Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>CN1CCCN(C)C1=O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cc1ccccc1OCc1ccccc1I
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(C(=O)OC)c1ccccc1COc1ccccc1C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion) (15.4 g) in 90 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2[1H]-pyrimidinone (DMPU), cooled in an ice-water bath, was added dropwise a solution of dimethyl malonate (44 mL) in DMPU (150 mL). The mixture was stirred 20 minutes after the addition was completed, and then 1-iodo-2 -[(2-methylphenoxy)methyl]benzene (62.5 g) and cuprous iodide (73.3 g) were added. The resulting mixture was stirred at 100° C. for 5 h, then stirred at 25° C. overnight. The mixture was diluted with 1 N. HCl (~150 mL) and extracted with diethyl ether (3×400 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to a semi-solid, which was purified by flash chromatography on silica get (5:2 hexane:ethyl acetate as eluant). The major material was collected and concentrated to a white solid, which was triturated in hexane and collected by filtration to yield 56.9 g (79% of the title compound of Step C as a white solid, mp 99-103° C.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)[C:5](N[C@H](C1C=CC=CC=1)CO)=[O:6])[CH3:2].S(=O)(=O)(O)[OH:39].O1CCOCC1>O>[CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=2)=[CH:22][CH:23]=1)[C:5]([OH:6])=[O:39])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Yield: 79 %

Procedure:
(S)-2-Ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide (4.49 g; 8.59 mmole), concentrated sulfuric acid (12.5 ml), dioxan (50 ml) and water (50 ml) were stirred at 80° C. for 6 hours. After cooling, water (100 ml) was added and the product was extracted with dichloromethane (2×100 ml). The organic phases were combined and washed with brine (60 ml), dried (sodium sulfate), filtered and evaporated in vacuo. Purification by chromatography on silica gel using heptan:ethyl acetate:acetic acid (10:10:1) as gradient and azeotropic destination with toluen gave 2.78 g (yield 79%) of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]propanoic acid.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][O:24][CH2:23]1)#[CH:21]>>[F:19][C:3]1[C:2]([C:21]#[C:20][C:22]2([OH:27])[CH2:26][CH2:25][O:24][CH2:23]2)=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC1(O)CCOC1
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CCOC3)c(F)cc1OCC2
Yield: 19 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-ethynyloxolan-3-ol (US2010/144757 A1, 2010) to give the titled compound as a light brown solid (41 mg, 19%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2([C:16](=[O:18])[CH3:17])[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]1([C@H:7]([NH:9][C:10]([C:12]2([C:16]3([O:21][CH2:20][CH2:19][O:18]3)[CH3:17])[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C1(C(=O)N[C@H](C)c2ccccc2)CCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C[C@@H](NC(=O)C1(C2(C)OCCO2)CCC1)c1ccccc1

Procedure:
A mixture, of 13.9 g of N-[1-(R)-phenylethyl]-1-acetyl-1-cyclobutanecarboxamide, 15 ml of ethylene glycol, a catalytic amount of p-toluenesulfonic acid and 100 ml of benzene was heated under reflux for 3 hrs. The water formed in the reaction was removed using a Dean-Stark apparatus. After cooling, the mixture was washed with a saturated sodium bicarbonate aqueous solution, then washed with water and then dried. The solvent was removed under reduced pressure to yield 16.5 g of the titled compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([Cl:10])=[C:7]([Cl:9])[CH:8]=1)([O-])=O.[C:11](O)(=[O:13])[CH3:12].C(OC(=O)C)(=O)C.Cl>[Fe].O>[Cl:9][C:7]1[CH:8]=[C:4]([NH:1][C:11](=[O:13])[CH3:12])[S:5][C:6]=1[Cl:10]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)s1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of the above 4,5-dichlorothiophene (13.0 g, 66.0 mmol) are added acetic acid (78 ml) and acetic anhydride (78 ml), followed by iron powder (13.0 g) in portions over 30 min. at such rate that the mixture is kept at 5°-10°. The suspension is stirred at RT overnight, after which it is poured into water, acidified with conc. HCl and cooled in an ice bath for 6 hours. It is then filtered, and the solid is washed with water and dried, dissolved in ether and filtered. Charcoal is added to the filtrate, which is then filterded and stripped of solvent to give N-(4,5-dichloro-2-thienyl)acetamide, a solid.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)CO2
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)NC(=O)CO4)nc2c1
Yield: 48.4 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.15 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.3 g) and 2-amino-4-methylpyridine (2.5 g). mp. 239°-241° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]#[C:13][Si](C)(C)C)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:8]3[C:9](=[C:10]([C:12]#[CH:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]=3[OH:28])[S:18][N:19]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Yield: 86.7 %

Procedure:
A mixture of 3-(4-Chloro-phenyl)-4-hydroxy-7-trimethylsilanylethynyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (51.5 mg, 0.119 mmol), glycine (269.7 mg, 3.59 mmol) and NaOMe (5.98 mL, 2.99 mmol, 0.5 M solution in MeOH) was refluxed for 24 h before it was concentrated in vacuo. The residue was dissolved in water (50 mL). The solution was then washed with CH2Cl2 (2×20 mL) before it was acidified by addition on aqueous 1N HCl solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo to give the title compound (40 mg) as white solid: MS (m/z) 388.0 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]1=O)[CH3:2].[OH-].[K+]>CCO.CCOC(C)=O>[CH2:1]([C:3]12[CH2:16][C:17](=[O:19])[CH:18]=[C:4]1[C:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8]([O:13][CH3:14])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC12CCc3cc(OC)ccc3C1=CC(=O)C2

Procedure:
A solution of crude 2-ethyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone (758 mg, 3 mmol) in EtOH (15 mL) was treated with freshly prepared 2N KOH in EtOH (1.5 mL, 3 mmol). The resulting solution was heated at reflux for 24 hours. After cooling, the mixture was diluted with EtOAc (70 mL) and washed with 1N HCl (35 mL) followed by 5% NaHCO3 (35 mL). The NaHCO3 phase was back-extracted with EtOAc (60 mL). The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40 M (4×15 cm) silica gel column, eluting with 4:1 hexane-EtOAc, to provide 3a-ethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an oil.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][OH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OCCCOCc1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCCCOCc1ccccc1

Procedure:
The title compound, colorless oil, MS: m/e=403.5 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 3-benzyloxy-propan-1-ol.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 67.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 82 mg of 5-methoxy-2-oxindole, and 2 drops piperidine in 2 mL of ethanol were heated to 95° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 110 mg (67%) of the title compound as a brown solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(O[CH:10]1[C@H:15]([N:16]=[C:17]=[S:18])[C@@H:14]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:23][C:24](=[O:26])[CH3:25])[C@@H:12]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:11]1)(=O)C.C(N(CC)CC)C>ClCCl>[C:24]([O:23][C@@H:13]1[C@@H:12]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:11][C@H:10]2[C@H:15]([N:16]=[C:17]([N:2]3[CH2:5][CH2:4][CH2:3]3)[S:18]2)[C@H:14]1[O:19][C:20](=[O:22])[CH3:21])(=[O:26])[CH3:25]
Reactant: C1CNC1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of azetidine hydrochloride (12 g, 129 mmol) and (3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (48 g, 123 mmol) in dichloromethane (500 mL) was treated with triethylamine (18.7 g, 185 mmol) for 1 h at room temperature, and followed by addition oftrifluoroacetic acid (56.2 g, 493 mmol). The reaction mixture was stirred overnight at room temperature, and then quenched by aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous MgSO4, and condensed under vacuum to give a residue, which was purified by a silica gel column, eluted with 1% methanol in dichloromethane to provide compound 2 as a light yellow syrup (29 g, 61%). (ES, m/z) [M+H]+ 386.9; 1H NMR (300 MHz, CDCl3) 6.28-6.30 (d, J=6.6 Hz, 1H), 5.44-5.46 (m, 1H), 4.95-4.99 (m, 1H), 4.34-4.37 (t, J=5.4 Hz, 1H), 4.04-4.17 (m, 6H), 3.86-3.92 (m, 1H), 2.34-2.44 (m, 2H), 2.06-2.14 (m, 9H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(-c2csc(Br)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Yield: 52 %

Procedure:
A solution of 2-bromo-4-(4-fluorophenyl)-1,3-thiazole (4.49 g, 17.4 mmol), tert-butyl piperazine-1-carboxylate (6.48 g, 34.8 mmol) and potassium carbonate (2.4 g, 17.4 mmol) in dimethylformamide (55 ml) was stirred at 120° C. for 8 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (3.29 g, 52%) as an oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CC2)nn1
Yield: 80 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (118 mg, 80%) which was obtained as a white solid. MS: m/e=369.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=2[CH2:9][CH2:8]1.[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.O>[CH2:19]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][CH2:8][CH2:7]2)[CH:18]=[CH2:17]
Reactant: Oc1cccc2c1CCC2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of potassium carbonate (23.49 g, 0.170 mol) in N,N-dimethylformamide (350 mL) was added indan-4-ol (7.60 g, 0.057 mol) followed by allyl bromide (8.22 g, 0.068 mol) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (1000 mL) to dissolve any solids and extracted with diethyl ether (3×250 mL). The combined organic layers were washed with water (4×500 mL), aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give 4-(allyloxy)indane. The allyl ether was dissolved in mesitylene (40 mL) and heated at reflux for 8 h. Removal of the solvent in vacuo provided 5-allylindan-4-ol, which was re-dissolved in N,N-dimethylformamide (250 mL). Potassium carbonate (14.28 g, 0.103 mol), benzyl bromide (6.48 g, 0.038 mol), and tetrabutylammonium iodide (2.54 g, 0.007 mol) were added to the reaction mixture. The reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (1000 mL) to dissolve any solids and extracted with diethyl ether (3×250 mL). The combined organic layers were washed with water (4×500 mL), aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 10.22 g (68%) of 5-allyl-2,3-dihydro-1H-inden-4-yl benzyl ether as a pale yellow oil. Rf=0.45 (silica, ethyl acetate:hexanes 1:19); Anal. calcd. for C19H20O: C, 86.32; H, 7.63. Found: C, 85.90; H, 7.49.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([N:28]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]4)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: OC1CCNC1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCC(O)C4)cc3)cc12

Procedure:
1-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2yl)ethyl)phenyl)ethyl)pyrrolidin-3-ol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and pyrrolidin-3-ol following the procedures described for Example 187, except that in this case, acetic acid was used instead of triethylamine (20%). 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.76 (s, 1H), 8.72 (s, 1H), 8.29 (d, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.33-7.38 (m, 3H), 4.41 (m, 2H), 3.77 (m, 2H), 3.33 (t, 2H), 3.21 (t, 2H), 3.19 (m, 2H), 3.10 (m, 2H), 2.10 (s, 3H), 1.75 (d, 3H). LRMS [M+H]=427.2
Reaction SMILES: CS(O[CH:6]([CH:18]1[CH2:20][CH2:19]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=O)=O.C([O-])(C)(C)C.[K+].O>CS(C)=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]1[CH2:7][CH:6]1[CH:18]1[CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Reaction time: 1.5 h

Procedure:
1.06 g of 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate (3.54 mmol) is dissolved in 20 ml of dimethyl sulfoxide, 1.05 g of potassium tert-butanolate (97%, 10.62 mmol) are added, and stirring is carried out for 1.5 hours at ambient temperature under a nitrogen atmosphere. Water is added to the reaction mixture. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate/hexane 1:10). After removal of the eluant, 0.68 g of 2-(2-nitrophenyl)-bicyclopropane (67% of theory) are obtained in the form of an orange-coloured liquid (trans:cis ratio: 7.7:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:26]([CH3:25])(=[O:28])=[O:27])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(N)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Cc2ccc(NS(C)(=O)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
To a solution of 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine (P-252) synthesized above (70 mg, 0.18 mmol) in pyridine (2 ml) was added methanesulfonyl chloride (23 mg, 0.20 mmol) at 0 C under nitrogen, and stirred at room temperature for 20 h. The reaction mixture was diluted with water, neutralized with 6N HCl, extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. After it was concentrated in vacuo, the residue was purified by a chromatography on silica gel to yield N-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methanesulfonamide (P-258) (25 mg, 32%). 1H NMR (400 MHz, CDCl3) 8.15 (s, 1H), 7.58 (dd, J=8.8, 2.1 Hz, 1H), 7.38 (s, 1H), 7.34 (t, J=6.6 Hz, 3H), 7.24-7.31 (m, 2H), 7.11 (t, J=8.5 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 3.89 (s, 2H), 3.77 (s, 3H), 3.09 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[C-:19]#[N:20].C(OCC)(=O)C>N1C=CC=CC=1>[NH2:18][C:3]1[C:2]([C:19]#[N:20])=[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:6]=[C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:4]=1
Reactant: Nc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Reactant: [C-]#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1c(N)nc(-n2cccn2)nc1-n1cccn1
Yield: 39.6 %

Procedure:
A mixture of 0.2 g (0.65 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine and 0.06 g (0.72 mmol) of cupper (I) cyanide in 3 ml of pyridine was irradiated with microwaves at 250° C. for 20 min. After nearly complete conversion to the corresponding carbonitrile as was indicated by TLC, ethyl acetate was added and filtered throw celite. The solution was extracted two times with 10 ml of saturated solution of NaHCO3 and Brine. The organic layer was separated, dried with MgSO4 and concentrated to give 0.065 g (39.6%) of the desired product.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@:14]3([CH3:38])[C@@H:23]2[CH2:22][CH2:21][C@H:20]2[C@@:15]3([CH3:37])[CH2:16][CH2:17][C@@:18]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:29][C@@H:28]([C:31]([CH3:33])=[CH2:32])[C@@H:19]32)[C:10]1([CH3:40])[CH3:39]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:2]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@:14]3([CH3:38])[C@@H:23]2[CH2:22][CH2:21][C@H:20]2[C@@:15]3([CH3:37])[CH2:16][CH2:17][C@@:18]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:29][C@@H:28]([C:31]([CH3:33])=[CH2:32])[C@@H:19]32)[C:10]1([CH3:40])[CH3:39])(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
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](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: 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
Temperature: 25 °C
Yield: 59.8 %

Procedure:
Ac2O (about 0.93 ml, 9.87 mmol) was added to a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (Betulinic acid, about 0.3 g, 0.657 mmol) and DMAP (about 0.167 g, 1.32 mmol) in pyridine (about 15 ml) at about 0° C. then the reaction mixture was slowly warmed to room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture poured in to ice water and extracted with EtOAc and washed with water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200, elution 10% EtOAc in hexane) to afford title compound as a off white solid. Wt: 0.196 g; Yield: 59.8%; 1H NMR (300 MHZ, CDCl3): δ 4.74 (s, 1H), 4.61 (s, 1H), 4.50-4.44 (m, 1H), 3.02-2.97 (m, 1H), 3.01-2.12 (m, 2H), 2.04 (s, 3H), 1.99-1.92 (m, 2H), 1.69 (s, 3H), 1.68-1.57 (m, 6H), 1.56-1.32 (m, 10H), 1.31-1.01 (m, 5H), 0.97, 0.93 (2s, 6H), 0.85 (Brs, 9H); Mass: [M−1] 497 (100%); IR (KBr, cm−1): 3296, 2945, 1736, 1694, 1464, 1368, 1247, 1196, 1161, 1024, 980, 884, 777, 543; M.R: 283.7° C.-290.1° C.; HPLC: 97.17%.