.18 (m, 4H), 2.30-2.51 (m, 1H), 2.58-2.72 (m, 1H), 2.87-3.06 (m, 1H), 4.25-4.56 (m, 4H), 5.15 (dd, J=5.0, 13.3 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 7.02 (dd, J=2.5, 8.6 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.54 (s, 1H), 7.73 (d, J=7.7 Hz, 1H), 8.32 (br. s., 1H), 11.02 (s, 1H); 13C NMR (DMSO-d6) δ 16.15, 22.51, 31.20, 42.77, 47.12, 51.56, 114.47, 117.11, 121.32, 121.83, 122.88, 123.61, 126.86, 130.22, 131.72, 142.35, 145.17, 150.10, 155.58, 170.99, 172.85; LCMS MH=423; Anal. Calcd for C22H22N4O5+0.25CH2Cl2: C, 60.23; H, 5.11; N, 12.63. Found: C, 60.14; H, 5.43; N, 12.54.