Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:27])[N:18]=1>O>[Cl:27][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[N:25]=[CH:26][C:17]([NH:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=1)(=[O:11])=[O:12])=[N:18]2
Reactant: Clc1cnc2c(Cl)cccc2n1
Reactant: NS(=O)(=O)c1ccc2occc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(Nc1cnc2c(Cl)cccc2n1)c1ccc2occc2c1
Yield: 15.2 %

Procedure:
In a manner similar to Example 4, the reaction mixture from benzofuran-5-sulfonamide (397 mg, 2.01 mmol), sodium hydride (60%, 315 mg, 7.9 mmol) and 2,5-dichloroquinoxaline (600 mg, 3.01 mmol) was poured carefully into water and washed with hexanes. The hexane-free aqueous was acidified to a pH of 1-2 by the addition of 5N hydrochloric acid solution and the resulting precipitate was collected and dried. This precipitate was washed with methylene chloride and the solid obtained by evaporation of the filtrate was purified by radial silica gel chromatography (EtOAc/hexanes) followed by silica gel flash chromatography (diethyl ether/hexanes). The resulting foam which was broken up in hexanes, collected and dried, finally under vacuum at 80° C. to yield the title product (110 mg, 15%) as a solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[CH2:24][C:25](OC)=[O:26]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:26]=[C:25]([CH2:24][CH:18]1[CH2:19][CH:20]2[CH2:23][CH:17]1[CH2:22][CH2:21]2)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CC1CC2CCC1C2
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CC1CC2CCC1C2)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 63.9 g (0.516 mole) dimethyl methylphosphonate (Aldrich) in 645 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 251 ml of 2.2 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose about -65°. After an additional 5 minutes stirring at -78°, 43.5 g (0.258 mole) methyl (2-norbornyl)acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 35 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 100 ml portions of chloroform (4x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, dimethyl 2-oxo-3-(2-norbornyl) propylphosphonate (b.p. 138°-141°/0.3 mm).
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]([OH:19])[CH2:8][C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][CH2:6][C@@H:7]([OH:19])[CH2:8][C@H:9]([OH:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC[C@@H](O)CC(=O)CC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC[C@@H](O)C[C@H](O)CC(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 21 h
Yield: 71.3 %

Procedure:
In the same manner as in Example 5, 15.8 mg (0.009 mmole) of Ru2Cl4 ((S)-Tol-BINAP)2 (NEt3) was weighed, and 500 mg (1.75 mmole) of t-butyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate as synthesized in Example 4 and 50 ml of methanol were added thereto to form a solution. The resulting solution was transferred to a 100 ml-volume autoclave whose atmosphere had been displaced with nitrogen, and the mixture was stirred at 30° C. for 21 hours under a hydrogen pressure of 50 kg/cm2 to conduct hydrogenation. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (diethyl ether/hexane: 5/1 by volume) to obtain 345 mg (yield: 70%) of t-butyl (3S,5S)-6-t-butoxy-3,5-dihydroxyhexanoate. The diastereoselectivity of t-butyl (3S,5S)-6-t-butoxy-3,5-dihydroxyhexanoate was determined in the same manner as in Example 5 and found to be 71 %de.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH:13]3[C:18](O)=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].ClC(OCC)=O.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[Na+]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([N:3]1[C:15]2[CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH:13]3[C:18]([N:27]=[N+:28]=[N-:29])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1c2c(c3ccccc31)C1CCC2C(C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1c2c(c3ccccc31)C1CCC2C(C(=O)N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a stirred solution of 9-ethyl-1,2,3,4-tetrahydro-1,4-ethanocarbazole-2-carboxylic acid (5.0 g, 0.0186 mole, described in Example 3) in dry tetrahydrofuran (50 ml), under nitrogen at 20°-22° C., triethylamine (11.5 ml) was added, followed by ethyl chloroformate (2.8 ml) at 20° C. After stirring at room temperature for 3 hr, the suspension of mixed anhydride was cooled to -10° C. and treated dropwise with a solution of sodium azide (2.94 g in 10 ml of water). The slurries were stirred for 1 hr at -10° C. Water was added and saturated with sodium chloride, then extracted with diethyl ether. The organic layer was washed with water, dried, evaporated to give a yellow oil (ca. 5 g) of 9-ethyl-2,3,4,9-tetrahydro-1,4-ethano-1H-carbazole-2-carbonyl azide: IR (CHCl3) 2135 cm-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](OC)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[Li+].[I-].[Na+].[N:21]1C=CC=CC=1>CN1CCCC1=O>[NH2:21][C:4]1[CH:3]=[CH:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: c1ccncc1
Agent: [Cl-]
Agent: [I-]
Agent: [Li+]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: Nc1ccc2ccccc2n1

Procedure:
The conversion of (4-chloroquinolin-7-yl)methyl ether B to compound IA is accomplished with an appropriate amine at temperatures between 0-200° C. optionally in a sealed tube and/or under microwave irradiation, either using a large excess of the amine without solvent, or on reaction with a 2-20-fold excess, in a suited solvent such as ethanol or 1-methylpyrrolidin-2-one, optionally in the presence of lithium chloride or sodium iodide and pyridine. In the case of R30=halogen, the isomeric 2-aminoquinoline derivative, which may result as a side product, is separated from the desired 4-aminoquinoline, e.g., by chromatography or crystallization.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[CH:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[CH2:10].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][CH2:2][C:3]([C:4]1[CH2:10][CH:9]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[O:6][N:5]=1)=[O:8]
Reactant: O=C(CCl)C(Cl)=NO
Reactant: C=Cc1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCl)C1=NOC(c2c(F)cccc2F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
To a stirred solution of 3-chloro-N-hydroxy-2-oxopropanimidoyl chloride (0.89 g, 5.71 mmol) in acetonitrile (20 mL) was added 2-ethenyl-1,3-difluorobenzene (1.0 g, 7.14 mmol) and sodium bicarbonate (1.8 g, 2.14 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h, concentrated in under reduced pressure and the resulting material was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, washed with saturated aqueous sodium chloride solution and concentrated in under reduced pressure. The resulting material was triturated with petroleum ether and filtered to provide the title product as white solid (1.1 g) melting at 82.1-83.4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([O:13]CC)(=[O:12])[CH:10]=[CH2:11].C(O)(=O)C.[OH-].[Na+]>>[Br:8][C:4]1[N:3]=[C:2]([NH:1][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1cccc(Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CCNc1cccc(Br)n1
Temperature: 130 °C
Yield: 68 %

Procedure:
2-Amino-6-bromopyridine (25.0 g) was added to a mixture of ethyl acrylate (17.39 g) (1.2 eq) and acetic acid (4.55 g, 0.52 eq). The reaction mixture was heated at 130° C. for 70 hours and then cooled to room temperature. An aqueous NaOH solution (6N, 60 mL, 2.50 eq) was added and the resulting mixture was heated at reflux for one (1) hour and then cooled to room temperature. The solution was washed twice with ether and then acidified to pH 4-5 with concentrated HCl. The precipitate was collected by filtration to give the title compound as a tan solid (68% yield). M.p. 108-109° C., LCMS: m/z=245.06 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.33-3.40 (m, 4H), 6.46 (d, J=8.2 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 7.02 (t, J=5.4 Hz, 1H), 7.27 (dd, J=8.2 and 7.3 Hz, 1H), 12.22 (bs, 1H).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1.S(Cl)([Cl:25])=O.CN(C)C=O>O>[Cl:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1Cl
Yield: 50 %

Procedure:
5.0 g of 2-hydroxy-3-nitro-6-(2-chloro-4-trifluoromethylphenoxy)pyridine prepared in Preparation Example 3, 3.55 g of thionyl chloride, and 0.2 ml of dimethylformamide were charged in a flask, and the mixture was allowed to react at 80° C. for 4 hours while stirring. After completion of the reaction, the reaction product was poured into water, followed by subjecting to purification in the same manner as in Preparation Example 2 to obtain 2.64 g of a titled compound having a melting point of 53° to 59° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OCC2C=CC=CC=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[NH2:7][CH:4]1[CH2:3][CH2:2][N:1]([C:23]([C:22]2[CH:21]=[N:20][C:19]([CH3:18])=[CH:27][CH:26]=2)=[O:24])[CH2:6][CH2:5]1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCC(N)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Triethylamine (14 mL; WAKO) was added to a dichloromethane (98 mL) solution of Benzyl piperidin-4-ylcarbamate (5.33 g), 6-methylnicotinic acid (which may be referred to as sco100; 4.0 g; Ald), HOAt (4.0 g; Wata) and WSC.HCl (5.7 g; Wata) and the resulting mixture was stirred overnight at room temperature. Saturated sodium hydrogencarbonate solution (50 mL) was added to the reaction mixture solution, the resulting mixture was extracted, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). Palladium carbon (10% by weight, Pe-type, 3.45 g; NECHEM) was added to a methanol (90 mL) solution of this product under a nitrogen atmosphere. The atmosphere in a reaction vessel was replaced with hydrogen at room temperature, the resulting mixture was stirred overnight, the atmosphere in the reaction vessel was returned to a nitrogen atmosphere, the residue was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound (4.05 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([F:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.C(Cl)Cl.O>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10]([F:11])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Fc1c[nH]c2nc(Cl)nc(Cl)c12
Reactant: NC1CCC1
Solvent: CCCCO
Solvent: ClCCl
Solvent: O
Product: Fc1c[nH]c2nc(Cl)nc(NC3CCC3)c12
Yield: 93.5 %

Procedure:
A solution of 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.24 mmol), cyclobutylamine (0.041 mL, 0.48 mmol) and TEA (0.070 mL, 0.50 mmol) in nBuOH (2 mL) was stirred at 70 C for 5 h. CH2Cl2 and H2O were added. The organic phase was separated, washed with 5% NaHCO3, then with 1N HCl, dried over Na2SO4, concentrated in vacuo to give 2-chloro-N-cyclobutyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (54 mg).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43](C(O)=O)([CH3:45])[CH3:44])=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=O)C.C(O[C:62]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)=[O:63])C1C=CC=CC=1.C(N1CCNCC1)C1C=CC=CC=1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:62]([N:64]4[CH2:65][CH2:66][NH:67][CH2:68][CH2:69]4)=[O:63])([CH3:44])[CH3:45])=[CH:33][C:32]=3[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(OCCCC(=O)NC(C)(C)C(=O)N2CCNCC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:23])[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([NH:6][C:5]4[C:4]([F:23])=[CH:3][C:2]([Cl:1])=[CH:21][C:20]=4[F:22])=[N:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1O
Product: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 48 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 9, 4-(4-chloro-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (150 mg, 0.44 mmol) was reacted with 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (150 mg, 0.88 mmol), (prepared as described for the starting material in Example 1), to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (113 mg, 59%).
Reaction SMILES: N1C=CC(B(O)O)=N1.Br[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=1)=[O:20])[CH2:13]2.BrC1C=C2C(=CC=1)CN(C(NC1C=C[C:53]([C:56](=O)[NH:57][CH2:58][CH2:59][CH3:60])=CC=1)=O)C2>>[CH:31]1([CH2:30][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:19]([N:14]3[CH2:13][C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:60]5[CH:53]=[CH:56][N:57]=[CH:58][CH:59]=5)[CH:11]=4)[CH2:15]3)=[O:20])=[CH:23][CH:24]=2)=[O:36])[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: OB(O)c1cc[nH]n1
Product: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(-c4ccncc4)cc3C2)cc1

Procedure:
The title compound was prepared as described in Example 280, substituting pyridin-4-ylboronic acid for 1H-pyrazol-3-ylboronic acid and 5-bromo-N-(4-(2-cyclopentylacetamido)phenyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 8.69-8.61 (m, 2H), 8.33 (s, 1H), 7.82-7.69 (m, 4H), 7.54-7.41 (m, 5H), 4.81 (bs, 4H), 2.31-2.15 (m, 3H), 1.82-1.68 (m, 2H), 1.68-1.43 (m, 4H), 1.26-1.11 (m, 2H); MS (ESI(+)) m/e 441 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:18])[C:6]1[CH:15]=[CH:14][CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[C:7]=1[O:16][CH3:17].[CH3:19]O>>[CH3:19][C:14]1[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([O:16][CH3:17])=[C:6]([CH:15]=1)[C:5]([OH:4])=[O:18]
Reactant: CO
Reactant: COC(=O)c1cccc(C(=O)OC)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)cc(C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
An aqueous solution of sodium hydroxide (5M, 100 mL) was added under cooling to a solution of 5 (0.5 mol) in methanol (1.5 L). The mixture was stirred for 3 days at room temperature. The solvents were removed under reduced pressure and the residue dissolved in hot acetone (2 L). A thick paste precipitated from the acetone solution overnight (room temperature). TLC reveals that the upper acetone solution mainly contained the starting diester and the mono-sodium salt of the acid and that the lower paste was a mixture of the mono- and disodium salt of the acid. Acetone was removed from both fractions and the chromatographic separation on a gradient flash silica gel column (0-3% methanol in CH2Cl2) of both fractions gave 40 g the desired product. Yield 63%. 1H NMR (500 MHz, CDCl3, 25° C.), δ: 3.913 (s, 3H, OCH3), 3.982 (s, 3H OCH3), 7.252 (t, J=7.75, 1H, ArH), 7.991 (d, J=7.5, 1H, ArH), 8.166 (d, J=7.5, 1H, ArH). 13C NMR (500 MHz, CDCl3, 25° C.), δ: 52.48, 64.09, 124.10, 125.67, 136.38, 136.49, 159.76, 165.46, 167.69.
Reaction SMILES: C([O:8][C:9]([C@:11]12[CH2:55][CH2:54][C@@H:53]([C:56]([CH3:58])=[CH2:57])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:52])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH2:51][C:35]4([CH2:38][C:37]([C:45]([O:47][CH:48]([CH3:50])[CH3:49])=[O:46])([C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:36]4)[CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10])C1C=CC=CC=1.C(N(CC)CC)C.[C:66]([SiH:70]([CH3:72])[CH3:71])([CH3:69])([CH3:68])[CH3:67]>ClCCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:70]([O:10][C:9]([C@:11]12[CH2:55][CH2:54][C@@H:53]([C:56]([CH3:58])=[CH2:57])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:52])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:31])([CH3:32])[C:20]([C:33]2[CH2:51][C:35]4([CH2:36][C:37]([C:39]([O:41][CH:42]([CH3:43])[CH3:44])=[O:40])([C:45]([O:47][CH:48]([CH3:50])[CH3:49])=[O:46])[CH2:38]4)[CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:8])([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:72])[CH3:71]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C[SiH](C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 44.7 %

Procedure:
To a rbf containing a solution of diisopropyl 6-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((benzyloxy)carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (0.053 g, 0.047 mmol (based on 70% purity)) in DCE (2 mL) was added triethylamine (10.43 μl, 0.075 mmol), t-butyldimethylsilane (0.016 mL, 0.094 mmol), and palladium(II) acetate (2.63 mg, 0.012 mmol). The mixture was flushed with nitrogen, then was heated to 60° C. for 4.5 h. An additional 3 mg of palladium (II) acetate were added along with 16 μL of t-butyldimethylsilane. The mixture was flushed with nitrogen, then was heated to 60° C. for an additional 2.5 h. The mixture was cooled to rt and was filtered through a plug of celite and sicla gel which was then washed with 25% EtOAc in hexanes. The filtrate was concentrated under reduced pressure to give diisopropyl 6-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-3a-(((tert-butyldimethylsilyl)oxy)carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (0.026 g, 0.021 mmol (based on 65% purity), 44.2% yield) as a clear, colorless foam. 1H NMR (500 MHz, chloroform-d) δ=5.86 (s, 1H), 5.51 (dd, J=6.3, 1.7 Hz, 1H), 5.13-5.01 (m, 2H), 4.73 (s, 1H), 4.60 (s, 1H), 3.06 (td, J=10.8, 4.1 Hz, 1H), 2.73-2.66 (m, 4H), 2.62-2.55 (m, 2H), 1.69 (s, 3H), 0.96 (s, 9H), 2.54-0.76 (m, 49H), 0.30-0.28 (m, 6H). The material was used in the next step with no additional purification.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:49]1([S:55]([N:58]2[CH2:62][C@@H:61]([C:63]([N:65]3[CH2:70][CH2:69][N:68]([C:71]4[CH:76]=[C:75]([CH3:77])[CH:74]=[CH:73][C:72]=4[CH3:78])[CH2:67][CH2:66]3)=[O:64])[NH:60][C:59]2=[O:79])(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Br[C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][N:82]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:49]1([S:55]([N:58]2[CH2:62][C@@H:61]([C:63]([N:65]3[CH2:66][CH2:67][N:68]([C:71]4[CH:76]=[C:75]([CH3:77])[CH:74]=[CH:73][C:72]=4[CH3:78])[CH2:69][CH2:70]3)=[O:64])[N:60]([C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][N:82]=3)[C:59]2=[O:79])(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3)CC2)c1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccn3)CC2)c1
Temperature: 100 °C

Procedure:
Under argon an oven-dried flask was charged with tris(dibenzylideneacetone)dipalladium (2.5 mg), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (4.7 mg), cesium carbonate (41.2 mg) and dioxane (0.75 mL). The mixture was stirred for 30 min, before a mixture of (S)-1-benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (example 66, step 3) (40 mg) and 2-bromopyridine (17.1 mg) in dioxane (0.75 mL) was added. The reaction mixture was heated to 100° C. for 4 hours and was stirred at room temperature over night. The mixture was cooled to room temperature, an aqueous solution of NaHCO3 was added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, CH2Cl2/ethyl acetate 4:1 to ethyl acetate) gave (S)-1-benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-pyridin-2-yl-imidazolidin-2-one as a light yellow solid, MS: 519.8 ([M+H]+).