Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].F[B-](F)(F)F.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O.C(O)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([Br:1])[C:7]([N:26]=[N:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)=[N:6][CH:5]=1
Reactant: Oc1cncc(Br)c1
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Agent: F[B-](F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(N=Nc2ncc(O)cc2Br)cc1
Reaction time: 1 h
Yield: 33.7 %

Procedure:
5-bromo-3-pyridinol (8.7 g, 0.05 mol) and potassium hydroxide (Fisher Scientific) were dissolved in water (200 ml). A suspension of p-nitrobenzenediazonium tetrafluoroborate (J. Org. Chem., Vol. 44, No. 9. 1979 p 1572-1573) (11.845 g, 0.5 mol) was added, and the mixture was stirred for 1 hour, diluted with acetic acid (50 ml) and filtered. The crude product was allowed to dry in air, then was chromatographed (silica gel; CHCl3 /MeOH, 95:5 to 90:10) provided 5.45 g (33.7%) of the title compound. MS (DCI/NH3) m/e 323-325 (M+H)+. 1H NMR (D6DMSO, 300 MHz) δ: 8.48-8.43 (m, 2H), 8.21-8.20 (d, J=2.37 Hz, 1H), 8.09-8.06 (m, 2H), 7.72-7.71 (d, J=2.37 Hz, 1H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]([CH:14]=[CH2:15])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[N+](=[CH2:18])=[N-]>C(OCC)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:14]1([C:13]2[C:4]([CH2:3][CH2:2][OH:1])=[CH:5][C:6]3[CH2:10][O:9][C:8](=[O:11])[C:7]=3[CH:12]=2)[CH2:18][CH2:15]1
Reactant: C=Cc1cc2c(cc1CCO)COC2=O
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1OCc2cc(CCO)c(C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 ml flask containing a stir bar was added 5-(2-Hydroxyethyl)-6-vinyl-2-benzofuran-1(3H)-one (0.9 g, 4.41 mmol), and Palladium diacetate (0.049 g, 0.220 mmol), followed by addition of a freshly prepared diazomethane (3.7 g, 88 mmol) in diethyl ether (10 mL) over a course of 20 minutes. The resulting mixture was then stirred at room temperature in a shielded environment for 1 h. When the reaction was complete, the solvent was concentrated to dryness, dissolved in EtOAc, and washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The resulting residue was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1.CCOCC>[O:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 6-bromo-2-napthol (1.12 g, 5 mmol) in anhydrous THF (15 mL) was added imidazole (0.476 g, 7 mmol) followed by TBSCl (1.05 g, 7 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 40 h and was diluted with ether, washed with brine and dried over anhydrous Mg2SO4. The solvent was removed to yield the crude product, which was recrystallized from methanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[C:19]([O:17][C:6]1[CH:7]=[CH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)c1cc(C2CCCCC2)ccc1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C2CCCCC2)ccc1OC(=O)c1cccnc1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
12 g (52 mmol) of 2-t-butyl-4-cyclohexylphenol and 10 g (56 mmol) of nicotinic acid chloride hydrochloride was mixed with 150 ml of dry pyridine and stirred for 48 hours at 35° C. After cooling precipitated pyridine hydrochloride was sucked off and the filtrate mixed with 75 ml of water. The precipitated raw product was freed from pyridine by washing with water and recrystallized from alcohol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[OH:16])[CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])([O-:3])=[O:2].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.C(O)CCC>[OH-].[Na+]>[C:18]([NH:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][C:6]1[CH:13]=[CH:14][C:15]([OH:16])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17]
Reactant: N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 1.36 g (6.00 mmol) of 3-nitro-L-tyrosine in 30 mL of 1N NaOH, 1.74 g (8.00 mmol) of (BOC)2O in 8 mL of tent-butanol was added. The stiffing was continued overnight and the tert-butanol was removed in vacuo. Ethyl acetate (25 mL) was added to the residual aqueous layer and the resulting solution was cooled to 0° C. A solution of 1N KHSO4 was used to acidify the solution to pH 2 and the aqueous layer was separated and extracted with 25 mL of ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 0.265 g (13%) of the title compound as yellow solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH2:32]=[C:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:37]([CH:35]2[CH2:36][C:33](=[CH2:32])[CH2:34]2)=[O:38])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: C=C1CC(C(=O)O)C1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylamino pyridine DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1′—Carbonyldiimidazole (CDT) (0.824 g, 5.08 mmol, 1.1 eq.) and 3-methylenecyclobutanecarboxylic acid (0-570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60° C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, IRS); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar—7 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li][CH2:23][CH2:24][CH2:25]C.C(Br)C=C>C1COCC1>[CH2:25]([C@@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[NH:12][C:11]1=[O:21])[CH:24]=[CH2:23]
Reactant: [Li]CCCC
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Temperature: 0 °C

Procedure:
A 100 mL flame-dried round-bottomed flask equipped with a magnetic stir bar was charged with (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (1.32 g, 4.12 mmol) (Example 1, Step E) and anhydrous THF (41.2 mL). This solution was cooled to 0° C. under argon and BuLi (3.30 mL, 8.24 mmol) was added. After 10 minutes allyl bromide (0.357 mL, 4.12 mmol) was added. After an additional 45 minutes the reaction was quenched by the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification using a Combiflash Companion (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) with a 120 g SiO2 column and eluting with 10 to 100% EtOAc/hexanes provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])[C:18]([Cl:36])=[CH:17][N:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)cc2N1
Yield: 60.5 %

Procedure:
8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.037 g, 0.21 mmol), (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine (0.072 g, 0.19 mmol) and 10-Camphorsulfonic acid (0.0045 g, 0.019 mmol) in Isopropyl alcohol (1 mL) was irradiated in a CEM microwave (120° C., 30 min). One mL Sodium bicarbonate and 1 mL water were added to the reaction mixture, which was then filtered and the resulting ppt was washed first with water then three times with 1 mL of Isopropyl alcohol. The solid was then purified by silica gel chromatography (ISCO, 0-100% EtOAc) to afford 8-{5-Chloro-4-[2-(pyrrolidine-1-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a white powder (59 mg, 60%). MP 249-251° C.; LCMS: 513 (M+H); 1H-NMR (DMSO): 9.56 (s, 1H), 9.45 (s, 1H), 9.41 (s, 1H), 8.61 (s, 1H), 8.29 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.67 (dd, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 3.14 (t, J=4.0 Hz, 4H), 2.62 (t, J=8.0 Hz, 2H), 2.15 (t, J=8.0 Hz, 2H), 2.07 (m, 2H), 1.68 (m, 4H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:19](=[O:32])[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[C:14]([CH:18]=1)[C:15](O)=[O:16])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O[N:35]1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:18]=[C:14]2[C:13]([C:19]([OH:32])([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[NH:35][C:15]2=[O:16])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: COc1cc(C(=O)c2ccc(OC(=O)c3ccccc3)cc2C(=O)O)cc(OC)c1OC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2(O)NC(=O)c3cc(OCc4ccccc4)ccc32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of 5-benzoyloxy-2-(3,4,5-trimethoxybenzoyl)benzoic acid 50 mg, 14.8M aqueous ammonia 50 μl, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimido.hydrochloride 68 mg and 1-hydroxybenzotriazole 15.9 mg is dissolved under ice cooling in N,N-dimethylformamide 2 ml and the mixture is stirred overnight at room temperature. To the reaction mixture is added water. The mixture is extracted with ethyl acetate and the extract is washed with water and dried, followed by removal of the solvent. The residue is purified with silica gel chromatography (solvent: chloroform:ethyl acetate=1:1) and left to be crystallized. The crystals are triturated with diisopropyl ether-ethyl acetate to give 6-benzyloxy-3-hydroxy-3-(3,4,5-trimethoxyphenyl)-2,3-dihydroisoindol-1-one 46.7 mg. mp 187-189° C.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])#[N:7].[CH2:26]([O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH2:26]([O:33][C:34]1[CH:39]=[C:38]([C:12]2[C:13]([CH3:14])=[C:8]([C:6]#[N:7])[C:9]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:10]([O:17][CH3:18])[C:11]=2[F:16])[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(F)c(-c2cccc(OCc3ccccc3)c2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Temperature: 95 °C
Reaction time: 5.5 h
Yield: 73 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (287 mg, 249 μmol) was added to an N,N-dimethylformamide (16.5 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2,2-trifluoroacetamide (I-35) (500 mg, 1.24 mmol), 3-benzyloxyphenylboronic acid (425 mg, 1.87 mmol), potassium phosphate n-hydrate (74-78%, 713 mg, 2.49 mmol), followed by stirring at 95° C. for 5.5 hours. The reaction liquid was cooled, then ethyl acetate (100 ml) was added, followed by washing with saturated brine (50 ml×3), drying over anhydrous magnesium sulfate, concentration under reduced pressure. The residue was purified twice by silica gel column chromatography (n-hexane:ethyl acetate=4:1), (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (415 mg, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12]([O:19][CH2:20][CH2:21]O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:12]([O:19][CH2:20][CH2:21][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCOCc1ccccc1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
3-Methyl-4-nitrophenol (17.48 g, 114 mmoles), 2-benzyloxyethanol (17.38 g, 114 mmoles, 16.22 ml) and triphenylphosphine (44.6 g, 170.2 mmoles) were dissolved in anhydrous tetrahydrofuran (200 ml) under nitrogen at room temperature. The stirred reaction mixture was then cooled to 0° C. and stirred for 10 minutes. Diisoproplyazo-dicarboxylate (23.49 g, 116.2 mmoles, 22.97 ml) was then added in one lot, and the reaction mixture was allowed to warm to room temperature and stirred overnight (16 hours). The solvent was removed under reduced pressure and the crude mixture was purified via column chromatography (silica gel, 5% ethyl acetate-hexane) to give the product. The remaining impurities were removed by means of crystallization from hexane ethyl acetate. The result crystals were filtered off and the mother liquor was evaporated under reduced pressure to give 21.56 g of 4-(2-(benzyloxy)ethoxy)-2-methyl-1-nitrobenzene. 1H-NMR (CDCl3) 8.08 (d, 1H), 7.38.7.31 (m, 3H), 6.82 (m, 2H), 4.65 (s, 2H), 4.23 (t, 2H), 3.87 (t, 2H), 2.63 (s, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:43][C@@H:44]1[CH2:47][C@H:46]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])[C:45]1([CH3:57])[CH3:56]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:43][C@@H:44]4[CH2:47][C@H:46]([C:48]([N:50]5[CH2:55][CH2:54][O:53][CH2:52][CH2:51]5)=[O:49])[C:45]4([CH3:57])[CH3:56])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.270 g, 0.542 mmol) in DCM (1 ml) 2M solution of (COCl)2 in DCM (2.71 ml, 5.42 mmol) was added at about 0° C. and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of ((1S,3R)-3-amino-2,2-dimethylcyclobutyl)(morpholino)methanone (Intermediate 14, 0.172 g, 0.0813 mmol) in DCM at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, 1N HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.310 g: Yield: 82%; 1H NMR (300 MHz, CDCl3): δ 5.83 (d, 1H, J=7.8 Hz), 4.72 (s, 1H), 4.58 (s, 1H), 4.51-4.40 (m, 1H), 4.19-4.08 (m, 1H), 3.81-3.40 (m, 8H), 3.18-3.05 (m, 1H), 2.90-2.82 (m, 1H), 2.54-2.21 (m, 3H), 2.04 (s, 3H), 1.99-1.83 (m, 2H), 1.80-1.12 (m, 27H), 1.08-1.70 (s, 18H); Mass: [M+1]+ 693 (15%), [M+Na]+ 715 (28%); JR (KBr, cm−1): 3388, 2954, 2867, 1716, 1659, 1633, 1524, 1449, 1366, 1271, 1235, 1119, 1038, 980, 892; M.R: 71.6° C.-78.9° C.
Reaction SMILES: C(OC(=O)C([N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=O)C.[Li+].[OH-]>C1COCC1.O>[C:16]([O:15][C:13](=[O:14])[NH:7][CH:8]1[CH2:9][CH:10]=[CH:11][CH2:12]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C(=O)N(C(=O)OC(C)(C)C)C1CC=CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC=CC1
Temperature: 0 °C
Yield: 53 %

Procedure:
To a stirred solution cooled in an ice-water bath of the above crude product, (tert-butoxycarbonyl-cyclopent-3-enyl-amino)-oxo-acetic acid ethyl ester, (3.80 g) in THF (35 mL) was added a solution of LiOH (0.0765 mol) in water (35 mL). The mixture was stirred in the ice-water bath for 3 h. The organic material was extracted with CH2Cl2 (30 mL×3), the organic layers were combined and washed with brine (30 mL×2), and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 100% dichloromethane) to obtain white crystals of pure product (53%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][CH2:27][CH2:26][CH2:25][Br:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCCBr
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 12.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 240 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.08 mol. of sodium hydride (3.5 g. of a 55% dispersion in mineral oil) and stirred in an ice-bath for 30 minutes. Then, there are added thereto at -10° C. 26.0 g. of 1,4-dibromobutane in one batch; the mixture is thereafter stirred at room temperature for 1 hour and subsequently heated at 60° C. for 18 hours. After cooling, the mixture is poured into 2 liters of ice-water, 100 g. of sodium chloride are added and the separated oily product is immediately extracted with methylene chloride. The organic phase, shielded from daylight, is washed with a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness under reduced pressure. The resulting oil is taken up in chloroform and chromatographed on 500 g. of silica gel with chloroform/n-heptane/ethanol (10:10:1) as the eluant, care is taken that the eluate remains shielded from daylight. The uniform fractions are combined and evaporated, and there is obtained 2-(4-bromobutyl)-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester as an oil, which has to be employed in the next stage as quickly as possible.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][OH:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][O:19][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc(O)c1
Reactant: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OC[C@@H]2CN(CCN3CCc4ccccc43)CCO2)c1
Yield: 62.4 %

Procedure:
Essentially the same procedure was used to make compound 25s as was used for compound 18s (Example 16), with compound 51 (Example 10; 52 mg, 0.2 mmol), 3-methoxyphenol (0.032 ml, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), and THF (1 ml). The crude residue was purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2) to afford the title compound as a colourless oil (46 mg; 62%). Analyses were performed on the free base, and the free base was converted to the HCl salt for testing.