Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:10][C:11](=[O:34])[C@H:12]([NH:26]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15](=O)[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=1)[CH3:9]>C(OCC)(=O)C>[CH2:8]([O:10][C:11]([C@H:12]1[CH2:13][CH2:14][C:15]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)=[N:26]1)=[O:34])[CH3:9]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCC(c2cc(F)c(F)c(F)c2)=N1
Reaction time: 3 h
Yield: 80.2 %

Procedure:
4 N hydrochloric acid/ethyl acetate (163 mL) was added to an ethyl acetate (30 mL) solution of (R)-2-t-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl) valeric acid ethyl ester (22.2 g), and stirring was continued for 3 hours at room temperature. The solvent was removed under a vacuum, and ethyl acetate and sodium bicarbonate aqueous solution were added to the residue, and the organic layer was partitioned. After washing the organic layer with brine, the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the title compound (12.4 g) was obtained. The physical property values are as follows.
Reaction SMILES: C[N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]1.CN1[C:32](=O)[CH:31]=[C:30]([C:34]2[CH:39]=CN=CN=2)N=C1OC[C@H]1CCCN1.Cl[C:48](OC1C=CC=CC=1)=O>>[CH3:21][CH:16]([O:15][C:3]1[NH:2][C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=1)[C@H:17]1[CH2:48][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]1[CH:39]=[CH:34][CH:30]=[CH:31][CH:32]=1)=[O:23]
Reactant: Cn1c(OC[C@H]2CCCN2)nc(-c2ccncn2)cc1=O
Reactant: COC(=O)N1CCCC(Oc2nc(-c3ccncn3)cc(=O)n2C)C1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(Oc1nc(-c2ccncn2)cc(=O)[nH]1)[C@H]1CCCN1C(=O)Oc1ccccc1

Procedure:
Phenyl (2R)-2-(1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-yloxymethyl)pyrrolidine-1-carboxylate was prepared by the same manner as that of methyl 3-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidine-1-carboxylate except for utilizing (R)-1-methyl-2-(pyrrolidin-2-ylmethoxy)-1H-[4,4′]bipyrimidinyl-6-one (0.20 g, 0.70 mmol) instead of 1-methyl-2-(piperidine-3-yloxy)-1H-[4,4′]bipyrimidinyl-6-one and phenyl chloroformate (125 μl, 1.0 mmol) instead of methyl chloroformate. Phenyl (2R)-2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxymethyl)pyrrolidine-1-carboxylate was isolated as a white solid (29 mg, 0.07 mmol, 10%).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH2:8][CH2:9][C:10](O)=O)=[CH:6][CH:7]=1)#[N:2].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1>ClCCl.CO>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]([C:21]1[CH:26]=[CH:25][C:24]2[N:27]([CH3:28])[C:10]([CH2:9][CH2:8][C:5]3[S:4][C:3]([C:1]#[N:2])=[CH:7][CH:6]=3)=[N:29][C:23]=2[CH:22]=1)=[O:30]
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Reactant: N#Cc1ccc(CCC(=O)O)s1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)s1)n2C)c1ccccn1
Yield: 18 %

Procedure:
Prepared analogously to Example 25c from 3-(2-cyanothiophen-5-yl)-propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide. Yield: 18% of theory, Rf value: 0.66 (silica gel; dichloromethane/methanol=9:1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:25])[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[CH:23]=[N:22][N:21]=[C:20]1[CH3:24].[CH2:26]=[O:27]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:25])[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:10]=1[N:19]1[C:20]([CH3:24])=[N:21][N:22]=[C:23]1[CH2:26][OH:27]
Reactant: Cc1nncn1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Reactant: C=O
Solvent: Cc1ccccc1C
Product: Cc1nnc(CO)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Temperature: 122 °C

Procedure:
In the manner given in Example 4, 2'-chloro-5-(trifluoromethyl)-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone, paraformaldehyde and xylene are warmed under nitrogen to about 122° C. to give 2'-chloro-5-(trifluoromethyl)-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:16]([O:18][C:19]([C:21]1(N)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:16]([O:18][C:19]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]1[NH:32][C:7]([C:2]1[C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])=[O:20])[CH3:17]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1Cc2ccccc2C1NC(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of biphenyl-2-carboxylic acid (289 mg, 1.46 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (300 mg, 1.46 mmol), HATU (666 mg, 1.75 mmol) in anhydrous DMF (1.8 mL) is added DIPEA (3814, 2.19 mmol). The resulting solution is stirred at RT overnight. Poured reaction into water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers are concentrated in vacuo and the residue purified by flash column chromatography (12 g silica gel, gradient elution: 0-30% EtOAc in heptane) to give product (245) as off-white solid (525 mg, 93%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][N:11]([CH2:14][C@H:15]([NH:23][C:24]([O:26][C:27](C)(C)[CH3:28])=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.[C:45](=[O:63])([O:56][CH2:57][C:58]1[S:62][CH:61]=[N:60][CH:59]=1)OC1C=CC([N+]([O-])=O)=CC=1>ClCCl.C(OCC)(=O)C>[CH2:12]([N:11]([CH2:10][C@@H:9]([NH:8][C:45]([O:56][CH2:57][C:58]1[S:62][CH:61]=[N:60][CH:59]=1)=[O:63])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:62][CH:61]=[N:60][CH:59]=1)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:13]
Reactant: CCN(C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
The product from Example 70E (87 mg, 0.17 mmol) in dichloromethane (1.8 mL) was treated with trifluoroacetic acid (1.0 mL) at ambient temperature. After stirring for 2 hours, the mixture was concentrated and treated with aqueous 10% K2CO3 (2.4 mL). The aqueous solution was extracted with ethyl acetate (3×3 mL). The ethyl acetate extracts were combined and treated with 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (100 mg, 0.36 mmol) by extraction with aqueous NaHCO3] in ethyl acetate (6 mL). After heating at 60° C. for 18 hours, the mixture was allowed to cool to ambient temperature and concentrated. The residue was purified by flash column chromatography on silica gel eluting with (chloroform:methanol, 98:2) to provide the title compound (33.5 mg, 31%). 1H NMR (CDCl3) δ 8.76 (s, 2H), 7.85 (s, 2H), 7.32-7.09 (m, 10H), 5.37-5.17 (m, 6H), 4.15 (br s, 2H), 3.61-2.65 (m, 10H), 1.24 (t, 3H); MS (ESI+) m/z 594 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:39][CH2:38][CH2:37][CH2:41]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCC4)c(C)c3C)c2cc1OC
Yield: 64 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclopentanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (43 mg, yield 56%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:10][CH2:11][CH2:12][CH2:13][C:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:15]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)CCCCl
Product: O=C(CCCCl)N1CCc2ccccc21

Procedure:
from 2,3-dihydro-1H-indole and 4-chlorobutanoyl chloride
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:34])[N:14]([CH3:35])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=2)[C:37]1=[O:51])(=O)C.[OH-].[Na+].C(Cl)[Cl:55]>C1COCC1.C([O-])(O)=O.[Na+]>[ClH:55].[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:26][CH2:27][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:29][CH2:30]5)=[CH:21][N:20]=4)[C:15](=[O:34])[N:14]([CH3:35])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:45]=[CH:44]2)([CH3:48])([CH3:49])[CH3:47]
Reactant: ClCCl
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(C)C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Product: Cl
Temperature: 60 °C
Yield: 38 %

Procedure:
To 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (153 mg, 220 μmol, Eq: 1.00) in THF (2.0 ml) was added an aqueous solution of 1N NaOH (2.0 mL, 2.00 mmol, Eq: 9.08). The resulting solution heated at 60° C. for 2 h. The mixture was cooled to room temperature. The solution was diluted with saturated NaHCO3 and DCM. The layers were separated. The aqueous layer was extracted three times with DCM. The combined organics were dried over MgSO4. The solution was filtered. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a cream solid. The solid was triturated with Et2O. The solid was filtered, then dissolved in 2 ml DCM. A solution of 1.0 M HCl in Et2O (2 ml) was added. A solid formed. The solid was filtered and dried under vacuum to give 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one HCl (57.5 mg, 38%). LC/MS-ESI observed [M+H]+ 653. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.80 Hz, 6H) 1.37 (s, 9H) 3.08 (d, J=11.33 Hz, 2H) 3.46 (d, J=10.20 Hz, 2H) 3.76 (s, 5H) 4.39 (d, J=6.04 Hz, 2H) 7.41-7.59 (m, 5H) 7.73 (d, J=13.97 Hz, 1H) 7.86 (s, 1H) 8.06 (d, J=2.27 Hz, 1H) 8.42 (s, 1H) 8.50 (d, J=2.27 Hz, 1H) 9.31 (s, 1H)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCOCC1.[CH:22]([N:25]([BH2:29])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>[Pd].CCOCC>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([BH:29][N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cc1
Reactant: BN(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(BN(C(C)C)C(C)C)cc1
Temperature: 70 °C

Procedure:
0.343 g (0.49 mmol) of palladium catalyst (Ph3P)2PdCl2, 2.129 g (9.8 mmol) of p-iodotoluene, 6.8 ml (49 mmol) of triethylamine, 30 ml of dioxane and 3 ml (19.5 mmol) of diisopropylaminoborane were introduced into a 250 ml Schlenk vessel dried beforehand under argon. The Schlenk vessel was subsequently equipped with a reflux condenser connected at the top to a bubbler. The reaction mixture was stirred magnetically and heated at 70° C. for 15 h. The reaction mixture was subsequently allowed to return, under argon, to ambient temperature. The solvent and the excess reactants were evaporated under the vacuum of a vane pump. The residue obtained was taken up in anhydrous ether and then filtered under argon through dry Celite® 545. The filtrate was again evaporated and the residue was distilled in a Kügelrohr distillation apparatus (T=30–35° C.) under a vacuum of 0.01 mmHg. 1.694 g (Yd=85%) of a colorless oil were isolated. The spectroscopic characteristics are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NC(=O)NCC(=O)O)ccn1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(NC(=O)NCC(=O)N2CCC(Cc3ccccc3)CC2)ccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a cooled (0° C.) mixture of [3-(2-methyl-pyridin-4-yl)-ureido]-acetic acid (Example D3., 105 mg, 0.5 mmol), 4-benzylpiperidine (Example A1., 105 mg, 0.6 mmol), HOBt (81 mg, 0.6 mmol), TEA (0.14 mL, 1 mmol) and a cat. amount of DMAP in CH2Cl2 (20 mL) are added, followed by EDC (115 mg, 0.6 mmol). The mixture is stirred at r.t. for 15 h. The mixture is quenched with sat. aq. Na2CO3 (25 mL), the phases are separated, and the aq. phase is extracted with CH2Cl2 (3×30 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to provide the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH2:62])=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1>C1COCC1.C(Cl)(Cl)Cl>[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH:62][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)cc1OC

Procedure:
From 3,4-dimethoxybenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+33.4° (c=0.53, CHCl3), ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]2[C:29]3[C:28](=[O:30])[CH2:27][CH:26]([CH2:31][CH2:32][CH3:33])[CH2:25][C:24]=3[NH:23][C:22]([CH3:34])=[C:21]2[C:35]#[N:36])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl.C(OCC)(=O)C>[Br:19][C:6]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH:3]=[C:4]([CH:20]2[C:29]3[C:28](=[O:30])[CH2:27][CH:26]([CH2:31][CH2:32][CH3:33])[CH2:25][C:24]=3[NH:23][C:22]([CH3:34])=[C:21]2[C:35]#[N:36])[CH:5]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc([N+](=O)[O-])c2)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc([N+](=O)[O-])c2)c(NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
A solution of 4-[3-amino-5-bromo-4-(3-nitro-benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (1.15 g) and triethylamine (740 μl) in dichloromethane (20 ml) was treated with methanesulfonyl chloride (203 μl). After stirring for 18 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude N,N-bis-methanesulfonyl-aniline derivative was dissolved in THF (20 ml) and treated with 2N NaOH (3 ml). After 2 h, the mixture was quenched with sat. aq. NH4Cl and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH:5]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[O:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH:5]=[C:4]1[CH2:3][CH2:2][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ICCC1=COc2ccccc2O1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC1=COc2ccccc2O1
Temperature: 60 °C

Procedure:
1 g (3.47 mmol) of the iodinated compound obtained in Step D and 0.964 g (5.2 mmol) of potassium phthalimide are dissolved in 20 ml of anhydrous N,N-dimethylformamide; the reaction mixture is then heated at 60° C. for 22 hours under argon. After cooling of the mixture, the solvent is evaporated in vacuo; the residue is then taken up in ethyl acetate. After washing with water and extraction of the aqueous phase with ethyl acetate, the organic phases are dried over magnesium sulphate. The solvent is then evaporated in vacuo; the title phthalimide is then obtained pure in the form of a white solid after passage over a silica column (eluant:AcOEt/PE:30/70).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(Br)c(C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(O)ccc1Br
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene (Intermediate 143, 2.20 g, 9.60 mmols) in 50 mL CH2Cl2 at −78° C. was added BBr3 (4.81 g, 19.2 mmols; 19.2 mL of a 1M solution in CH2Cl2). After stirring for 3 hours at −78° C. the solution was warmed to 0° C. for 3 hours and then at 25° C. for 1 hour before being quenched with H2O. The mixture was diluted with Et2O and washed with H2O and saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (2.5-10% EtOAc-hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][N:25]2[S:2]([CH3:1])(=[O:4])=[O:3])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulfonyl chloride (120 μL, 1.55 mmol) and DIPEA (187 μL, 1.07 mmol) were added to a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in DCM (20 mL) and the reaction mixture stirred at ambient temperature for 17 h, then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to give (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a white solid (170 mg, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.37 (d, J=2.0 Hz, 1H); 3.83 (d, J=2.0 Hz, 1H); 3.41 (dd, J=9.2, 2.19 Hz, 1H); 3.25 (d, J=9.2 Hz, 1H); 3.20 (d, J=10.3 Hz, 1H); 3.01 (dd, J=10.3, 2.14 Hz, 1H); 2.89 (s, 3H); and 1.79 (bs, 2H)
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:15]=3[CH:16]=2)=[N:4][N:3]=[N:2]1.O1CCOCC1.[Br:28]Br.C1CCCCC=1>C(Cl)(Cl)(Cl)Cl>[Br:28][C:16]1[C:15]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[NH:1][N:2]=[N:3][N:4]=1
Reactant: BrBr
Reactant: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)cc2c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1=CCCCC1
Solvent: C1COCCO1
Product: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Yield: 84.6 %

Procedure:
A 1 L 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, dropping funnel and nitrogen bubbler was charged with 12.97 g (46.9 mmol) of 2-[2-(1H-tetrazol-5-yl)phenyl]-5-methylbenzofuran and 500 mL of 1,4-dioxane. To the well-stirred solution at room temperature was added a solution of 4.8 mL (93.2 mmol) of bromine in 35 mL of carbon tetrachloride dropwise over 1 hour. Cyclohexene (16 mL) was added to the reaction mixture then it was concentrated under vacuum to an oily residue that was partitioned between 100 mL of 1N aqueous sodium hydroxide and 100 mL of ether. The aqueous layer was removed, acidified with 50 mL of 2N aqueous hydrochloric acid, and extracted several times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum to give a white foam that was triturated with 100 mL of hot toluene. The mixture was cooled in an ice bath and the solids removed by filtration then washed with cold toluene, air dried and dried under vacuum to give 14.11 g (39.7 mmol,85%) of product. 1H NMR (200 MHz,CDCl3 +1 drop DMSO-d6)2.44 (s,3H), 7.1-7.3(m,4H), 7.6 (m,2H), 7.86 (m,1H), 7.95 (m,1H).