Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=O)=[O:15])=[C:9]([C:25](=[O:42])[NH:26][C:27]3[CH:31]=[CH:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=4)[N:28]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:52]CC1C=C(C=CC=1)C(Cl)=O>O1CCCC1>[Br:52][CH2:19][C:18]1[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=1)[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:8][C:9]=1[C:25]([NH:26][C:27]1[CH:31]=[CH:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=2)[N:28]=1)=[O:42])=[O:15]
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Reactant: O=C(Cl)c1cccc(CBr)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 111 %

Procedure:
Into a 50-mL round bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and N,N-diisopropylethylamine (60 mg, 0.47 mmol, 2.00 equiv). To this was added 3-(bromomethyl)benzoyl chloride (75 mg, 0.32 mmol, 1.39 equiv), in portions at 0° C. The resulting solution was stirred for 2.5 h at room temperature. The reaction progress was monitored by LCMS/TLC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water, extracted with 3×10 mL of ethyl acetate, and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 160 mg (88%) of product as a brown solid.
Reaction SMILES: [CH3:1][CH:2](NCCC(O)=O)[CH2:3][CH2:4]CC.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.BrCCCCC.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].C(=O)(O)[O-].[K+]>>[CH2:13]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C)NCCC(=O)O
Reactant: CNCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCBr
Product: CCCCCNCc1ccccc1

Procedure:
The present invention also provides a process for the synthesis of 3-[N-(methylpentyl)amino]propionic acid (III) wherein N-methylbenzylamine is reacted with 1-bromo pentane in presence of a base like potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate preferably potassium carbonate to get N-methyl, N-pentyl benzyl amine (VI) which is subjected to debenzylation using 10% Pd/C as catalyst in an alcoholic solvent to get N-methyl, N-pentylamine (V) which is isolated in pure form as an acid addition salt of an organic acid such as fumaric acid, citric acid, maleic acid, edetic acid preferably it is isolated as an oxalate salt. Compound (V) is reacted with methyl-3-halopropionate like methyl 3-chloro propionate, methyl-3-bromo propionate, methyl 3-iodo propionate more preferably methyl-3-bromo propionate in a suitable solvent preferably toluene in the presence of a base preferably potassium carbonate at a temperature ranging from 25° C. to 80° C. preferably at 70° C. to get 3-[N-(methylpentyl)amino]propionate (IV), which is further hydrolyzed to give 3-[N-(methylpentyl)amino]propionic acid hydrochloride (III) which is the key intermediate for the synthesis of Ibandronate sodium.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:38]4[CH2:39][CH2:40][N:35]([C:32](=[O:34])[CH3:33])[CH2:36][CH2:37]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: CC(=O)N1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-acetylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=557.97 (M+H+); retention time=0.68 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[NH:13][CH:12]=[N:11][C:10]=2[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]3[CH2:22][C@@H:21]3[C:23](O)=[O:24])=[CH:16][CH:15]=2)=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C[CH2:41][N:42](C(C)C)[CH:43](C)C.CNC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[NH:13][CH:12]=[N:11][C:10]=2[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]3[CH2:22][C@@H:21]3[C:23]([N:42]([CH3:43])[CH3:41])=[O:24])=[CH:16][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(O)[C@H]1C[C@@H]1c1ccc(-c2nc[nH]c2Sc2ccc(Cl)cn2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H]1C[C@@H]1c1ccc(-c2nc[nH]c2Sc2ccc(Cl)cn2)cc1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
(1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-1H-imidazol-4-yl}phenyl)cyclopropanecarboxylic acid (Step 3 product, 73 mg, 0.196 mmol), HOBT (60 mg, 0.393 mmol), and EDC (113 mg, 0.589 mmol) were dissolved in 3 mL of DMF, to which were added Hunig's base (0.206 mL, 1.178 mmol) and dimethyl amine (2 M THF solution, 0.294 mL, 0.589 mmol). The reaction was heated at 80° C. for 30-60 min. Upon cooling to rt, the reaction was diluted with EtOAc (80 mL), and the reaction mixture was washed with water (2-3 times) and brine, dried, and concentrated to dryness. The residue was purified by silica column (80-100% EtOAc in hexanes) to give 62 mg (79%) of the title compound. 1H NMR (500 MHz, (CD3OD): 8.38 (s, 1H), 7.97 (s, 1H), 7.65 (d, 2H), 7.59 (d, 1H), 7.18 (d, 2H), 6.82 (d, 1H), 3.16 (s, 3H), 2.97 (s, 3H), 2.38 (m, 1H), 2.19 (m, 1H), 1.54 (m, 1H), 1.27 (m, 1H). LCMS: m/z 399 (M+H)+. Human FAAH lysate assay: IC50=649.6 nM.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-nitrophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (14 mg, 0.04 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (14 mg, 0.12 mmol). Methyl iodide (0.03 mL, 0.08 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 10 mg (70%) of the title compound as a white solid. mp 59°-60°. FDMS: m/e=350.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:25]=[N+:26]=[N-:27].[Na+].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[NH:27][N:26]=[N:25][N:14]=2)=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A mixture of 285 g of the nitrile, 262.5 g triethylamine hydrochloride and 124 g of sodium azide in 1.5 L of DMF under nitrogen was stirred under reflux for 18 hrs. The reaction mixture was cooled to room temperature, poured into 4 L of cold water and acidified with 3N HCl. The resulting white solid was collected, washed with water and dried at 60° C. in vacuo for 48 hrs to give 337 g of 5-(4-benzyloxyphenyl)tetrazole.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])=[CH:25][N:26]=1)[C:21](O)=[O:22]>>[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])=[CH:25][N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: Nc1cc(C(=O)O)c(F)cn1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: CC(NC(=O)c1cc(N)ncc1F)c1ccc(OCC(F)(F)F)nc1
Yield: 24 %

Procedure:
The title compound is prepared in 24% yield (102 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.17 mmol, Amine-1, single enantiomer) and 2-amino-5-fluoroisonicotinic acid (182 mg, 1.17 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[CH:21]([O:24][C:25]1[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([NH2:32])[CH:26]=1)([CH3:23])[CH3:22]>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:26]2[C:25]([O:24][CH:21]([CH3:22])[CH3:23])=[N:30][C:29]([NH2:31])=[N:28][C:27]=2[NH:32][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: CC(C)Oc1cc(N)nc(N)n1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2nc(N)nc(OC(C)C)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.37 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione and 62 mg (0.37 mmol) of 6-isopropoxypyrimidine-2,4-diamine are dissolved in 5 ml of isopropanol and heated under reflux under argon for 2 days. The mixture is filtered and the remaining solid is washed with isopropanol. 80 mg (51% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: O.[F:2][C:3]1[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]([O:7][C:8]2[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[N:12][CH:13]=2)=[C:5]([N+:35]([O-])=O)[CH:4]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:35][C:5]1[CH:4]=[C:3]([F:2])[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]=1[O:7][C:8]1[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[N:12][CH:13]=1
Reactant: COC(=O)COc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 35 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a mixture of 0.4 g of an iron powder, 2 ml of acetic acid and 0.2 ml of water was added a solution of 0.393 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxypyrimidine in 1 ml of acetic acid and 2 ml of ethyl acetate dropwise. After completion of the addition, the mixture was stirred for 1 hour at room temperature, for 2 hours at 30-40° C. Water was added to the mixture, then, the mixture was filtrated through Celite, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was subjected to silica gel chromatography to obtain 0.315 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C:19]4([CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[N:18]4[C@@H:13]([C:14](=[O:39])[O:15][C@@H:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@H:17]4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:12]3[C:40]3[CH:45]=[CH:44][N:43]=[C:42]([Cl:46])[C:41]=3[F:47])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-:49].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:12]([C:40]4[CH:45]=[CH:44][N:43]=[C:42]([Cl:46])[C:41]=4[F:47])[C@H:13]([C:14]([OH:49])=[O:39])[N:18]([C@H:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:16]([OH:15])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]43[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1ccnc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
The compound (630 mg, 0.94 mmol) obtained in Step 2 was dissolved in acetonitrile (10 ml) and water (4 ml), potassium carbonate (130 mg, 0.94 mmol) was added and the resulting mixture was heated to reflux at 85° C. for 16 hours. After cooling, anhydrous magnesium sulfate (113 mg, 0.94 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. After extraction with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-1′-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylic acid (650 mg, 100%) as a solid [MS (ESI) m/z: 688 (M+H)+]. The carboxylic acid (650 mg, 0.94 mmol) obtained was dissolved in methanol (30 ml) and water (8 ml), cerium (IV) diammonium nitrate (1.55 g, 2.82 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. Potassium carbonate (780 mg, 5.64 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. Insoluble matter was removed by filtration through celite, then the filtrate was concentrated under reduced pressure and water was added to the residue obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=20:1→4 4:1 (v/v)] to give 152 mg (33%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16]C(C)(C)C)=[O:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(F)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-(3-fluorophenyl)picolinate 33-5 (414 mg, 1.51 mmol) in dichloromethane (3 mL) was added TFA (1.5 mL) dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (100 mL) and H2O (100 mL), adjusted with Na2CO3 to pH around 4, and separated. The organic layer was washed with H2O and brine, dried over Na2SO4, concentrated to dryness to afford 5-(3-fluorophenyl)picolinic acid 6-7 as an off-white solid. MS m/z 218.1 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:19](=[C:16]1[CH:17]=[CH:18][NH:13][CH:14]=[CH:15]1)[C:5]2=[O:12]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: Cc1ccncc1
Solvent: CCO
Product: O=C1C(=C2C=CNC=C2)C(=O)c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Under N2 atmosphere, a mixture of 30 g (132 mmol) 5-bromoisobenzofuran-1,3-dione (≡4-bromophthalic acid anhydride; Apin, GB) and 12.87 ml (132 mmol) 4-picoline is heated for 15 h to 180° C. The resulting black mass is cooled to 100° C., mixed with 160 ml ethanol, boiled for 2 hours, and filtered off. The dried residue is triturated in a mortar, boiled further for 1 h in 180 ml ethanol, filtered, and washed with ethanol. The residue is dissolved at 140° C. in 90 ml DMEU, cooled, mixed with 250 ml ethyl acetate and filtered (→residue is washed out with ethyl acetate and discarded). The ethyl acetate from the filtrate is evaporated off and the residue then diluted with 260 ml acetonitrile, the title compound crystallizing out in the process: HPLC: tRet(Grad20-100)=10.4; MS (M)+=301/303.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:17]=[N:16][N:15]=1.O.[CH2:29]([C:31]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46](B3OCC(C)(C)CO3)=[CH:45][CH:44]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)[CH3:30]>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.C1(C)C=CC=CC=1.CO>[CH2:29]([C:31]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)[N:17]=[N:16][N:15]=3)=[CH:45][CH:44]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)[CH3:30]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2Br)cc1
Reactant: CCc1cc(OCc2ccc(B3OCC(C)(C)CO3)cc2)c2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 58.2 %

Procedure:
A mixture of potassium carbonate (1.08 g; 7.8 mmol), 5-(2-bromophenyl)-1-(4-nitrophenyl)-1H-tetrazole (1.16 g; 3.2 mmol) water (10 ml), toluene (10 ml), and methanol (10 ml) was heated to 60° C. to give a clear solution. 2-(4-[(2-Ethylquinolin-4-yloxy)-methyl]phenyl)-5,5-dimethyl-1,3,2-dioxaborinane (1.0 g; 2.6 mmol) and tetrakis(triphenylphosphine)palladium (0.06 g; 0.05 mmol) were added and the reaction mixture heated at reflux for 6 hours. The mixture was allowed to cool and further toluene (10 ml) added. The organic phase was separated and the aqueous phase extracted with toluene (2×20 ml). The combined organic phases were evaporated and the resultant solid recrystallised from toluene to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline as a solid (0.8 g); m.p. and NMR similar to that of the product of Example 5.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:35])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:34])[CH2:9][CH2:10][C@@:11]3(/[CH:28]=[C:29](\[CH3:33])/[C:30](O)=[O:31])[CH2:23][C:22](=[O:24])[C:21]([CH:25]([CH3:27])[CH3:26])=[C:12]32)[C:3]1([CH3:37])[CH3:36].Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2([NH2:49])[CH2:48][CH2:47]2)=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2([NH:49][C:30](=[O:31])/[C:29](/[CH3:33])=[CH:28]/[C@:11]34[CH2:23][C:22](=[O:24])[C:21]([CH:25]([CH3:26])[CH3:27])=[C:12]3[C@@H:13]3[C@@:8]([CH3:34])([CH2:9][CH2:10]4)[C@@:7]4([CH3:35])[C@@H:16]([C@:17]5([CH3:20])[C@@H:4]([CH2:5][CH2:6]4)[C:3]([CH3:37])([CH3:36])[C@@H:2]([OH:1])[CH2:19][CH2:18]5)[CH2:15][CH2:14]3)[CH2:47][CH2:48]2)=[CH:44][CH:45]=1
Reactant: NC1(c2ccc(Cl)cc2)CC1
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylic acid (350 mg, 0.685 mmol), 1-(4-chlorophenyl)cyclopropanamine hydrochloride (154 mg, 0.754 mmol) and HATU (521 mg, 1.371 mmol) in DMF (2 mL) stirred at 0° C. was added DIPEA (0.479 mL, 2.74 mmol). The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was pH adjusted to 3-4 with 2 M HCl and filtered. The solid was washed with water (50 mL), dissolved into DCM, dried over sodium sulfate and evaporated in vacuo to give the crude (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylamide (650 mg, 0.680 mmol, 99%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34]O)=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[CH3:38][S:39](Cl)(=O)=O.C[S-].[Na+]>C(N(CC)CC)C>[CH3:38][S:39][CH2:34][CH2:33][C:29]1[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:14]3[N:15]=[C:11](/[CH:10]=[CH:9]/[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:37])([F:36])[F:1])=[CH:4][CH:5]=4)[O:12][CH:13]=3)=[CH:19][CH:20]=2)[CH:32]=[CH:31][N:30]=1
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: C[S-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CSCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
Using 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (1.00 g), triethylamine (0.544 ml), methanesulfonyl chloride (0.182 ml) and sodium thiomethoxide (288 mg), the same reaction as Reference Example 6-(iii) was carried out to yield the titled compound (761 mg) as a colorless amorphous form.